Cancer as a Metabolic Disease: Thomas Seyfried

[obyvatel]

I recently read the book "Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer" by Thomas Seyfried, biochemical geneticist and Professor in Dept Of Biology, Boston College after Hesper mentioned this book in the ketogenic diet thread. Dr Seyfried has had a long career as a cancer researcher and is presently focused on therapeutic and preventive properties of the diet on cancer. His book is well-written; it has a lot of technical details which are suitable for biochemists and geneticists but at the same time he does a good job in making things comprehensible to the layperson. He has taken apart the official stand on cancer research - one that uses billions of dollars in research grants ultimately coming out of public money - while producing little if any useful results for the millions of cancer patients who suffer and die more perhaps from the toxicity of treatment rather than the diease itself, hoping for the next miracle drug which the drug companies  promise to be just around the corner. His anguish at the state of cancer research as well as clinical management comes out quite clearly in the book. I will try to provide a somewhat detailed review of the key points in the book.

Synopsis

Seyfried references the research done by Nobel laureate Otto Warburg quite extensively in the book.  Warburg postulated in 1924 that cancer was principally a disease of mitochondrial dysfunction.

   "Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar." 

   Seyfried has slightly modified the above hypothesis put forward by Warburg by including the fermentation of amino acids (glutamine in particular) by mitochondria of cancerous cells as an additional energy producing mechanism along with fermentation of glucose. In this model, the millions of genetic modifications seen in cancer,which are being enthusiastically chased around by countless researchers at the expense of taxpayers while roughly 1500 people die each day from cancer in USA alone, are treated as a downstream epiphenomenon of impaired cellular respiration. He sites hundreds of research publications which essentially support the Warburg hypothesis on cancer and meticulously addresses the key scientific objections raised by dissenters who choose to swim endlessly (but profitably) in the genetic soup.

Malignant cells use glucose and amino acids like glutamine as their energy source through the process of fermentation even in the presence of oxygen. So cutting off glucose and glutamine should help in starving cancer cells of their fuel. That is where the energy restricted ketogenic diet comes in which drastically lowers supply of carbs as well as proteins and generates ketone bodies through fat metabolism. While healthy cells can switch to ketone bodies for their energy requirements, cancer cells are unable to make the transition and consequently die. In a nutshell, this is the essence of the book's message.

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Cellular Respiration

   In order for cells to live and perform their programmed functions, they must produce energy. This cellular energy is governed by ATP (adenosine triphosphate ) molecules.  ATP is synthesized  inside the cell during cellular respiration. Hydrolysis (breakdown of ATP under the action of water) of ATP releases energy stored in its phosphate bonds. The standard energy of ATP hydrolysis under physiological conditions is tightly regulated in all cells between − 53 and − 60 kJ/ mol. Energy from ATP is used to gate ion channels and maintain cell membrane potential.

   There are several sources of ATP synthesis that can be used to maintain membrane potentials. The mitochondria produce most of the energy in normal mammalian cells. In cells with functional mitochondria, ATP is derived mostly from oxidative phosphorylation (OxPhos) where approximately 89% of the total cellular energy is produced (about 32/ 36 total ATP molecules during the complete oxidation of glucose). This value can differ among different cells depending on which shuttle systems are used in the transport of cytoplasmic reducing equivalents (nicotinamide adenine dinucleotide (reduced form), NADH) from the cytoplasm to the mitochondria. Through OxPhos, mitochondria produce the bulk of intracellular ATP, and hence are considered the cell's “power plants.” In addition, mitochondria regulate Ca2 + homeostasis and modulate several other metabolic circuitries including the Krebs cycle, the urea cycle, gluconeogenesis, ketogenesis, heme biosynthesis, fatty acid β-oxidation, steroidogenesis, metabolism of certain amino acids, and the formation of iron/ sulfur clusters. .....

    Besides OxPhos, approximately 11% (4/ 36 total ATP molecules) of the total cellular energy is produced through substrate-level phosphorylation.

   In oxidative phosphorylation, ATP is produced through electron transfer reactions in the presence of oxygen, using a gradient of protons across the inner mitochondrial membrane. Substrate level phosphorylation on the other hand,  generates ATP through addition of phosphates to ADP from the substrate or an intermediate reaction product. There are two main pathways in mammalian cells for substrate level phosphorylation:

a) glycolysis in the cyptoplasm of the cell where glucose (substrate) is broken down generating net 2 ATP molecules

b) succinyl-CoA synthetase reaction in the TCA (tricarboxylic acid cycle or Kreb's cycle) cycle which takes place in the mitochondrial matrix and generates 2 ATP molecules.

  Unlike OxPhos, substrate level phosphorylation does not require oxygen. 

   The number of ATP molecules produced from TCA cycle, substrate-level phosphorylation would need to increase if OxPhos were insufficient to maintain energy homeostasis. This would be similar to the increase in the number of ATP molecules produced through glycolysis when OxPhos is reduced. Nonoxidative energy production through amino acid fermentation and substrate-level phosphorylation has been documented in developing mammalian embryos, in diving animals, and in heart and kidney tissue under hypoxia.

An important point to consider is that  the standard energy of ATP hydrolysis under physiological conditions is tightly regulated in all cells as mentioned earlier. Energy production in heart and liver which contain many mitochondria is largely through OxPhos while the red blood cells (erythrocytes) which do not have a nucleus or mitochondria produces energy through glycolysis. The  membrane potentials for these cells are
heart : -86mV
liver: -56mV
red blood cells: -6mV

  Despite the differences in resting membrane potentials as well as mechanism of energy production among various cells in the body, the free energy of ATP hydrolysis is maintained around -56 KJ/mol. This indicates that the balance of energy consumption and production (energy homeostasis) is independent of the energy source and the total amount of ATP produced. . Any disturbance in this energy homeostasis affects cell function and cell viability. Normal cells have the capacity to balance the energy use and production with respiration and substrate level phosphorylation thus maintaining the free energy of ATP hydrolysis. However, energy dysregulation is the characteristic of cancer cells.



Energy regulation in cancer cells

    If OxPhos becomes compromised in a normal cell through some injury, then substrate level phosphorylation must increase to maintain the stable free energy of ATP hydrolysis and cell viability. The cell could reduce energy expenditure to balance the reduced energy production. The cell could also die through apoptosis (programmed cell death) or necrosis (stress induced uncontrolled cell death). 

It is important to recognize that prolonged reliance on substrate-level phosphorylation for energy production in previously normally respiring cells produces genome instability, disorder, and increased proliferation, that is, the hallmarks of cancer. Entropy refers to the degree of disorder in systems and is the foundation of the second law of thermodynamics . Szent-Gyorgyi described cancer as a state of increased entropy, where randomness and disorder predominate . Protracted OxPhos insufficiency coupled with persistent compensatory fermentation increases entropy. Cells that do not increase fermentation energy to compensate for insufficient OxPhos simply die off and never become neoplastic. Adaptation to  fermentation allows a cell to bypass mitochondrial-induced senescence. Cancer arises in those cells that bypass mitochondrial-induced senescence (akin to programmed cell death).
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  Warburg was the first to describe in detail the dependence of cancer cells on glucose and glycolysis in order to maintain viability following irreversible respiratory damage. He considered respiration and fermentation as the sole producers of energy within cells, and energy alone as the central issue of tumorigenesis. “We need to know no more of respiration and fermentation here than that they are energy-producing reactions and that they synthesize the energy-rich adenosine triphosphate, through which the energy of respiration and fermentation is then made available for life” [Warburg] . Warburg considered fermentation as the formation of lactate from glucose in the absence of oxygen. This type of energy is also produced in mammalian embryos and in our muscles during strenuous exercise.

     A dependence on glucose with lactate production in the presence of oxygen later became known as the Warburg effect, which is essentially aerobic glucose fermentation or the continued production of lactic acid in the presence of O2. Why would cancer cells continue to ferment glucose in the presence of O2? Warburg attributed the aerobic fermentation in tumor cells to respiratory damage or respiratory insufficiency. Tumor cells grown in the presence of O2 behave as if they were abnormal facultative anaerobes in continuing to ferment in the presence of O2.

   
   Here it may be worthwhile to understand the  difference between respiration and fermentation. From a cellular perspective, fermentation is evolutionarily older than respiration. Fermentation is linked to relatively uncontrolled cell proliferation and less  differentiation. Respiration in the presence of oxygen on the other hand is a characteristic of more complex, differentiated structures. So in the presence of injury to the mitochondria which disrupts respiration, cells which do not die but revert to fermentation as their main source of energy can eventually transform into malignant cancer cells.

   There is considerable experimental evidence of mitochondrial injury in cancer cells. Mitochondria in tumors differ in number, size and  shape from regular mitochondria. There is experimental evidence to show that OxPhos capability is closely linked to the structural integrity  of healthy mitochondria; conversely when OxPhos capability  is impaired, the morphology becomes abnormal. It has been reported that greater the degree of mitochondrial morphological abnormality, greater is the degree of malignancy of the tumour.



Disputes about Warburg's Theory  

   One insufficiently rigorous criticism of Warburg's theory comes from the observation that cancer cells do use O2. This is then taken as an indication of normal respiration in cancer cells. However, there is experimental evidence to show that is not true.

    Indeed, O2 consumption increases with increased malignancy in some tumor cells. Does this mean that respiration is normal or increased in such cells? Not necessarily. Warburg has attributed this phenomenon to defects in the coupling of respiration to ATP production . In other words, some cancer cells produce CO2 and consume O2, but produce insufficient energy through respiration.
     Defects in the inner mitochondrial membrane of tumor cells dissipate the proton motive gradient, thus uncoupling the linkage between electron transport and ATP production through OxPhos.

     When such uncoupling occurs between the electron transport mechanism (where oxygen is utilized as in OxPhos ) and usable energy production ( ATP synthesis as in OxPhos), there is often a production of heat. More aggressive tumours are known to be "hot". The author's hypothesis ties the heat produced in aggressive tumours to the mechanism of mitochondrial uncoupling.   

Role of amino acid fermentation
One of the criticisms of Warburg's hypothesis was that not all cancer cells showed elevated lactic acid production through glycolysis. The author provides evidence which supplied the missing link in Warburg's hypothesis. 

