Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?

Exert from Metabolites – August 2021

MDPI Concept Paper

Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?

Thomas N. Seyfried 1,* and Christos Chinopoulos 2 Citation: Seyfried, T.N.;

Chinopoulos, C. Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory

Abstract: A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than a theory that is less able to explain the facts. Cancer is generally considered a genetic disease based on the somatic mutation theory (SMT) where mutations in proto-oncogenes and tumor suppressor genes cause dysregulated cell growth. Evidence is reviewed showing that the mitochondrial metabolic theory (MMT) can better account for the hallmarks of cancer than can the SMT. Proliferating cancer cells cannot survive or grow without carbons and nitrogen for the synthesis of metabolites and ATP (Adenosine Triphosphate). Glucose carbons are essential for metabolite synthesis through the glycolysis and pentose phosphate pathways while glutamine nitrogen and carbons are essential for the synthesis of nitrogen-containing metabolites and ATP through the glutaminolysis pathway. Glutamine-dependent mitochondrial substrate level phosphorylation becomes essential for ATP synthesis in cancer cells that over-express the glycolytic pyruvate kinase M2 isoform (PKM2), that have deficient OxPhos, and that can grow in either hypoxia (0.1% oxygen) or in cyanide. The simultaneous targeting of glucose and glutamine, while elevating levels of nonfermentable ketone bodies, offers a simple and parsimonious therapeutic strategy for managing most cancers. Keywords: mutation

Introduction: Cancer is a systemic disease involving multiple time- and space-dependent changes in the health status of cells and tissues that lead to malignant tumors [1,2]. Dysregulated cell growth, i.e., neoplasia, is the biological endpoint of the disease [3]. Tumor cell invasion into surrounding tissues and their spread (metastasis) to distant organs is the primary cause of morbidity and mortality of most cancer patients [4–7]. Data from the American Cancer Society showed that the number of people dying in the US from cancer in 2013 was 580,350, and in 2020 it was 606,520, an increase of 4.3% [8,9]. The US population increase over this same period was 4.5%, indicating no real progress in cancer management. Cancer is predicted to overtake heart disease as the leading cause of death in Western societies. Is the failure to reduce the cancer death rate due to an incorrect theory on the origin of the disease? 2. Scientific Theories A scientific theory is simply an attempt to explain the facts of nature. Reality is based on replicated facts, whereas interpretation of the facts is based on credible theories. The heliocentric theory of Copernicus, Galileo, and Keppler was able to explain better the Metabolites 2021, 11, 572. https://doi.org/10.3390/metabo11090572 https://www.mdpi.com/journal/metabolites Metabolites 2021, 11, 572 2 of 21 movements of celestial bodies than was the geocentric theory of Ptolemy. The germ theory of Louis Pasteur was able to explain better the origin of contagious diseases than was the miasma “bad air” theory of Hippocrates and Galen. The Darwin–Wallace theory of evolution by natural selection was able to explain better the origin of species than was the theory of special creation [10]. In none of these examples could a hybrid theory be envisioned. A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than is a theory less able to explain the facts. The provocative question before us is whether the Mitochondrial Metabolic Theory (MMT) can explain better the origin and management of cancer than can the current Somatic Mutation Theory (SMT)

