Is Cancer a Genetic or Metabolic Disease? Part 6

Our lack of progress in developing effective treatments for the majority of cancers (outside of breast, colon, and lung cancers, and some liquid tumors) suggests that the dominant framework used to understand the origin and progression of cancer — and so its potential causes and treatments — is flawed. The rationale for precision medicine, gene-targeted therapies, and immunotherapies is based on the premise that cancer is a genetic disease according to the somatic mutation theory (SMT).

Unfortunately, this lack of progress in cancer treatment has been met not by a diversification of efforts but by a concentration on a limited scope of research based on the SMT, crowding out alternative hypotheses. Worse still, there is evidence to suggest that many of the treatments developed through this framework are harmful, as was recently highlighted in a review of the multiple failed therapeutic approaches used to manage glioblastoma (57). New immunotherapies can accelerate the growth rate of some cancers and actually expedite patient mortality (58). Although many people survive cancer by using conventional cancer therapies, many also pay a high price as new health issues arise out of the therapies they received. “Cancer survivor medicine” is emerging as a new medical field to address the multitude of health issues that afflict cancer survivors, including depression fatigue, pain, neuropathy, lymphedema, sleep issues, weight gain, cognitive dysfunction, sexual dysfunction, and fear of recurrence (59). Most cancer survivor health issues arise indirectly from therapies based on the gene theory of cancer.

Clearly, the stakes are high and demand a careful consideration of our current understanding of cancer and its origins. It is unlikely, if not impossible, that effective cancer therapies will be developed if the origin of the disease is misunderstood. To that end, over the past several weeks, we have contrasted the SMT with the mitochondrial metabolic theory of cancer (MMT).

The MMT Is the Most Compelling Explanation for the Origin of Cancer

The credibility of a theory’s explanation of a complicated phenomenon is dependent on the extent to which the theory can explain the facts associated with the phenomenon (56). The MMT can better explain critical hallmarks of cancer than can the SMT.

Figure 1: Mitochondrial respiratory dysfunction as the origin of cancer. Reprinted with modifications from (60).

Figure 1 shows how mitochondrial dysfunction as an initial event can account for the major hallmarks of cancer.

Cancer can arise from any number of non-specific events that damage the respiratory capacity of cells over time. These events can include carcinogens, radiation, intermittent hypoxia, chronic inflammation, rare inherited mutations, oncogenes, oncogenic viruses, and age. Albert Szent-Györgyi originally referred to the phenomenon by which a broad range of non-specific events could cause cancer through a common pathophysiological mechanism as the “oncogenic paradox” (61). Siddhartha Mukherjee also struggled to explain the oncogenic paradox in his Pulitzer Prize-winning book, The Emperor of All Maladies (62). Thomas Seyfried has shown that the common pathophysiological mechanism linking the non-specific events to cancer is oxidative respiratory dysfunction, thus solving the oncogenic paradox (56, 63).

The path to carcinogenesis will occur only in those cells capable of enhancing energy production through aerobic fermentation (substrate-level phosphorylation, or SLP).  Although aerobic fermentation was thought to involve only glucose (the Warburg effect), Christos Chinopoulos and Seyfried recently showed that glutamine also could drive energy production in cancer cells through SLP at the succinyl CoA ligase step in the mitochondria (18). Despite the shift from respiration to SLP, the ΔG’ of ATP hydrolysis remains fairly constant at approximately -56 kJ, indicating that the energy from SLP compensates for the reduced energy from OxPhos (Figure 1). Indeed, Chinopoulos and Seyfried consider mitochondrial SLP to be the major source of ATP production in some cancer cells. The replacement of OxPhos with SLP ultimately leads to the formation of tumors. This is directly connected to abnormalities in the number, structure, and function of mitochondria (transition from green to red in Figure 1).

The mitochondrial stress response or retrograde signaling (RTG) will initiate the oncogene upregulation and tumor suppressor gene inactivation that are needed to maintain the viability of incipient cancer cells when respiration becomes incapable of maintaining energy homeostasis. The non-specific events that damage respiratory function produce reactive oxygen species (ROS) that are both mutagenic and carcinogenic (64,65). Genomic instability thus will arise as a secondary consequence of protracted mitochondrial stress from disturbances in the intracellular and extracellular microenvironment (66). Oncogenes are simply facilitators of tumor formation as they upregulate those pathways needed for fermentation metabolism.