  Although many tumor cells have active TCA cycles and might appear to respire, in that they consume oxygen and produce CO2 and ATP in the mitochondria, I will present data showing that this is pseudo respiration in some cases. In other words, pseudo respiration has all the characteristics of respiration, but does not involve ATP synthesis through OxPhos. I propose that this apparent respiratory energy is derived from amino acid fermentation. Just as tumor cells ferment glucose in the presence of O2, some tumor cells also ferment glutamine and possibly other amino acids in the presence of elevated glucose and O2. Glucose and glutamine interact synergistically to drive tumor cell fermentation. Fermentation is the bioenergetic signature of tumor cells.   
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Mitochondrial amino acid fermentation is known to maintain metabolic homeostasis under hypoxia in several species of diving animals. Mitochondrial amino acid fermentation can also maintain metabolic homeostasis in the heart and kidney under low glucose and low O2 conditions. The possibility that tumor cells might also obtain energy through amino acid fermentation has not been considered previously as an alternative energy source to OxPhos. Although Warburg considered respiration and glucose fermentation as the sole producers of energy within cells, amino acid fermentation in the mitochondria can also produce energy through substrate-level phosphorylation.

     We were the first group to report that Krebs cycle substrate-level phosphorylation might compensate for insufficient respiration in metastatic cancer cells . On the basis of preliminary studies, I suggest that energy through glutamine fermentation could compensate for insufficient or suppressed respiration in those tumor cells that can use glutamine for energy. While it is well known that glucose can be fermented, less is known about amino acid fermentation. Lactate is the by-product of glucose fermentation, whereas succinate, alanine, and aspartate are by-products of glutamine or amino acid fermentation under hypoxia (insufficient oxygen availability). ...........

   The expression of lactate in the presence of O2 is abnormal and would indicate that the cells are fermenting. The degree of fermentation (lactate production) is positively correlated with the degree of malignant growth . Also, the less is the respiration, the greater is the fermentation.
....If the cells consume oxygen, it is unlikely that succinate would accumulate. Under high glucose, amino acid fermentation can occur whether or not succinate accumulates. Hence, it is important to account for the multiple variables required to assure that cells are actually using OxPhos alone or are using some combination of OxPhos and mitochondrial substrate-level phosphorylation to maintain their viability.
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    Using a bioluminescent-based in vitro ATP assay, we found that ATP production and cell viability were similar in the metastatic cells grown in media containing either glutamine alone or glucose alone. Shelton  also showed that lactate production was significantly lower in the metastatic cells grown in glutamine than in the cells grown in glucose, indicating that these cells produce little lactate from glutamine alone. ...However, ATP synthesis and lactate production were significantly greater in the VM-M3 tumor cells grown in glucose and glutamine than that for the tumor cells grown in either glutamine alone or glucose alone . These findings show that glucose and glutamine work synergistically to enhance ATP synthesis, lactate production, and growth..... The synergy we found in the VM-M3 tumor cells was due to glutamine, as neither aspartate nor alanine (alternative nitrogen sources) could replace glutamine for the effect.
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   In other words, mitochondria are capable of metabolizing glutamine in these tumor cells. The question arose as to whether these cells were using the glutamine to produce energy through OxPhos or through mitochondrial fermentation. The role for glutamine in energy production would be in addition to the known role of glutamine in replenishing TCA cycle metabolites (anapleurosis).

We showed that tumor cell viability and ATP production were robust in either anoxia or cyanide as long as both glucose and glutamine were present in the media. Since anoxia (95% N2, 5% CO2) or cyanide (an inhibitor of complex IV respiration) inhibits OxPhos, the robust synergy seen for glucose and glutamine is unlikely due to significant energy from OxPhos.

We propose that the glucose/ glutamine energy synergy observed in our metastatic mouse cells arises from linked fermentation redox couples in the cytoplasm and mitochondria that synthesize ATP largely through nonoxidative substrate-level phosphorylations.

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Genetic Theory of Cancer

 

  How was it possible for the gene theory to gain precedence over Warburg's metabolic theory for the origin of cancer? As with most man-made fiascos, there is usually a convergence of several mishaps. The same can be said for why the gene theory displaced the Warburg metabolic theory for the origin of cancer.

    First, the appearance of normal respiratory function in cancer cells leads many to question Warburg's central hypothesis that injury to OxPhos was the origin of cancer. As discussed in Chapter 4, the attacks of Weinhouse and other investigators were especially effective in discouraging investigation into the respiratory origin of cancer. Moreover, how could cancer cells arise from injured respiration if so many investigators working in the cancer metabolism field have reported that OxPhos is normal in many tumor cell types? I have addressed the shortcomings of these arguments in Chapters 4, 5, and 8. The experimental evidence linking the origin of cancer to defective energy metabolism appeared to be confused to many investigators working both within and outside the metabolism field. It was also difficult to see how defective respiration could cause gene mutations or metastasis. The failure to craft a cohesive cancer theory based on defective energy metabolism raised the possibility that other explanations of cancer might be more credible than any metabolic hypothesis. The gene theory gained momentum over the viral theory of cancer once the perceived molecular mechanisms of viral action were revealed. A mechanistic linkage between gene defects and viruses was convenient, as viruses had long been recognized as the origin of cancer. It gradually became recognized that viruses might cause cancer by turning on certain cancer-causing genes called oncogenes, or by turning off other genes that prevented cancer, that is, tumor suppressor genes. Oncogenes are those that are assumed to cause cancer. This accounts for the attention given to these kinds of genes in the cancer field. According to James German, a pioneer in cytogenetics, 1981 was the turning point when scientific evidence overwhelmingly supported the mutational origin of human cancer. Stratton and colleagues have considered 1982 as this turning point with the seminal discovery that the human HRAS oncogene could transform normal mouse NIH3T3 cells into cancer cells . In 1994, Harold Varmus was quoted as saying “there's incontrovertible evidence that cancer is a genetic disease” . Dr. Varmus now heads the NCI (National Cancer Institute).
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     Although there is incontrovertible evidence that genomic instability is found in most cancers, this does not mean that cancer is primarily a genetic disease. According to Gibbs, “No one questions that cancer is ultimately a disease of the DNA” . I must apologize to Dr. Gibbs, but I seriously question this notion. I consider the majority of gene defects described in tumor cells as downstream epiphenomena of insufficient or damaged respiration. This includes the majority of recognized oncogenes and tumor suppressor genes. Alterations in these genes are required in order to enhance nonoxidative energy metabolism. In other words, the genetic damage seen in cancer arises as an effect of damaged respiration with compensatory fermentation rather than as the direct cause of cancer. If oncogene upregulation does not follow respiratory injury, the cell will die. Oncogenes are needed to maintain cellular viability following protracted respiratory insufficiency. There is growing evidence supporting this concept.

    How would the genomic instability theory of cancer be viewed if there were evidence showing that nuclear genomic stability is dependent on normal respiratory function? How would the genomic instability theory of cancer be viewed if there were evidence showing that oncogene upregulation and suppressor gene downregulation are required for maintaining cell viability following respiratory damage? How would the genomic instability theory of cancer be viewed if there were evidence showing that tumor suppressor gene mutations and viruses damage respiration? I will review evidence showing that genomic instability, DNA damage, and abnormal expression of many oncogenes and tumor suppressor genes arise as secondary downstream effects of abnormal respiration rather than as primary causes of most cancers. I will review evidence showing that inherited cancer genes damage respiration, which then produces cancer. Once genomic defects become established in the tumor cell, they can contribute to the irreversibility of the disease. The persistent view of cancer as a DNA disease is largely responsible for the failure to develop effective cancer therapies. It is difficult to develop an effective therapy for a disease when the origin of the disease is misunderstood.

Inconsistencies in the genetic theory of cancer

    It is important for readers to carefully consider the multiple inconsistencies supporting the gene theory of cancer.

Soto and Sonnenschein state:

“the emergence of conflicting data within the SMT (somatic mutation theory) did not result in the rejection of premises and hypotheses. For example, an oncogene could be ‘dominant’ and express a gain of function with respect to the non-mutated  homologue, and its biological effect could be contextual at the same time. That is, a mutation that should have produced uncontrolled cell proliferation resulted in cell death or arrest of cell proliferation. Again, ad hoc explanations were proposed to resolve conflicting evidence, leading to a situation whereby any possible conclusion is valid because no alternative concept is ever disproved and abandoned. The lack of fit is attributed to the unfathomable complexity of nature/ biology. In short, something can be anything and its opposite” .

 
  Support for the Soto and Sonnenschein argument was recently highlighted regarding mutations in the gene for isocitrate dehydrogenase 1 (IDH1) [50]. Some investigators suggest that the IDH1 gene acts as a tumor-provoking oncogene, whereas others suggest that IDH1 acts as a tumor-inhibiting suppressor gene. The problem becomes even more confusing with suggestions that IDH1 can act simultaneously as an oncogene and as a tumor suppressor gene . In other words, when it comes to the SMT (somatic mutation theory) of cancer, “something can be anything and its opposite.”
 
Rous may have hit the nail on the head regarding the SMT as early as 1959 when he stated: “Most serious of all the results of the somatic mutation hypothesis has been its effect on research workers. It acts as a tranquilizer on those who believe in it”.


   The concerns raised over the years regarding the SMT as a rational explanation for the origin of cancer are so profound that it is remarkable that this theory has persisted for as long as it has. How many more patients must die before the cancer field abandons the failed therapies based on the SMT of cancer?
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    Just because the majority of cancer researchers do not question the theory that guides their work does not mean that the theory is correct. Indeed, it appears that the average cancer researcher is not guided by any grand theory, rather they formulate restricted hypotheses for the next few experiments and tend to go on collecting data without reference to the problem of carcinogenesis (Ponten J. In: Iversen OH, editor. New Frontiers in Cancer Causation. Washington, DC: Taylor & Francis; 1992. p. 59). More disturbingly, many investigators pursue their research in areas considered to be “hot” simply because well-known researchers have defined the area as such. Many correctly surmise that it is easier to get papers published and grants funded in hot areas than in areas not considered hot. Cancer is one of the few fields where research areas are consistently hot, but progress toward the cure is consistently cold.

   The cancer research field has drifted off course for too long in my opinion. It is now time for all cancer researchers to pause, and to reconsider the foundation upon which their views rest. In light of the compelling counterarguments against the gene-based theories of cancer together with our extensive in vivo studies in brain cancer [53– 55], it has become clear to me that genetic theories are wanting in their ability to explain the origin of cancer. I do not dispute the overwhelming evidence that defects in DNA, genes, and chromosomes occur in all cancers. The evidence is massive. What I do question, however, is whether these defects actually cause the disease. I will review evidence showing that most of the genomic defects seen in tumor cells can be linked directly or indirectly to insufficient respiration.

    This should sound familiar to the readers of this forum as a consequence of ponerization of society at large and science in this particular case .