According to the SMT, cancer is a complex genetic disease that arises from inherited or random somatic mutations in proto-oncogenes or in tumor suppressor genes [11–13]. While many mutations have been found in various tumors, the so-called driver gene mutations are considered most responsible for causing the disease [11,14]. Although the SMT is the dominant scientific explanation for the origin of cancer, numerous inconsistencies have emerged that seriously challenge the credibility of this theory [15–17]. The major inconsistencies include: (1) The absence of gene mutations and chromosomal abnormalities in some cancers [17–21]. For example, Greenman et al. found no mutations following extensive sequencing in 73/210 cancers [13], whereas Parsons et al., found no mutations in the P53, the PI3K, or the RB1 pathways in the Br20P tissue sample of a glioblastoma patient [22]. Cancer cells with no mutations should not exist according to the SMT. (2) The identification and clonal expansion of numerous driver gene mutations in a broad range of normal human tissues [23–27]. If driver genes cause cancer according to the SMT, then how is it possible that so many driver genes are found in normal human tissues that do not express cancer? No explanation has been presented on how the SMT can account for, (a) malignant tumors that have no mutations, or (b) normal cells that express driver mutations, but do not develop tumors [14]. (3) The general absence of cancers in chimpanzees despite having about 98% gene and protein sequence identity with humans even at the BRCA1 locus [28–31]. Despite anatomical differences between the breasts of humans and chimpanzees, breast cancer has never been documented in a female chimpanzee [31]. As DNA replication would be similar in normal tissue stem cells in chimpanzees and humans, the rarity of cancer in all chimpanzee organs undermines the “bad luck” hypothesis of Tomasetti and Vogelstein that cancer risk is due to random mutations arising during DNA replication in normal, noncancerous stem cells [32]. The rarity of cancer in primitive humans and in chimpanzees suggests that environmental factors (diet and lifestyle), rather than genetic mutations, are largely responsible for cancer [31,33]. It is important to remember that nothing in either general biology or in cancer biology makes sense except in the light of evolution [34,35]. (4) Theodor Boveri, the person most recognized as the originator of the SMT [36,37], never directly studied cancer and was highly apologetic for his general lack of knowledge about the disease. Indeed, Boveri stated: “I have no personal experience worth mentioning in any of the numerous specialized fields of tumour research. My knowledge comes almost exclusively from books. Given this, it is inevitable that I am unaware of many reports in the literature, that I overestimate the significance of many known facts and that I do not set enough store by others. But this article will doubtless contain even more serious defects, as is so often the case when an author makes an incursion into a field with which he is unfamiliar” [38]. Most importantly, Boveri also mentioned that defects in the cytoplasm could just as well be responsible for cancer as defects in the nucleus. The distinguished British geneticist C. D. Darlington also emphasized the importance of the cytoplasm in the origin of cancer [39]. The most compelling evidence against the SMT comes from the nuclear/cytoplasm transfer experiments showing that growth-regulated cells can be produced from tumorigenic nuclei, as long as the tumorigenic nuclei are localized in the cytoplasm containing Metabolites 2021, 11, 572 3 of 21 normal mitochondria [40,41]

(Figure 1). Moreover, recent studies show that normal mitochondria can down-regulate multiple oncogenic pathways and abnormal growth in glioma, melanoma, and metastatic breast cancer cells [42–46]. These findings indicate that normal mitochondrial function can suppress dysregulated cell growth regardless of the number of gene or chromosomal abnormalities that might be present in the tumor nucleus. Although the somatic mutations present in the cancer nuclei of developing frogs and mice did not cause dysregulated cell growth, they did abort development suggesting an inhibitory lethal effect on the proliferation of normal cells [40]. If nuclear encoded driver genes were responsible for dysregulated cancer cell growth, then the results from the nuclear/mitochondrial transfer experiments would be opposite to the results shown in Figure 1. When viewed collectively, these findings imply that the nuclear somatic mutations found in many cancers cannot be the primary cause of the disease and seriously challenge the SMT as a credible explanation for the origin of cancer [14]. Despite these glaring inconsistencies, the SMT is presented as if it were a settled issue in most current college textbooks of genetics, biochemistry, and cell biology, as well as in the National Cancer Institute in stating that, “Cancer is a genetic disease—that is, it is caused by changes to genes that control the way our cells function, especially how they grow and divide” (12 October 2017) [40]. The view of cancer as a genetic disease has become a “silent assumption”, so completely accepted that it is no longer questioned. Could the continued acceptance of the SMT as an explanation for the origin of cancer be based more on dogmatic ideology than on rational thought [40,47]? If nuclear somatic mutations cannot be the origin of cancer, then how do cancer cells arise?