In other words, the genomic defects seen in tumor cells arise as effects rather than causes of cancer.

Defects in the number, structure, and function of mitochondria can account for the six major hallmarks of cancer as outlined by Douglas Hanahan and Robert Weinberg (2). As normal mitochondrial function maintains the differentiated state of quiescence, a loss of OxPhos leads to the default state of proliferation. Carlos Sonnenschein and Ana Soto showed that proliferation rather than quiescence is the default state of all metazoan cells (67). A return to the default state of proliferation thus can explain the first three cancer hallmarks in Figure 1. As cancer cells ferment, they acidify the microenvironment, thus leading to sustained vascularization or angiogenesis (hallmark 4). This is consistent with the view that many solid tissue cancers behave as unhealed wounds (68). As mitochondria control the cellular kill switch (programmed cell death or apoptosis), defects in mitochondrial function can cause evasion of apoptosis (hallmark 5). Metastasis is the primary cause of mortality in most cancers.

According to the MMT, metastasis arises from respiratory damage in cells of myeloid/macrophage origin (41). See Figure 2 below (published with additional detail in Part 4 of this series on 190208).

Figure 2. The metastatic cascade. A key aspect of metastasis is the non-random manner by which the metastatic cancer cells invade distant organs and tissues, with lung, liver, and bone as some of the more preferred sites. The green cells depicted here are the tumor cells.

The degree of malignancy is linked directly to the energy transition from OxPhos to substrate-level phosphorylation. This scenario links all major cancer hallmarks to an extrachromosomal respiratory dysfunction and can explain the origin of cancer better than can the SMT (56). The T in Figure 1 signifies an arbitrary threshold where the shift from OxPhos to SLP might become irreversible.

Therapeutic Implications for the Mitochondrial Metabolic Origin of Cancer

If cancer is a mitochondrial metabolic disease rather than a disease of somatic mutation, there are significant implications for successful treatment and therapies. Our interest in this series is to explore the evidence for or against the SMT and MMT rather than present a thorough investigation into potential therapies. We note, however, that additional research by Seyfried and Dominic D’Agostino, among others, indicates that metabolic therapies based on the MMT (and considering cancer as a systemic disease regardless of the specific tissue or organ system containing invasive or metastatic tumor cells) may target the metabolic abnormalities in tumor cells while enhancing the metabolic efficiency in normal cells (55, 69). This type of investigation into alternative therapies underscores the need for an accurate understanding of cancer’s nature and origins.

Conclusion

Once again, we note that the credibility of a theory’s explanation of a complicated phenomenon is dependent on the extent to which the theory can explain the facts associated with the phenomenon. The evidence presented in this series indicates that the mitochondrial metabolic theory can explain the facts of cancer better than the somatic mutation theory. An accurate understanding of the nature of cancer is essential to addressing the current cancer crisis via effective therapies.

Related

Is Cancer a Genetic or Metabolic Disease? Part 1
Is Cancer a Genetic or Metabolic Disease? Part 2
Is Cancer a Genetic or Metabolic Disease? Part 3
Is Cancer a Genetic or Metabolic Disease? Part 4
Is Cancer a Genetic or Metabolic Disease? Part 5

Thomas N. Seyfried is professor of biology at Boston College. He received a doctorate in genetics and biochemistry from the University of Illinois—Urbana-Champaign in 1976. He did his undergraduate work at the University of New England, where he recently received the distinguished Alumni Achievement Award. He also holds a master’s degree in genetics from Illinois State University. Seyfried served with distinction in the United States Army’s 1st Cavalry Division during the Vietnam War and received numerous medals and commendations.

He was a postdoctoral fellow in the Department of Neurology at the Yale University School of Medicine and then served on the faculty as an assistant professor in neurology. Seyfried previously served as chair of the Scientific Advisory Committee for the National Tay-Sachs and Allied Diseases Association. He recently received a Lifetime Achievement Award from the Academy of Complementary and Integrative Medicine and the Uncompromising Science Award from the American College of Nutrition for his work on cancer.

He presently serves on several editorial boards, including those for Nutrition & Metabolism, Neurochemical Research, the Journal of Lipid Research, and ASN Neuro. Seyfried has over 180 peer-reviewed publications and is author of the book “Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer” (Wiley Press).

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