Here are just some experimental results reviewed by the author that supports his pov about the genetic origins of cancer.

   If respiratory insufficiency is the origin of cancer, then tumor nuclei should not induce malignancy when placed in cytoplasm containing respiration competent normal mitochondria. Alternatively, if mitochondrial dysfunction is the origin of cancer, normal nuclei should be unable to prevent tumorigenesis when placed into the tumor cytoplasm. I refer to these types of experiments as nuclear– cytoplasm transfer studies.
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   In a more extensive series of experiments, Israel and Schaeffer showed that suppression of the malignant state could reach 100% in cybrids containing normal cytoplasm and tumorigenic nuclei. The unique aspect of their study was that all of the cells utilized, both normal and transformed, were derived from an original cloned progenitor [4]. They also showed that nuclear/ cytoplasmic hybrids derived by fusion of cytoplasts from malignant cells (nucleus absent) with karyoplasts from normal cells (nucleus present) produced tumors in 97% of the animals injected. These findings showed that normal cell nuclei could not suppress tumorigenesis when placed in tumor cell cytoplasm. In other words, normal nuclear gene expression was unable to suppress malignancy.
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    It is also well documented that nuclei from cancer cells can be reprogrammed to form normal tissues when transplanted into normal cytoplasm despite the continued presence of the tumor-associated genomic defects in the cells of the derived tissues.

  Experimental evidence shows that "Normal mitochondria suppress respiratory dysfunction and tumorigenicity, whereas abnormal mitochondria cannot suppress respiratory dysfunction or tumorigenicity."

(a)  Normal cells beget normal cells.

(b) Tumor cells beget tumor cells.

(c) Delivery of a tumor cell nucleus into a normal cell cytoplasm begets normal cells despite the persistence of tumor-associated genomic abnormalities.

(d) Delivery of a normal cell nucleus into a tumor cell cytoplasm begets tumor cells or dead cells, but not normal cells.

The results show that nuclear genomic defects alone cannot cause tumors and that normal mitochondria can suppress tumorigenesis. .

   In summary, the origin of carcinogenesis resides with the mitochondria in the cytoplasm, not with the genome in the nucleus. How is it possible that so many in the cancer field seem unaware of the evidence supporting this concept? How is it possible that so many in the cancer field have ignored these findings while embracing the flawed gene theory? Perhaps Payton Rous was correct when he mentioned “the somatic mutation theory acts like a tranquilizer on those who believe in it”.

   Emerging evidence indicates that a persistent retrograde response can link respiratory injury to the genomic instability seen in tumor cells [5– 7]. The RTG response is the general term used for mitochondria-to-nuclear signaling and involves cellular responses to changes in respiration and the functional state of mitochondria [6, 8– 14]. The RTG response is initiated following interruption in the respiratory energy production. Genomic stability is dependent on the integrity of the mitochondrial function. If respiratory insufficiency is not corrected, the RTG response will persist, thus producing the Warburg effect, genomic instability, and the path to tumorigenesis.

Metastasis

     Metastasis is the general term used to describe the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality [1– 8]. It is estimated that metastasis is responsible for about 90% of cancer deaths [9]. This estimate has not changed significantly in more than 50 years [10, 11]. Although systemic metastasis is responsible for 90% of cancer deaths, most research in cancer does not involve metastasis in the in vivo state [5]. That about 1500 people continue to die each day from cancer further attests to the failure in managing the disease once it spreads to other organs. Metastasis involves a series of sequential and interrelated steps. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs [1– 4, 7, 12, 13]. Metastatic cells also establish a microenvironment that facilitates angiogenesis (development of new blood vessels) and proliferation, resulting in macroscopic, malignant secondary tumors.

   A difficulty in characterizing the cellular origin of metastasis comes in large part from the lack of animal models that show systemic metastasis. As I have mentioned in Chapter 3, tumor cells that are naturally metastatic should not require intravenous injection to initiate the metastatic phenotype. The key phenotype of metastasis is that the tumor cells spread naturally from the primary tumor site to secondary locations. Nevertheless, numerous investigators use intravenous tumor cell injection models to study metastasis. While these models can provide information on tumor cell survival in the circulation, it is not clear if this information is relevant to survival of naturally metastatic tumor cells.

Cellular origin of metastasis

  Epithelial to Mesenchymal Transition (EMT) (from genetic theory of cancer)

    The epithelial to mesenchymal transition (EMT) posits that metastatic cells arise from either epithelial stem cells or differentiated epithelial cells through a stepwise accumulation of gene mutations that eventually transform the epithelial cell into a tumor cell with mesenchymal features [8, 9, 16– 20]. This idea comes from findings that many cancers arise in epithelial tissues where abnormalities in cell– cell and cell– matrix interactions occur during tumor progression. Eventually, neoplastic cells emerge that appear as mesenchymal cells, which lack cell– cell adhesion, are dysmorphic in shape, and eventually spread to distant organs.
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  The idea for the EMT arose from attempts to draw parallels between the behavior of normal cells during metazoan morphogenesis and the behavior of cancer cells during tumor progression [9, 16]. Adaptation of the EMT into the gene theory of cancer suggested that metastasis is the endpoint of a series of genomic alterations and clonal selection. This then provided the neoplastic cells with a growth advantage over normal cells [17, 20, 24, 25]. It is difficult to understand how a collection of gene mutations, many of which are random, could produce cells with the capacity to detach from the primary tumor, intravasate into the circulation and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and recapitulate epithelial characteristics following invasion and proliferation in distant organs. This would be quite a feat for a cell with a disorganized genome.

   The recapitulation of epithelial characteristics at distant secondary sites is referred to as the mesenchymal– epithelial transition (MET) and is thought to involve a reversal of the changes responsible for the EMT [9, 16, 17]. No explanation has appeared on how the genomic instability and multiple point mutations and chromosomal rearrangements responsible for the neoplastic mesenchymal phenotype could be reversed or suppressed when the tumor cells recapitulate the epithelial phenotype at distant sites.

 If many of the nuclear genomic mutations are not reversed, how is it possible that they could be responsible for EMT in the first place? I think the imagination must be stretched to the limits in order to accept the EMT/ MET as a credible explanation for metastasis. The changes in cell behavior and morphology linked to this explanation of metastasis and their dramatic reversibility are similar in some ways to those of the werewolf.
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Myeloid Cells as the origin of metastasis

     
The myeloid cell ( a blood cell which is not a lymphocyte, having its origin in the bone marrow or spinal cord)  origin of metastasis proposes that metastatic cancer cells arise from myeloid cells regardless of tissue origin [26]. Myeloid cells are already mesenchymal cells and would therefore not require the complicated genetic mechanisms proposed for the EMT in order to metastasize. Macrophages (big eaters which engulf and digest cellular debris and pathogens in a process called phagocytosis) arise from the myeloid lineage and have long been considered the origin of human metastatic cancer [15, 26,42– 45] . Macrophages can fuse with epithelial cells within the inflamed microenvironment, thus manifesting properties of both the epithelial cell and macrophage in the fusion hybrids [29, 46]. The origin of metastatic cancer from hematopoietic stem cells (which makes cellular components of blood) , derived from bone marrow cells, is also consistent with the myeloid hypothesis. In his recent excellent review on metastasis, David Tarin states:

“Hence, it would appear that tumor metastasis first appears in the lower chordates in parallel with the origin of lymphocytes and this may indicate that metastasis cannot occur until an organism has evolved the genes for lymphocyte trafficking.” 

 According to our hypothesis, it is hematopoietic stem cells themselves or their lineage descendants that become the metastatic cells either through direct transformation in the inflamed microenvironment or through their fusion with neoplastic tumor cells. The idea that transformed myeloid cells can give rise to invasive and metastatic cells within tumors is not widely recognized. Rather than being recognized as part of the neoplastic cell population, many investigators consider macrophages and other myeloid cells as part of the tumor stroma.
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  What are the properties of macrophages that would make them prime suspects for the origin of metastasis? Macrophages are among the most versatile cells of the body with respect to their ability to migrate, to change shape, and to secrete growth factors and cytokines [36, 60– 62]. These macrophage behaviors are also the recognized behaviors of metastatic cells.
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  Phagocytosis involves the engulfment and ingestion of extracellular material and is a specialized behavior of M2 macrophages and other professional phagocytes [62]. This process is essential for maintaining tissue homeostasis by clearing apoptotic cells, cellular debris, and invading pathogens. Like M2 macrophages, many malignant tumor cells are phagocytic both in vitro and in vivo. Tumor cell phagocytosis was first described over a century ago from histopathological observations of foreign cell bodies within in the cytoplasm of cancer cells, which displayed crescent-shaped nuclei [44]. This cellular phenotype resulted from the ingested material pushing the nucleus to the periphery of the phagocytic cell. These cells were commonly referred to as either bird's-eye or signet-ring cells [144, 158]. While this phagocytic/ cannibalistic phenomenon is commonly seen in feeding microorganisms, cell cannibalism is also seen in malignant human tumor cells [120, 144, 158, 159]. Fais and colleagues provided dramatic evidence of tumor cell phagocytosis in showing how malignant melanoma cells eat T-cells. This is remarkable as T-cells are thought to target and kill tumor cells.


There is also evidence that some tumor cells can eat NK cells [159]. If macrophage-derived metastatic cells can eat T-cells and possibly NK cells, then it is possible that immune therapies involving these cells might not be effective for long-term management of some metastatic cancers. Indeed, cancer immunotherapies have had little impact in reducing the yearly death rate from advanced metastatic cancers.


Fusogenicity is the ability of a cell to fuse with another cell through the merging of their plasma membranes [29, 154]. This process can arise in vitro as is seen with the formation of antibody-producing hybridomas. However, fusion in human cells is a highly regulated process that is essential for fertilization (sperm and egg) and skeletal muscle (myoblasts) and placenta (trophoblast) formation [183]. Outside of these developmental processes, cell-to-cell fusion is normally restricted to differentiated cells of myeloid origin (reviewed in Ref. 148).