The Mitochondrial Metabolic Theory of Cancer

The Mitochondrial Metabolic Theory of Cancer According to the MMT, cancer arises from a gradual disruption of ATP synthesis through oxidative phosphorylation (OxPhos) leading to compensatory ATP synthesis through substrate level phosphorylation. It is defective OxPhos that ultimately causes most of the genomic changes in cancer, not the reverse. Although Otto Warburg is rightfully credited with the original discovery of cancer as a mitochondrial metabolic disease [50,51], he was unaware of information now available that more strongly supports the linkage between OxPhos deficiency and the origin of cancer (discussed later). The disruption of OxPhos leads to the accumulation of reactive oxygen species (ROS), which are mutagenic and carcinogenic [52–56]. The genomic instability and somatic mutations seen in most cancers arise as a consequence of the chronic production of ROS and acidification of the microenvironment [15,55,57–61]. In other words, the somatic mutations arise as downstream effects rather than as causes of cancer. The information summarized in Figure 1 shows that nuclear genomic mutations alone cannot be the origin of dysregulated cell growth, i.e., the signature phenotype of cancer. Could this information change opinions on the importance of mutations in the origin cancer? It is our view that the MMT can explain better the hallmarks and facts of cancer than can the SMT. The MMT is the only theory to provide a credible explanation for the “oncogenic paradox” that has perplexed the cancer field for decades [62–64]. Albert Szent-Gyorgyi first described the oncogenic paradox as a specific process (malignant transformation) that could be initiated by a plethora of unspecific events (radiation, asbestos, viral infections, rare inherited mutations, irritation, inflammation, chemicals etc.) [62]. Siddhartha Mukherjee also struggled to understand the paradox in stating on page 285 of his book: “What beyond abnormal, dysregulated cell division, was the common pathophysiological mechanism underlying cancer?” [64]. We solved the paradox in showing how the protracted loss of OxPhos, following mitochondrial damage, is the common pathophysiological mechanism responsible for the oncogenic paradox and the origin of cancer (Figure 2). .

