Re: Cancer as a Metabolic Disease: Thomas Seyfried
Genetic Theory of Cancer
[quote author=Cancer as a Metabolic Disease]
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.
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Inconsistencies in the genetic theory of cancer
[quote author=Cancer as a Metabolic Disease]
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.
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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.
[quote author=Cancer as a Metabolic Disease]
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.
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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. .
[quote author=Cancer as a Metabolic Disease]
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”.
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[quote author=Cancer as a Metabolic Disease]
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.
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Metastasis
[quote author=Cancer as a Metabolic Disease]
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.
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Cellular origin of metastasis
Epithelial to Mesenchymal Transition (EMT) (from genetic theory of cancer)
[quote author=Cancer as a Metabolic Disease]
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.
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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).
[quote author=Cancer as a Metabolic Disease]
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.
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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.
[quote author=Cancer as a Metabolic Disease]
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.”
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