During differentiation, subsets of macrophages fuse with each other to form multinucleated osteoclasts in bone or multinucleated giant cells in response to foreign bodies [43]. Osteoclasts and giant cells have increased cell volume that facilitates engulfment of large extracellular materials [43]. Macrophages are also thought to fuse with damaged somatic cells during the process of tissue repair.
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  Mekler et al. and Warner proposed that fusion of committed tumor cells with host myeloid cells would produce tumor hybrids capable of migrating throughout the body and invading distant organs [149, 187]. Recent studies from Wong and coworkers described how macrophages fuse with tumor epithelial cells [29, 188]. Besides inflammation, radiation also increases the fusion hybrid process [188]. Is it possible that decreased long-term survival in some irradiated cancer patients results from enhanced production of macrophage– epithelial fusion hybrids? We have stated that the human brain should rarely if ever be irradiated [189]. It is my opinion that radiation will contribute to brain tumor recurrence.
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   Although radiation therapy can help some cancer patients, radiation therapy will also enhance mitochondrial damage and fusion hybridization, thus potentially making the disease much worse.
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    As respiration is responsible for maintaining genomic stability and the differentiated state, respiratory insufficiency will eventually induce the default state of unbridled proliferation. If this occurs in cells of myeloid origin such as macrophages, then emergence of cells with enhanced metastatic potential would be a predicted outcome. Macrophages are genetically programmed to exist in the circulation and to enter and exit tissues [221]. While cells of myeloid origin can serve as the body's best friend during wound healing and in killing pathogenic bacteria, these same cells can become the body's worst enemy if they become transformed during tumorigenesis.

 Thus according to the author's hypothesis, both immunotherapy and radiation therapy have the potential to cause more damage in metastatic cancers.


  It is also worthwhile to note that metastatic tumor cells do not invade distant organs randomly. Lung, liver and bone are some of the most common sites of metastasis. The myeloid cell origin of metastasis can provide an explanation for this phenomenon - which has been called the "seed and the soil" hypothesis for breast cancer where the tumor cells (seed) are found to have an affinity for certain organs (soil).

  Basically, respiratory insufficiency in cells of myeloid origin can explain the seed and soil phenomenon. This comes from findings showing that mature cells of monocyte origin (macrophages) enter and engraft tissues in a nonrandom manner [224]. Macrophages are genetically programmed to exist in the circulation and to preferentially enter various tissues during wound healing and the replacement of resident myeloid cells [221, 224]. Some macrophage populations in liver are regularly replaced with bone marrow-derived monocytic cells, whereas other macrophage populations are more permanent and require fewer turnovers [225]. It is reasonable to assume that metastatic cancer cells derived from macrophages or fusions of monocytic cells with epithelial cells will also preferentially home to those tissues that naturally require regular replacement of resident macrophages.
   
    This prediction comes from findings that many metastatic cells express characteristics of macrophages [29]. Macrophage turnover should be greater in tissues such as liver and lung where the degree of bacterial exposure and the wear-and-tare on the resident macrophage populations is considerable [226]. This could explain why these organs are a preferred soil of many metastatic cancer cells. Bone marrow should also be a common target of metastatic cells because this site is the origin of the hematopoietic stem cells, which give rise to myeloid cells. Liver, lung, and bone are also preferential sites for metastatic spread for the VM mouse tumor cells [36]. This is one reason why the natural tumors in the VM mouse, which preferentially home to these tissues, are an excellent model for metastatic cancer.

   In addition, any unhealed wound is an ideal "soil" for macrophage infiltration. In a phenomenon called inflammatory oncotaxis, mechanically injured tissues (eg tooth extractions) are sometimes found to be susceptible to cancer metastasis.

   The crown-gall disease in plants share many features with tumours in animals and is referred to as a form of plant cancer. It shares all the important aspects of animal cancer except for the property of metastasis.

   The crown-gall tumors do not metastasize because they do not have macrophages or myeloid cells as part of their immune system [249]. The findings in crown-gall are also consistent with Tarin's [1] hypothesis, “that metastasis cannot occur until an organism has evolved the genes for lymphocyte trafficking.”

[obyvatel]

Prevention/Management/Healing of Cancer


What causes damaged cellular respiration

   Any unspecific condition that damages a cell's respiratory capacity, but is not severe enough to kill the cell, can potentially initiate the path to a malignant cancer. Reduced respiratory capacity could arise from damage to any mitochondrial protein, lipid, or mtDNA. Some of the many unspecific conditions that can damage a cell's respiratory capacity thus initiating carcinogenesis include inflammation, carcinogens,radiation (ionizing or ultraviolet), intermittent hypoxia, rare germline mutations, viral infections, and age.

  Chronic inflammation is said to be one of the most common causes of damage to mitochondria and cellular respiration. Several cellular mechanisms can be at play in the process - one of which is "persistent nitric oxide expression in the inflamed microenvironment. "


Metabolic Management of Cancer

   If we know what cancer cells can and cannot eat, we can kill them.  Ketone bodies and fatty acids can provide alternative metabolic fuels to glutamine for mitochondrial ATP synthesis. As these alternative fuels also require O2 for metabolism, death should occur quickly for any cell in the absence of both glucose and O2, especially if ketone bodies and fatty acids are the only available fuels. If cells maintain viability in O2 using either ketone bodies or fatty acids as the only energy substrates, then these cells are likely using OxPhos for survival. As far as I know, ketone bodies and fatty acids are not fermented for energy [4].
.....................

Because tumor cells ferment rather than respire, they are dependent on the availability of fermentable fuels (glucose and glutamine). Normal cells shift metabolism from glucose to ketone bodies and fats when placed under energy stress. This is dependent on genomic stability. Ketone bodies and fats are nonfermentable fuels in mammalian cells. Tumor cells have difficulty in using ketone bodies and fats for fuel when glucose is reduced. Because tumor cells lack genomic stability, they are less able than normal cells to adapt to changes in the metabolic environment.

    Such a metabolic approach to cancer therapy is applicable to the majority (if not all) types of cancer irrespective of tissue origin.


Therapeutic Fasting

There are numerous studies which show that dietary energy restriction (DER) is a general metabolic therapy that significantly reduces growth and progression of various types of tumour - including cancers of  brain, breast, colon, pancreas, lung and prostrate. DER reduces circulating glucose levels on which many tumours depend for survival and growth.  Such therapeutic fasting promotes a new state of energy homeostasis in the cells where stored fat and protein in the body is used to generate glucose through the process of gluconeogenesis (new glucose generation) as well as increase in blood ketones. Respiratory insufficiency and genomic instability prevents tumor cells from entering this new energy state. This is most effective for people who are just diagnosed with cancer.


Restricted Ketogenic Diet

    Studies have been conducted on the effect of cancer from following a restricted ketogenic diet (KD-R). KD-R has been shown to produce similar anti-tumor effects as that in DER. The key factor observed in studies with mice was that the KD had no therapeutic effect on tumor growth if consumed in unrestricted amounts.

    The data [] show that blood glucose levels remain high in mice that consume the KD in unreduced amounts. If glucose levels remain high, body weights remain stable or increase [36]. When the KD is fed to mice in unrestricted amounts, blood glucose levels remain high and ketones are largely excreted in the urine. We clearly showed, however, that blood ketones were higher in tumor-bearing mice under DER than under AL (unrestricted) feeding [34]. Under DER, ketones are retained in the body for use in metabolism rather than excreted in the urine. This information is critical when designing metabolic therapies for tumor management.
..........

  This means that it is the amount of the diet consumed rather than the composition of the diet that determines blood glucose levels. Many people have difficulty appreciating this fact because they often think that low carbohydrate diets will produce low blood glucose levels. This is clearly not the case here. We reported similar findings in our previous investigation of glucose and ketones in epileptic mice [36, 48]. Our data show that blood glucose levels are influenced more by the amount of calories consumed than by the composition of the calories consumed. Nutritional oncologists and cancer patients also need to know this information. Although ketone (β-OHB) levels are higher in the mice consuming the KD than in mice consuming the standard diet (SD), the β-OHB levels are even higher in mice that consume the KD in restricted amounts (KC {keto-cal}-R). Why would blood ketone levels be higher in mice that eat less KD than in mice that eat more KD? The answer is simple. Ketones are retained in the body when glucose levels are low. Ketones serve as an energy substitute for glucose. If glucose is not reduced as in the KC-UR (unrestricted keto cal)groups, then most ketones will be excreted in the urine. This is why it is better to measure blood ketone levels than to measure urine ketones as an indicator of ketosis. Cancer cells are placed under metabolic stress when glucose levels are reduced and ketone levels are elevated . The therapeutic action of ketones is best when blood glucose levels are low.

    This validates the usefulness of the ketogenic diet with intermittent fasting discussed in the main ketogenic diet thread. Since only cells with normal mitochondrial respiratory capacities can effectively use ketone bodies for energy, tumor cell viability is lost in the presence of ketone bodies resulting in death of tumor cells.  On the other hand, glucose is directly implicated in tumour growth: higher blood glucose levels lead to faster growth.


*  Malignancy and invasiveness of tumours are directly related to vascularity (blood vessel development or angiogenesis). Reduced availability of glucose has been observed to reduce vascularity and cell proliferation. DER and KD-R have both shown anti-angiogenic properties in both mouse and experimental human brain tumors. These  therapies target angiogenesis naturally in contrast to toxic anti-angiogenic drugs.

    In light of our findings, it is surprising that the cancer field would persist in treating cancer patients with toxic antiangiogenic drugs such as bevacizumab and cediranib, which show marginal efficacy and appear to enhance the invasive behavior of tumor cells [121– 123]. Compared to bevacizumab (Avastin), which targets angiogenesis, while producing adverse effects and enhancing tumor cell invasion [112, 122, 124– 126], DER targets angiogenesis, while improving general health and inhibiting tumor cell invasion [34, 45].  Is it better for oncologists to target tumor angiogenesis using toxic drugs with marginal efficacy or is it better to use nontoxic metabolic strategies such as DER with robust efficacy? Oncologists should consider this question. Patients with advanced cancers should be presented with therapeutic options.

   

* DER also promotes cell apoptosis (programmed cell death). Apoptotic cell death is different from necrotic cell death which is usually associated with inflammation. Apoptotic tumor cell death is preferred over necrotic tumor cell death as it is less harmful for the tumor microenvironment since tissue inflammation is less in apoptosis than in necrosis. Radiation as well as toxic chemotherapy kills tumor cells through necrosis and inflammation which often hurt long-term prognosis of the disease.


* DER also directly suppresses multiple pro-inflammatory pathways in tumours.

    There are no oncology drugs known to my knowledge that can simultaneously target inflammation and angiogenesis, while, at the same time, killing tumor cells through an apoptotic mechanism.

* The author advocates a suitable combination of drugs and dietary therapies for advanced cases.