Figure 2. Cancer as a Mitochondrial Metabolic Disease. Cancer can arise from any number of unspecific influences (risk factors) that would alter the number, structure, and function of mitochondria thus affecting energy production through OxPhos. Unspecific cancer risk factors can include, age, viral infections, the Ras oncogene, rare inherited mutations, chronic inflammation, intermittent hypoxia, radiation exposure, chemical carcinogens etc. [2,65–68]. Any of these risk factors could cause chronic damage to OxPhos thus increasing the production of reactive oxygen species (ROS), which would ultimately Metabolites 2021, 11, 572 5 of 21 link to the six major hallmarks of cancer [2,12,68]. The process by which each of these unspecific risk factors can chronically damage OxPhos was described previously in detail [16,66,69,70]. Excessive ROS, mostly generated from OxPhos dysfunction, are carcinogenic and mutagenic and would cause significant damage to lipids, proteins, and nucleic acids in both the mitochondria and the in the nucleus [71]. Nuclear genomic instability, including the vast array of somatic mutations and aneuploidy, would arise because of ROS damage together with extracellular acidification and inflammation through a bidirectional interaction between the provocative agent and cells within a tissue [1,2,57,72,73]. Indeed, mutations in the p53 tumor suppressor gene and genomic instability have been linked directly to OxPhos deficiency and mitochondrial ROS production in cancer stem cells [55,74]. Fermentation metabolism and ROS formation underlie the hyperproliferation of tumor cells. A gradual reduction in OxPhos efficiency would elicit a mitochondrial stress response through retrograde (RTG) signaling [69,75–77]. RTG activation would cause persistent expression of various oncogenes, e.g., Hif-1a and c-Myc, that upregulate receptors and enzymes in both the glycolysis and the glutaminolysis pathways [75,78–82]. Oncogenes become facilitators of fermentation metabolism. ATP synthesis through mSLP (Q effect) will compensate for lost ATP synthesis through OxPhos or from PKM2 expression in glycolysis [83,84]. The path to carcinogenesis will occur only in those cells capable of sustaining energy production through substrate level phosphorylation, (SLP). Cells unable to replace OxPhos with SLP, e.g., CNS neurons or cardiomyocytes, would die and rarely become tumorigenic. Despite the shift from respiration to SLP, the ∆G’ATP hydrolysis remains fairly constant at approximately −56 kJ, indicating that the energy from SLP compensates for the reduced energy from OxPhos. When respiration becomes unable to maintain energy homeostasis, the RTG will initiate oncogene up-regulation and tumor suppressor gene inactivation. Protracted RTG activation becomes necessary to maintain the viability of incipient cancer cells. Genomic instability will arise as a secondary consequence of protracted mitochondrial stress from disturbances in the intracellular and extracellular environments. Metastasis arises from respiratory damage in cells of myeloid/macrophage origin either directly or after fusion hybridization with epithelialderived tumor cells [4,85]. Tumor progression and degree of malignancy is linked directly to ultrastructure abnormalities (mitochondrial cristolysis) and to the energy transition from OxPhos to substrate level phosphorylation (Warburg effect and Q effect) [83]. The T signifies an arbitrary threshold when the shift from OxPhos to SLP becomes irreversible. This scenario links all major cancer hallmarks to an extrachromosomal and epigenetic respiratory dysfunction and can explain the oncogenic paradox [70]. Reprinted with modifications from [68,83]. Since no inherited cancer mutation has been found that is 100% penetrant, inherited cancer mutations are also considered secondary effects and not primary causes of cancer [66,86–88]. If an inherited or somatic mutation were to be found in all cancers, it could be considered a primary cause of cancer. Such mutations, however, have not been found. Inherited cancer mutations could cause cancer if they compromise OxPhos function, making OxPhos dysfunction the primary cause of cancer. While mtDNA mutations have been found in many cancers [89], we were unable to find a single pathogenic mutation in the fully sequenced mtDNA of five independently-derived mouse brain tumors [90]. These findings indicate that mtDNA mutations alone cannot be the origin of all cancers. The mtDNA mutations are considered secondary risk factors and can be linked to cancer origin only if they also disrupt OxPhos function [91]. A chronic disruption of ATP synthesis through OxPhos would induce, by necessity, a compensatory energy production through the process of substrate level phosphorylation in both the cytoplasm and in the mitochondria. As normal mitochondrial function maintains cellular differentiation, the rewiring