   Although DER is effective in reducing tumor growth and invasion, this therapeutic approach alone is unlikely to completely eradicate all types of malignant cancers [51, 229]. I believe that metabolic diet therapies will be enhanced when combined with drugs that also target glucose energy metabolism. Support for my hypothesis comes from our study showing that the nonmetabolizable glycolysis inhibitor, 2-DG, works synergistically with the KD-R to reduce CT-2A astrocytoma growth [30].
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   Few studies have evaluated the therapeutic efficacy of antiglycolytic or anticancer drugs in combination with DER [51]. Recent studies from Safdie and the Longo group suggest that CR and fasting can enhance patient health during chemotherapy [26, 232, 233]. We were the first to show that the KD-R supplemented with 25 mg/ dl of 2-DG was effective in reducing intracerebral tumor growth to a greater extent than was either 2-DG 2-DG or KD-R when administered alone. These findings showed a powerful synergistic interaction between 2-DG and the diet.
....................

  Combinations of CR mimetics (drugs which try to produce the same physiological state as achieved by calorie restriction) with the restricted KD could open new avenues in cancer drug development, as many drugs that might have minimal therapeutic efficacy or high toxicity when administered alone could become therapeutically relevant and less toxic when combined with energy-restricted diets. ....CR mimetics will also be more effective against advanced cancer if administered with drugs that also target glutamine, a major fuel for metastatic cancer [229].

   
* Targeting glutamine is important as experimental results showed that DER alone was unable to stop metastasis  in some cases. This led the author to direct his attention towards the role of glutamine in systemic metastasis.

   Although DER reduces blood glucose levels, it does not reduce blood glutamine levels. Indeed, blood glutamine levels might increase under DER in mice, as moderate physical activity can increase blood glutamine [72]. Mice increase physical activity food foraging under DER. We knew that the VM-M3 tumor cells shared several characteristics with macrophages and that glutamine is a major fuel of immune cells, including macrophages. We also knew that transformed macrophages or their fusion hybrids are the origin of metastatic cancer cells. Hence, it would be important to determine if glutamine restriction might reduce systemic metastasis. We found that the DON (a glutamine antagonist) prevented metastatic spread to the liver, lung, and kidney. In addition, we examined liver histology because liver becomes heavily infiltrated with VM-M3 cells. Indeed, liver metastasis was found in 100% of the control mice. Liver is also a common site for many metastatic human cancers. Histological analysis confirmed the lack of tumor cells in the liver of the DON-treated mice in comparison to the control AL (unrestricted feeding) nontreated mouse and control and CR-treated CR-treated groups.

* Finaly, inflammation is the cause of many diseases in humans in addition to cancer. Switching energy metabolism from glucose to ketones has been shown to have powerful anti-inflammatory effects. Hence, according to the author,  KD is under consideration for numerous neurological and neuro-degenerative diseases (like Alzheimers) where inflammation is a part of the pathology.

[Megan]

A very interesting and very readable (now -- after all the other reading) book. I want one! At $74.25 for the Kindle edition, and $111.52 for hardcover, however, a little more about what you personally learned and found of value from reading the book could be helpful.

I haven't yet finished reading the excerpts above; that might help too.

[Megan]

A couple of comments after reading through all of the excerpts:

1. It is easier to track and account for cellular pathology than it is for human pathology of the intraspecies kind. It would be interesting to know which individuals were primarily responsible for the promotion of genetic theories of cancer, as well as their ties to industry. Industry can profit hugely from a) avoiding the costs of preventing exposure of workers and consumers to carcinogenic materials and b) providing expensive "treatments" for the cancer thus produced. There is a strong potential incentive for individuals lacking conscience to do everything they can to skew the science.

2. Once again, an endorsement of calorie-restricted (CR) ketogenic diets (KD) appears. I believe that this idea is distinct from that of intermittent fasting. What bothers me most about what I have learned so far about CR KDs is the lack of awareness that the quality of food matters. One thing in particular seems to stand out: experimental KDs often include soybean oil. In non-human experiments it may be a pervasive component of the experimental diet. In human experiments it may be included as either an optional or required dietary component. This excerpt from TAASOLCP illustrates my concern.

Why Worry About Too Much Omega-6 PUFA?

Back in the day when Steve did his study with the bike racers on the ketogenic diet, they had to measure precisely how much of each nutrient his subjects were eating. That limited him to just five menu items from which his subjects could choose each day. Three of these were composed principally of animal fats and two used soybean oil mayonnaise as their fat source. Within a week or two of starting the high fat diet, most of the subjects developed a strong distaste for the mayonnaise-based meals. Opening a new container and then switching brands of mayonnaise didn’t help. Nobody actually got sick eating these tuna salad or chicken salad entrees – they just said that they didn’t feel completely well after eating them.

Out of curiosity, Steve put himself on a ketogenic diet for a month and fed himself most of his fat intake overnight via a tiny feeding tube in his stomach (so taste wasn’t an issue). Within 3 days of feeding himself 1500 Calories of either soybean or corn oil nightly, he developed quite prominent nausea and gastro-intestinal upset. However when he fed himself the same amount of calories as olive oil for two straight weeks, he had no such symptoms. In between testing these different oils via the feeding tube, Steve maintained nutritional ketosis and met his full calorie needs by eating mostly animal fats, again without symptoms.

The take-away message from this is that the human system doesn’t seem to tolerate a high fat diet prepared from high omega-6 oils (like soy and corn oils), but does just fine on one consisting mostly of monounsaturated and saturated fats (e.g., olive oil and animal fats)...

Phinney, Stephen; Jeff Volek (2012-06-15). The Art and Science of Low Carbohydrate Performance (p. 74). Beyond Obesity LLC. Kindle Edition.

The human system? What about laboratory mice? It's not like soy is a part of their natural diet, outside the laboratory!

[obyvatel]

however, a little more about what you personally learned and found of value from reading the book could be helpful.

    I have had up close and personal experiences with cancer, the most recent was when my mother passed away from it a couple of years back. I have spent some time and energy trying to decipher what exactly was known about the origins of cancer as well as the current "state of the art" treatments. I have also had some personal experience of interacting with molecular biologists and geneticists who are making a living out of cancer research. I myself am a layperson in terms of biochemistry, genetics etc - but a lot of visceral realizations I had during my past efforts to understand cancer has been elucidated in this book - viz, the experts do not really know what they are talking about and making things so convoluted and complex that common man is only happy to run away and leave it "up to the experts".

   What I have found of intellectual and practical value in the book is in the excerpts above.  It does take effort to read this book. I had to go back and look up many terms in order to understand what the author is trying to say a little better and I have tried to embed the auxilliary information wherever appropriate in the excerpts. Emotionally, it was a relief to read a book from a scientist which spoke about things as they are while providing plausible alternative hypothesis regarding the origin and a path towards prevention and cure of a disease which takes a huge emotional, physical and financial toll on patients and their families.

[Megan]

Thank you, that does help. My mother also died from cancer, and I have survived it myself. One of my personal concerns is doing what I can within reason to avoid the secondary cancer that can result from the treatment and follow-up itself, 10 or 15 years later (which could, for me, mean "in 5 more years"). It is also one of the reasons I am so interested in ketogenic diet.

I will consider reading the book when I have cleared off some of my existing backlog of books to read. Who knows, maybe the price will have dropped by then.

Thanks again!

[obyvatel]

2. Once again, an endorsement of calorie-restricted (CR) ketogenic diets (KD) appears. I believe that this idea is distinct from that of intermittent fasting.

   My current understanding is that the basic idea behind fasting and/or KD-R is to eat less and get  low blood sugar and high blood ketone levels. Seyfried says that to get the body into ketosis, a therapeutic fast was found to be the quickest way for healthy subjects.

  I have recorded the blood glucose and ketone levels in several of my students who have voluntarily fasted for up to 6 days. The students were all healthy young adults (males and females) between 21 and 28 years of age. The students consumed only water or decaffeinated green tea during the fast. All students, both males and females, were able to bring their blood glucose and ketone levels into the therapeutic ranges within 3 days (Chapter 18). Most cancer patients should have a similar experience as long as they are not taking any interfering medications.

   Glucose withdrawal symptoms were experienced by most of the students over the first couple of days, but these symptoms were transient and gradually subsided after 2 days. It is interesting that glucose withdrawal symptoms (anxiety, headache, nausea, etc.) are also seen in many persons following withdrawal from other addictive substances such as alcohol, tobacco, and drugs. Some of the students felt energetic after 5 days of fasting. They all learned that fasting is therapeutic and not harmful.

  One of my graduate students, Julian Arthur, lowered his blood glucose to 39 mg/ dl by the third day of the fast. I asked Julian how he felt walking around with such low blood glucose levels. He said, “I feel fine, no problems.” Julian's blood ketones were also at 1.1 mmol, which would compensate for low glucose and prevent adverse effects of hypoglycemia. Hypoglycemia is a concern only for those individuals who lower glucose levels without also elevating their blood ketone levels. The gradual transition from glucose to ketone metabolism protects tissues from the effects of hypoglycemia. George Cahill and colleagues have documented these observations [52, 54, 55].

   Another student, Ivan Urits, was unable to lower his glucose to the metabolic range despite 6 days of fasting and elevated ketone levels (2– 3 mmol). His glucose was reduced only to 68 mg/ dl during the fast. It turned out that Ivan was drinking caffeinated black coffee, rather than drinking only water during the fast. Caffeine can prevent glucose levels from entering the therapeutic zone necessary to target the energy metabolism of tumor cells. Herbert Shelton argues against coffee consumption during fasting [51]. It would be better to consume calorie-free decaffeinated beverages than caffeinated beverages.

  I suggest that persons avoid caffeinated beverages if they plan to use the restricted ketogenic diet (KD-R) as an approach to prevent cancer. It will be up to each person to know what they can or cannot do to maintain their blood glucose within the therapeutic ranges.

    Therapeutic levels of blood glucose is considered to be in the 55-65mg/dL range and blood ketone  is in the range of 3-5 mmol. Seyfried thinks that at these levels, autophagy and autolytic cannibalism sets in purging the body of diseased cells.

    The take away message from all this for me was to eat a ketogenic diet in restricted amounts accompanied by occasional fasts in order to get benefits . While the official KD is not what we consider to be healthy, the fundamental idea that blood glucose levels need to be low regardless of what one is eating still holds true to purge the body of weak and diseased cells. The process of gluconeogenesis generates glucose from available protein and fat even with low carb diets - so eating just enough to meet energy needs makes sense for keeping low blood glucose levels.

[Megan]

    Therapeutic levels of blood glucose is considered to be in the 55-65mg/dL range and blood ketone  is in the range of 3-5 mmol. Seyfried thinks that at these levels, autophagy and autolytic cannibalism sets in purging the body of diseased cells.

    The take away message from all this for me was to eat a ketogenic diet in restricted amounts accompanied by occasional fasts in order to get benefits . While the official KD is not what we consider to be healthy, the fundamental idea that blood glucose levels need to be low regardless of what one is eating still holds true to purge the body of weak and diseased cells. The process of gluconeogenesis generates glucose from available protein and fat even with low carb diets - so eating just enough to meet energy needs makes sense for keeping low blood glucose levels.

Phinney & Volek talk about a 0.5 to 3 mmol. range for optimum "athletic" ketosis, achieved with ~50 g/day of carbs. I see now that maintaining my carbs closer to this limit kept me out of the "therapeutic" zone, and I have had to readapt to lower levels in spite of staying under what appears to be my limit for ketogenesis. In other words, there is KD and then there is KD. Not all the same.

Therapeutic ketosis and weight loss may be conflicting goals. I am still trying to sort that one out. One of the reasons I had my carb levels so high is that it seemed to help with weight loss. More experimentation is required.

Kickstarting a KD with fasting makes sense to me. Sustained CR KD treatment protocols or experiments don't, and yet I have come across them in some of the literature.

Interestingly, Phinney & Volek refer to the 3-5 mol. range as the "starvation ketosis" range. I am not sure why. They do mention, however, that very low blood glucose levels are possible when ketone levels are high.

Factoid: Many decades ago in a provocative experiment to demonstrate the human brain’s ability to function well on ketones, some scientists in Boston keto-adapted 3 obese humans with a month of total starvation. With their BOHB levels around 5 millimolar, they slowly infused insulin into their blood stream over hours until the subjects’ blood glucose levels dropped to the point that they should have lapsed into a coma (1.5 millimolar, or less than 30 mg/dl). At that point, their BOHB levels were slightly reduced to 4 millimolar, and not only did they stay awake, these subjects had none of the typical symptoms of hypoglycemia[20].

Phinney, Stephen; Jeff Volek (2012-06-15). The Art and Science of Low Carbohydrate Performance (pp. 31-32). Beyond Obesity LLC. Kindle Edition. 

Don't try this at home.

[Laura]

Maybe you could put all this together in a short article/review/series of quotes for SOTT to publish and we could then share it on FB??  Very important material.

[Psyche]

Seyfried has slightly modified the above hypothesis put forward by Warburg by including the fermentation of amino acids (glutamine in particular) by mitochondria of cancerous cells as an additional energy producing mechanism along with fermentation of glucose.

I once read that aminos will fuel cancerous cells in the brain, but never thought that glutamine which is so recommended to heal the gut could be so detrimental within this context.

Wow, this book synopsis puts a whole new meaning on how mainstream cancer treatments are geared to precisely not heal cancer by further contributing with mitochondrial dysfunction. Not only through radiation and toxic chemotherapy, but also a person with cancer will have a natural instinct to not eat, perhaps like an instinct to attempt to heal with caloric restriction. Then, everybody tries to force feed cancer patients.

The thing of ketones in urine was the same point that Volek and Phinney brought in "Art of Low Carb". They may appear initially in the urine, but later they disappear as the body starts using all the ketones up and less and less are eliminated in the urine. Blood tests are the ideal thing to measure ketones, but they are expensive.

[Psyche]

FWIW, here is a basic introduction to biochemistry and the importance of ketosis in mitochondrial dysfunction: http://cassiopaea.org/forum/index.php/topic,28799.msg365107.html#msg365107

And a free full text article on carbohydrate restriction in the treatment and prevention of cancer:

Is there a role for carbohydrate restriction in the treatment and prevention of cancer?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267662/

It underlines the importance of how carbs are so evil:

Possible causes for the "Warburg effect"

Over the past years, however, it has become increasingly clear that malignant cells compensate for this energy deficit by up-regulating the expression of key glycolytic enzymes as well as the glucose transporters GLUT1 and GLUT3, which have a high affinity for glucose and ensure high glycolytic flux even for low extracellular glucose concentrations. This characteristic is the basis for the wide-spread use of the functional imaging modality positron emission tomography (PET) with the glucose-analogue tracer 18F-fluoro-2-deoxyD-glucose (FDG) (Figure ​(Figure1).1). There are mainly four possible drivers discussed in the literature that cause the metabolic switch from oxidative phosphorylation to aerobic glycolysis in cancer cells. The first one is mitochondrial damage or dysfunction [40], which was already proposed by Warburg himself as the cause for tumorigenesis [41]. Somatic mutations in mitochondrial DNA (mtDNA) and certain OXPHOS genes can lead to increased production of reactive oxygen species (ROS) and accumulation of TCA cycle intermediates (succinate and fumarate) that trigger the stabilization of hypoxia inducible factor (HIF)-1α, inactivation of tumor suppressors including p53 and PTEN and upregulation of several oncogenes of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway [42]. In tumor cells, Akt plays a major role in resisting apoptosis and promoting proliferation, and it does so by reprogramming tumor cell metabolism [43-45]. Akt suppresses β-oxidation of fatty acids [46], but enhances de novo lipid synthesis in the cytosol [47,48]. Akt also activates mTOR, a key regulator of cell growth and proliferation that integrates signaling from insulin and growth factors, amino acid availability, cellular energy status and oxygen levels [49,50]. In cancer cells, mTOR has been shown to induce aerobic glycolysis by up-regulating key glycolytic enzymes, in particular through its downstream effectors c-Myc and HIF-1α. Both of these transcription factors are involved in the expression of pyruvate kinase M2, a crucial glycolytic enzyme for rapidly proliferating cells [51].

[...]The observation that certain malignant cells are able to use both glycolysis and OXPHOS under aerobic conditions has been taken to argue that mitochondrial dysfunction alone is not a sufficient cause for the Warburg effect [53]. Indeed, somatic mutations in most oncogenes and tumor suppressor genes have been shown to directly or indirectly activate glycolysis even in the presence of oxygen. As described above, they do so mainly by hyperactivating major metabolic signaling pathways such as the insulin-like growth facor-1 receptor (IGFR1)-insulin receptor (IR)/PI3K/Akt/mTOR signaling pathway (Figure ​(Figure2).2). In principle, hyperactivation of this pathway can occur at several points from alterations in either upstream (receptor) or downstream (transducer) proteins and/or disruption of negative feedback loops via loss-of-function mutations in suppressor genes [44,45,54]. Thus, genetic alterations in oncogenes and tumor suppressor genes are a second possible cause for the Warburg effect.

But again, we are not talking about genes that causes cancer, we are talking about a diet rich in carbs which causes epigenetic changes that activates pathways that lead to cancer and less longevity, plus the environmental toxicity...

The impact of insulin and IGF1

Finally, chronic activation of the IGFR1-IR/PI3K/Akt survival pathway through high blood glucose, insulin and inflammatory cytokines has been proposed as a cause of carcinogenesis [30,58,59] and switch towards aerobic glycolysis. In this theory, hyperactivation of the IGFR1-IR signalling pathway does not occur primarily through somatic gene mutations, but rather through elevated concentrations of insulin and IGF1, allowing for more ligands binding to their receptors. Interestingly, gain-of-function mutations resulting in ligand-independent overactivation of both IGFR1 and IR are uncommon [60]. Furthermore, loss-of-function of the tumor suppressor PTEN may result in hypersensitivity to insulin/IGF1-mediated activation of the IGFR1-IR pathway rather than constitutive downstream activation [60]. Thus, it seems possible that high levels of insulin and IGF1 in the microenvironment favor cell survival and evolution towards malignancy instead of apoptosis in DNA-damaged cells. Indeed, both hyperglycemia and hyperinsulinemia are predictors of cancer occurrence and cancer-related mortality [23,25,26]. This highlights the link between the metabolic syndrome and cancer on the one hand and cancer and lifestyle factors like nutrition on the other. As indicated in Figure ​Figure2,2, restriction of dietary CHOs would counteract this signalling cascade by normalizing glucose and insulin levels in subjects with metabolic syndrome, in this way acting similar to calorie restriction/fasting [61,62]. Indeed, it has been shown in healthy subjects that CHO restriction induces hormonal and metabolic adaptions very similar to fasting [63-66]. Dietary restriction is able to inhibit mTOR signalling through a second, energy-sensing pathway by stimulating phosphorylation of AMP-activated protein kinase (AMPK) [67]. In vitro, AMPK phosphorylation is sensitive to the ratio of AMP/ATP within the cell; in vivo, however, concentrations of glucose and other nutrients are kept fairly stable throughout calorie restriction, suggesting that hormones such as insulin and glucagon might play a more dominant role in regulating AMPK and thus mTOR activation [60]. This may open a second route to mimic the positive effects of calorie restriction through CHO restriction (Figure ​(Figure22).

Indirect effects of glucose availability

Besides delivering more glucose to the tumor tissue, hyperglycemia has two other important negative effects for the host: First, as pointed out by Ely and Krone, even modest blood glucose elevations as they typically occur after a Western diet meal competitively impair the transport of ascorbic acid into immune cells [88,91]. Ascorbic acid is needed for effective phagocytosis and mitosis, so that the immune response to malignant cells is diminished. Second, it has been shown in vitro and in vivo that hyperglycemia activates monocytes and macrophages to produce inflammatory cytokines that play an important role also for the progression of cancer [92-94] (see below). Third, high plasma glucose concentrations elevate the levels of circulating insulin and free IGF1, two potent anti-apoptotic and growth factors for most cancer cells [60]. Free IGF1 is elevated due to a decreased transcription of IGF binding protein (IGFBP)-1 in the liver mediated by insulin [95]. Due to expression of GLUT2, the β-cells of the pancreas are very sensitive to blood glucose concentration and steeply increase their insulin secretion when the latter exceeds the normal level of ~5 mM. In the typical Western diet consisting of three meals a day (plus the occasional CHO-rich snacks and drinks), this implies that insulin levels are elevated above the fasting baseline over most of the day. Both insulin and IGF1 activate the PI3K/Akt/mTOR/HIF-1α pathway by binding to the IGF1 receptor (IGF1R) and insulin receptor (IR), respectively (Figure ​(Figure2).2). In addition, insulin stimulates the release of the pro-inflammatory cytokine interleukin (IL)-6 from human adipocytes [96]. Thus, it could be hypothesized that a diet which repeatedly elevates blood glucose levels due to a high GL provides additional growth stimuli for neoplastic cells. In this respect, Venkateswaran et al. have shown in a xenograft model of human prostate cancer that a diet high in CHO stimulated the expression of IRs and phosphorylation of Akt in tumor tissue compared to a low CHO diet [97]. In colorectal [27], prostate [24] and early stage breast cancer patients [23,98] high insulin and low IGFBP-1 levels have been associated with poor prognosis. These findings again underline the importance of controlling blood sugar and hence insulin levels in cancer patients. Dietary restriction and/or a reduced CHO intake are straightforward strategies to achieve this goal.