of energy metabolism from respiration to fermentation would cause dedifferentiation and dysregulated proliferation [2,40,50,51,58]. While aerobic fermentation (Warburg effect) is considered another emerging hallmark of cancer [12], the replacement of abnormal mitochondria with normal mitochondria will also reverse this hallmark [44,46,92]. In other words, OxPhos sufficiency will reverse the Warburg effect [44,93]. Hence, the energy transition from respiration to fermentation can explain the major hallmarks of cancer, as described by Hanahan and Weinberg (Figure 2). Metabolites 2021, 11, 572 6 of 21 A chronic loss of OxPhos will activate the mitochondrial stress response or the retrograde (RTG) signaling system [75–77]. Activation of this system stabilizes Hif-1α and upregulates the expression of c-Myc, key oncogenes necessary for the upregulation of substrate level phosphorylation through the glycolysis and the glutaminolysis pathways, respectively [83]. As plasma membrane pumps are perpetual consumers of ATP, no cell can survive for very long without constant synthesis of ATP for the pumps [94]. The transition from ATP synthesis through OxPhos to ATP synthesis through fermentation thus becomes essential for cell viability. Moreover, the energy transition from OxPhos to fermentation will cause a cell to enter its “default” state. Proliferation is the evolutionary conserved default state of metazoan cells, once freed from active control [3,17]. The mitochondrial OxPhos system provides the active control necessary for maintaining the quiescent or differentiated state. The protracted replacement of ATP synthesis through OxPhos with ATP synthesis through substrate level phosphorylation will cause the cell to enter its default state of proliferation [62]. Szent-Gyorgyi described how unbridled proliferation, driven by fermentation metabolism, was the common phenotype of all cells before oxygen entered the atmosphere some 2.5 billion years ago [62]. Based on the concepts of evolutionary biology, the transition from respiration to fermentation becomes the most logical explanation for the first three hallmarks of cancer involving dysregulated cell growth (Figure 2). The acidification of the cancer microenvironment, arising from the excretion of fermentation end products, e.g., lactate and succinate, will initiate angiogenesis. This process, however, can be bi-directional leading to an escalating situation of biological chaos [40,95]. Stabilization of Hif-1α is ultimately responsible for angiogenesis, i.e., the fourth hallmark [82,83,96,97]. As mitochondria control apoptosis [98], evasion of apoptosis would be an expected outcome of dysfunctional mitochondria and can account for the fifth cancer hallmark. While the rewiring of energy production from OxPhos to substrate level phosphorylation can easily explain the first five cancer hallmarks, how might this energy rewiring be linked to metastasis, the sixth major cancer hallmark? Emerging evidence indicates that metastasis involves transformation of myeloid cells or fusion hybridization between macrophages and transformed epithelial cells [4,99–107]. Macrophages and myeloid cells are mesenchymal cells that are already programed to migrate through tissues, to intravasate blood vessels, to function in the circulation, and to extravasate blood vessels for involvement in tissue repair and wound healing [4,108–110]. Similar to macrophages, many metastatic cancer cells are immunosuppressive and express phagocytic behavior [100,111–113]. The absence of metastasis in crown-gall plant cancers, despite expressing aerobic fermentation (Warburg effect), is due to the absence of a cellular immune system (macrophages and lymphocytes) in plants [4,7]. Macrophages can acquire mitochondria with dysfunctional OxPhos through various fusion hybridization events with neoplastic stem cells in an acidic and hypoxic microenvironment [101,114] (Figure 3). Radiation therapy can also facilitate tumor cell-macrophage/microglial fusion-hybridization thus producing highly invasive metastatic cells, as an unintended consequence [115,116]. It is also interesting that glutamine is a major energy metabolite for cells of the immune system including macrophages [117–119]. This fact could account in part for the glutamine dependency of metastatic cancer cells [120–123]. As macrophages are immunosuppressive, metastatic cells with macrophage properties would be powerful suppressors of the immune system. These properties could contribute to the failure of some immunotherapies [124,125]. The transition from respiration to fermentation can also explain the drug resistance of metastatic tumor cells [126,127]. The drug resistance of tumor cells is due in large part to the replacement of energy synthesis from OxPhos to fermentation [2]. Hence, the control of metastasis can be improved with better knowledge of macrophage biology. Figure 3.