Altered nutritional needs of cancer patients

Cancer patients and those with metabolic syndrome share common pathological abnormalities. Since 1885, when Ernst Freund described signs of hyperglycemia in 70 out of 70 cancer patients [99], it has been repeatedly reported that glucose tolerance and insulin sensitivity are diminished in cancer patients even before signs of cachexia (weight loss) become evident [100-102]. Both diabetes and cancer are characterized by a common pathophysiological state of chronic inflammatory signalling and associated insulin resistance. In cancer patients, insulin resistance is thought to be mediated by an acute phase response that is triggered by pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α [101] and IL-6 [103]. In animal and human studies, removal of the tumor resulted in improved glucose clearance, suggesting that these cytokines are secreted, at least in part, from the tumor tissue itself [104,105]. The impact on the metabolism of the host is illustrated in Figure ​Figure3.3. In the liver, the inflammatory process leads to increased gluconeogenesis that is fuelled by lactate secreted from the tumor as well as glycerol from fatty acid breakdown and the amino acid alanine [106] from muscle proteolysis. Gluconeogenesis is an energy-consuming process and might contribute to cancer cachexia by increasing total energy expenditure. Despite increased lipolysis, hepatic production of ketone bodies is usually not enhanced in cancer patients [107,108]. This is in contrast to starvation, where the ketone bodies acetoacetate and β-hydroxybutyrate counteract proteolysis by providing energy for the brain and muscles [109]. In muscle, glucose uptake and glycogen synthesis are inhibited already at early stages of tumor progression, while fatty acid oxidation remains at normal levels or is increased [110,111]. In the latter case, more fat has to be provided from lipolysis in the adipose tissue. In addition, muscles progressively lose protein to provide amino acids for hepatic synthesis of acute-phase proteins and as precursors for gluconeogenesis. Thus, insulin resistance contributes to fat loss and muscle wasting, the two hallmarks of cancer cachexia. At the same time, it makes more glucose in the blood available for tumor cells.

Fat and ketone bodies: anti-cachectic effects

It therefore seems reasonable to assume that dietary carbohydrates mainly fuel malignant cells which express the insulin-independent glucose transporters GLUT1 and GLUT3, while muscle cells are more likely to benefit from an increased fat and protein intake. This was summarized as early as in 1977 by C. Young, who stated that lipid sources predominate the fuel utilization of peripheral tissue of patients with neoplastic disease compared to healthy subjects [112]. In addition, most malignant cells lack key mitochondrial enzymes necessary for conversion of ketone bodies and fatty acids to ATP [40,113,114], while myocytes retain this ability even in the cachectic state [107]. This led some authors to propose a high-fat, ketogenic diet (KD) as a strategy to selectively improve body composition of the host at the expense of the tumor [113,115,116]. The traditional KDs, which recommended protein and CHO to account, in combination, for roughly 20 E% (in the incorrect assumption that they were equivalent due to gluconeogenesis) and fat for the remaining 80 E%, have been widely used to treat childhood epilepsia since the 1920s [117]. KDs are also used to treat adiposity [118] and currently adult epilepsy [119]. In the 1980s, Tisdale and colleagues investigated the effects of a ketogenic diet consisting mainly of medium chain triglycerides (MCTs) on two aggressive animal tumor models that were known to lack the ability to utilize ketone bodies. While the diet had no effect on rats bearing the Walker 256 sarcoma [120], it decreased the cachectic weight loss in proportion to its fat content in mice bearing the mouse-specific colon carcinoma MAC16 [121]. For the latter, they further proved an anti-cachectic effect of a ketogenic diet in which the MCTs were replaced with long chain triglycerides (LCTs), although to a somewhat lesser extent [122]. Contrary to LCTs, MCTs do not require transport in chylomicrones, but readily reach the liver where they are metabolized to yield high amounts of ketone bodies. Interestingly, administration of insulin was able to reduce the weight loss similar to the ketogenic MCT diet, but at the expense of a 50% increase in tumor size, which could be counteracted by addition of β-hydroxybutyrate in the drinking water [123]. The supporting effect of insulin on tumor growth has been known since 1924, when Händel and Tadenuma described the nourishing effect of insulin on tumor tissue in an animal model [124], showing evidence that reducing insulin might reduce tumor growth.

The benefits of mild ketosis

The study of Breitkreuz et al. shows that ketosis might not be necessary to improve the cachectic state of cancer patients. In recent years, however, more evidence has emerged from both animal and laboratory studies indicating that cancer patients could benefit further from a very low CHO KD. In their mouse models, Tisdale et al. already noted that the KD not only attenuated the cachectic effects of the tumor, but also that the tumors grew more slowly (although they did not attribute this to a direct anti-tumor effect of β-hydroxybutyrate). Tumor growth inhibition through a KD has now been established in many animal models, is supported by a few clinical case reports, and laboratory studies have begun to reveal the underlying molecular mechanisms.

In vitro studies

More than 30 years ago, Magee et al. were the first to show that treating transformed cells with various, albeit supra-physiological, concentrations of β-hydroxybutyrate causes a dose-dependent and reversible inhibition of cell proliferation [116]. Their interpretation of the results that ''...ketone bodies interfere with either glucose entry or glucose metabolism...'' has been confirmed and further specified by Fine et al., who connected the inhibition of glycolysis in the presence of abundant ketone bodies to the overexpression of uncoupling protein-2 (UCP-2), a mitochondrial defect occurring in many tumor cells [127]. In normal cells, abundant acetyl-CoA and citrate from the breakdown of fatty acids and ketone bodies would inhibit key enzymes of glycolysis to ensure stable ATP levels; in tumor cells, however, the same phenomenon would imply a decrease in ATP production if the compensatory ATP production in the mitochondria was impaired. For several colon and breast cancer cell lines, Fine et al. showed that the amount of ATP loss under treatment with acetoacetate was related to the level of UCP-2 expression.

Very recently, Maurer et al. demonstrated that glioma cells - although not negatively influenced by β-hydroxybutyrate - are not able to use this ketone body as a substitute for glucose when starved of the latter, contrary to benign neuronal cells [128]. This supports the hypothesis that under low glucose concentrations, ketone bodies could serve benign cells as a substitute for metabolic demands while offering no such benefit to malign cells.

Animal studies

To our knowledge, the first and - with a total of 303 rats and nine experiments - most extensive study of a KD in animals was conducted by van Ness van Alstyne and Beebe in 1913 [129]. Experiments were divided into two classes: in the first class, rats in the treatment arm were fed a CHO-free diet consisting of casein and lard for several weeks before plantation of a Buffalo sarcoma, while the control arm received either bread only or casein, lard and lactose. Rats on the CHO-free diet not only gained more weight than the controls, but also exhibited much less tumor growth and mortality rates, the differences being "... so striking as to leave no room for doubt that the diet was an important factor in enabling the rats to resist the tumor after growth had started." [and they used casein!]  In a second class of experiments using either the slow-growing Jensen sarcoma or the aggressive Buffalo sarcoma, the rats were put on the CHO-free diet on the same day that the tumor was planted. This time, differences between the treatment and control groups were "... so slight that ... one is left in no doubt of the ineffectiveness of non-carbohydrate feeding begun at the time of tumor implantation." Interestingly, this parallels the observation of Fearon et al. that rats who started to receive a KD at the same day as tumor transplantation did not differ from controls in either body or tumor weight after 14 d [120]. In these rats, it was noted that despite persistent ketosis, blood glucose levels were not significantly lower than in controls which were also fed ad libitum. This stability of blood glucose, independent of ketosis, was subsequently confirmed in studies in which mice were fed ad libitum on a KD [84,114,121-123,130] although two studies reported a drop in blood glucose concentrations compared with the control group [116,131]. In the study of Magee et al., however, diet was presented as a liquid vegetable oil and energy intake was not monitored, allowing for the possibility that the animals underate voluntarily, in this way consuming a "caloric restricted KD" used in several experimental settings from the Seyfried lab [84,114,132], which was shown therein to be superior to the unrestricted KD in tumor growth control. That "caloric restriction" per se can hamper tumor growth has been impressively demonstrated already in 1942 by A. Tannenbaum in a series of comprehensive mouse models with different mouse strains and tumor induction types [133]. Throughout all experimental series, a strict restriction of food intake (impeding weight gain) several weeks before inducing tumorigenesis by application of 3,4 benzpyrene decreased the appearance rate and appearance time of tumors in the diet mice compared to the ad libitum controls. Notably, the calorie-restricted diet was composed of 53% CHOs compared to 69% in the control group. Despite a lack of data on blood glucose and ketone body levels, it could be speculated that the strict restriction of food per se (to 50-60% of the control group) induced a ketotic state and thus the ketones were - at least to some extend - responsible for the effects observed.

Animal studies that have investigated the effects of a KD on tumor progression and host survival

Concerning fat quality, Freedland et al. observed that a diet rich in corn oil might stimulate prostate cancer growth to a greater extent than one rich in saturated fat [134].A recent study suggests, however, that tumor growth inhibition neither depends on fat quality nor ketone body levels[131]. In this case, mice injected with either murine squamous cell carcinoma or human colorectal carcinoma cells received a low CHO, high-protein diet in which ~ 60 E% was derived from protein, 10-15 E% from CHO and ~ 25 E% from fat. No systemic ketosis was measured, yet tumors grew significantly less compared with a standard diet containing 55 E% from CHO and 22 E% from the same fat source. IGF1 levels and body weight remained stable, so these findings could not be attributed to one of these factors. There was, however, a significant drop in blood glucose, insulin and lactate levels, and a positive correlation between blood lactate as well as insulin levels and tumor growth was found. The study of Venkateskwaran et al. indicates that in prostate cancer insulin and/or IGF1 play major roles in driving tumor cell proliferation [97].

The diversity of these findings should not be surprising, given the variety of mice strains, tumor cell lines, diet composition and time of diet initiation relative to tumor planting. Instead, it seems remarkable that the same basic treatment, namely drastic restriction of CHOs, apparently induces anti-tumoral effects via different pathways. Thus, it may depend on the circumstances which variables - including blood glucose, insulin, lactate, IGF1, fat quality and ketone bodies - are the best predictors of and responsible for the anti-tumor effects of very low CHO diets.

Human studies

Until now, no randomized controlled trials have been conducted to evaluate the effects of a KD on tumor growth and patient survival. It has to be noted in general, however, that any dietary intervention requiring a dramatic change of life style makes randomized studies nearly impossible - however, even prospective cohort studies are missing. There is only anecdotal evidence that such a diet might be effective as a supportive treatment. One study investigated whether a high-fat diet (80% non-nitrogenous calories from fat) would inhibit tumor cell replication compared to a high-dextrose diet (100% non-nitrogenous calories from dextrose) in 27 patients with gastro-intestinal cancers [137]. Diets were administered parenterally and cell proliferation assessed using thymidine labeling index on tumor samples. After 14 days, the authors found a non-significant trend for impaired proliferation in the high-fat group. Whether ketosis was achieved with this regime was not evaluated, but blood glucose levels were comparable in both trial groups. A very recent pilot trial demonstrated the feasibility of a low CHO up to a ketogenic regimen implemented for 12 weeks in very advanced outpatient cancer patients. Notably, severe side effects were not observed, nearly all standard blood parameters improved and some measures of quality of life changed for the better [138]. The first attempt to treat cancer patients with a long-term controlled KD was reported by L. Nebeling in 1995 for two pediatric patients with astrocytoma [139]. The results of those two cases were very encouraging and the diet was described in detail in another publication [140]. Implementing a KD with additional calorie restriction in a female patient with glioblastoma multiforme clearly demonstrated that this intervention was able to stop tumor growth [132]. This was achieved, however, on the expense of a dramatic weigh loss of 20% over the intervention period, which is no option for the majority of metastatic cancer patients being in a catabolic state. A first clinical study applying a non-restricted KD for patients with glioblastoma (ERGO-study, NHI registration number NCT00575146), which was presented at the 2010 ASCO meeting [141], showed good feasibility and suggested some anti-tumor activity. The protocol of another clinical interventional trial (RECHARGE trial, NCT00444054) treating patients with metastatic cancer by a very low CHO diet was published in 2008 [142], and preliminary data from this study presented at the 2011 ASCO-meeting showed a clear correlation between disease stability or partial remission and high ketosis, independent of weight loss and unconscious caloric restriction of the patients [136]. While a randomized study for the treatment of prostate cancer patents applying the Atkins diet (NCT00932672) is currently recruiting patients at the Duke University, another trial posted at the clinical trials database (ClinicalTrials.gov) is not yet open for recruitment (NCT01092247). Very recently, two Phase I studies applying a ketogenic diet based on KetoCal® 4:1 started recruitment at the University of Iowa, intended to treat prostate cancer patients (KETOPAN, NCT01419483) and non-small cell lung cancer (KETOLUNG, NCT01419587). Thus, in the future, several data should be available to judge whether this kind of nutrition is useful as either a supportive or even therapeutic treatment option for cancer patients.

Is there a role for carbohydrate restriction in the prevention of cancer?

"Prevention of cancer" can refer to either the inhibition of carcinogenesis per se or - once that cells made the transition to malignancy - the sufficient delay of tumor growth, so that it remains undetected and asymptomatic during a subject's lifespan. There is evidence that even modest CHO restriction may influence both of these mechanisms positively through various pathways. The IGF1R-IR pathway has already been discussed: once a potentially carcinogenic somatic mutation has occurred, the probability for carcinogenesis of a cell that is borderline between apoptosis and malignancy might be raised by high levels of insulin and IGF1 in the micro-environment. Once a cell became malignant, high insulin and IGF1 levels might accelerate proliferation and progression towards a more aggressive, glycolytic phenotype. In rats treated with the carcinogen N-methyl-N-nitrosourea, it has been shown that lowering the CHO content of the diet from 60 E% to 40 E% with a simultaneous increase in protein was sufficient to lower postprandial insulin levels as well as decrease the appearance rate of tumors from (18.2 ± 1.3)%/wk to (12.9 ± 1.4)%/wk (p < 0.05), however with no statistically significant effect on tumor latency and weight measured after 10 wk [143]. Similarly, a recent study reported that NOP mice, which normally have a 70 - 80% chance of developing breast cancer over their lifetime due to genetic mutations, stayed tumor-free at 1 year of age when their calories from CHO were limited to 15%, while almost half of those on a 55% CHO diet developed tumors [131]. Notably, only 3 out of 11 mice in the 15% CHO group died with having a tumor compared to 7 out of 10 in the 55% CHO group; at death, significantly lower plasma insulin levels had been measured for the low CHO group. These results support the epidemiological [25,29,31,32] and in vitro [81,144] findings that high CHO diets, in particular those including high GI foods, promote mammary tumorigenesis via the sustained action of insulin.

Lower insulin levels may further increase the chance of intermittent ketosis, in particular if CHO restriction is combined with exercise, calorie restriction or intermittent fasting. Seyfried and Shelton [40] pointed out the possibility of ketone bodies to help in cancer prevention through their ability to protect the mitochondria from inflammation and ROS. Being more satiating than low-fat diets [145,146], a low CHO diet would make it easier to avoid caloric overconsumption or to implement intermittent fasting as an additional lifestyle change [147].

Avoidance of chronic inflammation

Another potential benefit of low CHO diets might lie in their influence upon inflammatory processes that take place within various tissues. Inflammation is a well-established driver of early tumorigenesis and accompanies most, if not all cancers [148]. Chronic, 'smouldering' inflammation can both cause and develop along with neoplasia. There is evidence that chronic intake of easily digestible CHOs is able to promote such an inflammatory state in leukocytes and endothelial cells [94]. In obese individuals [149] and healthy subjects who underwent eccentric exercise training [150], the inflammatory state was further augmented postprandially through a high CHO intake, but not through high-fat, low CHO meals in the latter study. Maybe more importantly, even moderate CHO restriction has been shown to effectively target several important markers of atherosclerosis and type II diabetes, both of which are associated with chronic inflammation [151-157]. Forsythe et al. showed that in overweight individuals with dyslipidemia a very low CHO diet had a more favorable effect than a low fat diet in reducing several markers of inflammation [158]. Given these findings, it can be hypothesized that a diet with a low GL positively affects cancer risk through reducing postprandial hyperglycemia and the associated inflammatory response.

In this context, it is important to note that a low CHO diet offers further possibilities to target inflammation through omission or inclusion of certain foods. Usually, CHO restriction is not only limited to avoiding sugar and other high-GI foods, but also to a reduced intake of grains. Grains can induce inflammation in susceptible individuals due to their content of omega-6 fatty acids, lectins and gluten [159,160]. In particular gluten might play a key role in the pathogenesis of auto-immune and inflammatory disorders and some malignant diseases. In the small intestine, gluten triggers the release of zonulin, a protein that regulates the tight junctions between epithelial cells and therefore intestinal, but also blood-brain barrier function. Recent evidence suggests that overstimulation of zonulin in susceptible individuals could dysregulate intercellular communication promoting tumorigenesis at specific organ sites [161].

Paleolithic-type diets, that by definition exclude grain products, have been shown to improve glycemic control and cardiovascular risk factors more effectively than typically recommended low-fat diets rich in whole grains [162]. These diets are not necessarily very low CHO diets, but focus on replacing high-GI modern foods with fruits and vegetables, in this way reducing the total GL. This brings us back to our initial perception of cancer as a disease of civilization that has been rare among hunter-gatherer societies until they adopted the Western lifestyle. Although there are certainly many factors contributing to this phenomenon, the evidence presented in this review suggests that reduction of the high CHO intake that accounts for typically > 50 E% in the Western diet may play its own important role in cancer prevention and outcome.

Conclusions

We summarize our main findings from the literature regarding the role of dietary CHO restriction in cancer development and outcome.

(i) Most, if not all, tumor cells have a high demand on glucose compared to benign cells of the same tissue and conduct glycolysis even in the presence of oxygen (the Warburg effect). In addition, many cancer cells express insulin receptors (IRs) and show hyperactivation of the IGF1R-IR pathway. Evidence exists that chronically elevated blood glucose, insulin and IGF1 levels facilitate tumorigenesis and worsen the outcome in cancer patients.

(ii) The involvement of the glucose-insulin axis may also explain the association of the metabolic syndrome with an increased risk for several cancers. CHO restriction has already been shown to exert favorable effects in patients with the metabolic syndrome. Epidemiological and anthropological studies indicate that restricting dietary CHOs could be beneficial in decreasing cancer risk.

(iii) Many cancer patients, in particular those with advanced stages of the disease, exhibit altered whole-body metabolism marked by increased plasma levels of inflammatory molecules, impaired glycogen synthesis, increased proteolysis and increased fat utilization in muscle tissue, increased lipolysis in adipose tissue and increased gluconeogenesis by the liver. High fat, low CHO diets aim at accounting for these metabolic alterations. Studies conducted so far have shown that such diets are safe and likely beneficial, in particular for advanced stage cancer patients.

(iv) CHO restriction mimics the metabolic state of calorie restriction or - in the case of KDs - fasting. The beneficial effects of calorie restriction and fasting on cancer risk and progression are well established. CHO restriction thus opens the possibility to target the same underlying mechanisms without the side-effects of hunger and weight loss.

(v) Some laboratory studies indicate a direct anti-tumor potential of ketone bodies. During the past years, a multitude of mouse studies indeed proved anti-tumor effects of KDs for various tumor types, and a few case reports and pre-clinical studies obtained promising results in cancer patients as well. Several registered clinical trials are going to investigate the case for a KD as a supportive therapeutic option in oncology.

[obyvatel]

Maybe you could put all this together in a short article/review/series of quotes for SOTT to publish and we could then share it on FB??  Very important material.

    Will give it a shot.

[Danilo]

Prevention/Management/Healing of Cancer

    There are no oncology drugs known to my knowledge that can simultaneously target inflammation and angiogenesis, while, at the same time, killing tumor cells through an apoptotic mechanism.

About that, I wonder why Prof. Seyfried doesn't mention DCA (dichloroacetate) whose anticancer discovery by Univ. of Alberta dates by 2007 (http://www.sciencedirect.com/science/article/pii/S1535610806003722#sec1). No complete DCA clinical trials have been conducted but they're missing also
for KD diet.  DCA seems to reactivate mitochondria, induce apoptosis of cancer cells and inhibit angiogenesis   ("Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer" ,  http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2012198a.html ).

For more info:
http://www.chrcrm.org/en/rotm/dr-evangelos-michelakis
http://www.thedcasite.com/the_dca_papers.html

Mod edit: fixed quotes