Fusion-hybrid hypothesis for cancer cell metastasis. According to the fusion hybrid hypothesis, metastatic cancer cells can arise following fusion-hybridization between neoplastic epithelial cells and myeloid cells (macrophages). The fusion hybrid hypothesis originated with the work of Aichel in 1911 and was expanded by the Pawelek and the Munzarova groups [105,128–132]. Macrophages are known to invade in situ carcinoma as if it were an unhealed wound [95,109,133]. This creates a protracted inflammatory microenvironment leading to fusion hybridization between the neoplastic epithelial cell and the mesenchymal macrophage. Mitochondrial damage becomes the driver for the neoplastic transformation of the epithelial cell and of the fusion hybrids. Inflammation damages mitochondria leading to enhanced fermentation and acidification of the microenvironment. The gradual replacement of normal macrophage mitochondria with dysfunctional mitochondria in the hybrid cell cytoplasm leads to rogue behavior in cells that naturally possess the capability to, (1) move through tissues, (2) suppress the immune system, (3) enter (intravasate), and to exit (extravasate) the circulation. In addition to explaining the “seed-soil” hypothesis of metastasis, the fusion hybrid hypothesis can also explain how metastatic cells can re-capitulate the epithelial characteristics of the primary tumor at secondary micro-metastatic growth sites [4,85]. Furthermore, this hypothesis can explain the phenomenon of mesenchymal epithelial transition without invoking a mutation suppression mechanism. See text for more details. Modified from [85,134]. The macrophage/myeloid origin of metastasis, based on the mitochondrial metabolic theory, should be compared with the epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET) for the origin of metastasis, based on the somatic mutation theory [4,12]. It is unclear how random somatic mutations could be responsible for metastasis, as the metastatic cascade is a non-random phenomenon that is common to many cancer types [5]. Each part of the cascade involves an ordered regulation of evolutionary conserved biological processes. Moreover, the metastatic behavior of cells can occur in the absence of mutations [7,135,136]. The EMT/MET hypothesis has yet to explain how random somatic mutations could transform an epithelial cell into a biologically distinct mesenchymal cell (EMT), and then have these random mutations be suppressed or reversed to allow a transition of the mesenchymal phenotype back to an epithelial phenotype (MET) [12,134]. We consider these fantastical biological transitions as inconsistent with evolutionary biology [85]. In summary, the mitochondrial metabolic theory can explain better the facts of metastasis than can the somatic mutation theory. Figure 3. Fusion-hybrid hypothesis for cancer cell metastasis. According to the fusion hybrid hypothesis, metastatic cancer cells can arise following fusion-hybridization between neoplastic epithelial cells and myeloid cells (macrophages). The fusion hybrid hypothesis originated with the work of Aichel in 1911 and was expanded by the Pawelek and the Munzarova groups [105,128–132]. Macrophages are known to invade in situ carcinoma as if it were an unhealed wound [95,109,133]. This creates a protracted inflammatory microenvironment leading to fusion hybridization between the neoplastic epithelial cell and the mesenchymal macrophage. Mitochondrial damage becomes the driver for the neoplastic transformation of the epithelial cell and of the fusion hybrids. Inflammation damages mitochondria leading to enhanced fermentation and acidification of the microenvironment. The gradual replacement of normal macrophage mitochondria with dysfunctional mitochondria in the hybrid cell cytoplasm leads to rogue behavior in cells that naturally possess the capability to, (1) move through tissues, (2) suppress the immune system, (3) enter (intravasate), and to exit (extravasate) the circulation. In addition to explaining the “seed-soil” hypothesis of metastasis, the fusion hybrid hypothesis can also explain how metastatic cells can re-capitulate the epithelial characteristics of the primary tumor at secondary micro-metastatic growth sites [4,85]. Furthermore, this hypothesis can explain the phenomenon of mesenchymal epithelial transition without invoking a mutation suppression mechanism. See text for more details. Modified from [85,134]. The macrophage/myeloid origin of metastasis, based on the mitochondrial metabolic theory, should be compared with the epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET) for the origin of metastasis, based on the somatic mutation theory [4,12]. It is unclear how random somatic mutations could be responsible for metastasis, as the metastatic cascade is a non-random phenomenon that is common to many cancer types [5]. Each part of the cascade involves an ordered regulation of evolutionary conserved biological processes. Moreover, the metastatic behavior of cells can occur in the absence of mutations [7,135,136]. The EMT/MET hypothesis has yet to explain how random somatic mutations could transform an epithelial cell into a biologically distinct mesenchymal cell (EMT), and then have these random mutations be suppressed or reversed to allow a transition of the mesenchymal phenotype back to an epithelial phenotype (MET) [12,134]. We consider these fantastical biological transitions as inconsistent with evolutionary biology [85]. In summary, the mitochondrial metabolic theory can explain better the facts of metastasis than can the somatic mutation theory.

Source: Metabolites 2021, 11, 572. https://doi.org/ 10.3390/metabo11090572 Academic Editor: Daniel Oscar Cicero Received: 11 July 2021 Accepted: 20 August 2021 Published: 25 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biology, Boston College, Chestnut Hill, MA 02467, USA 2 Department of Medical Biochemistry, Semmelweis University, 1094 Budapest, Hungary; [email protected] * Correspondence: [email protected]

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