World Cancer Awareness Day – The Metastasis of Misinformation
By Kelsey Mabry, Haverford College Class of 2024
As World Cancer Awareness Day begins its course, millions across the globe dedicate their day to increasing cognizance around this disease. For many, the day, while well-intentioned, is just another reminder of the constant struggle against it, being deeply afflicted by this debilitating disease in every aspect of their life, whether suffering with cancer themselves or helplessly watching a loved one give everything they’ve got to live and win the fight. Yet, annually, despite the billions of dollars invested in treatment and prevention research, incidence and mortality are only increasing (1). Though the research and public focus on cancer is full-throttle, as scientists are oft to do (and understandably so), they see not the forest of cancer research, its progress, and impacts, but only the single tree that is their research focus. Therefore the relative stagnation of cancer treatment efforts in improving patient lives and reducing cancer incidence is likely to go unnoticed. It is only recently that some researchers are beginning to assess this global health crisis through digging up and exploring promising research shelved decades ago, after the discovery of DNA, from which cancer research took a major turn into genetic origins. While advances about our understanding of cancer and major advances in screening techniques did indeed occur through advanced genetic analysis, leading to advanced modes of detection and general prevention, they ultimately made the picture for treatment and cure more complicated as hundreds of oncogenes and tumor suppressor genes have been identified, without any definitive answer as to an underlying pathology that points to a general treatment strategy. Though, through revisiting older research, it would appear that scientists were much closer to understanding the pathogenesis of cancer than previously realized – through metabolic insult to the mitochondria.
Carcinogenesis: Of genes and mitochondria
The costliness of cancer is in part not without due reason. Regardless of the origins proposed, agreement at least seems to rest with principal insult to a complicated intracellular biological system – either genes or mitochondria. And in both theories, the means and the ends of the insult are complex and multifactorial, making research costly. Dozens of environmental stimuli can induce oxidative stress to the mitochondria, and likewise for DNA damage – many risk factors are identifiable. The result of this damage extends from single cells to across-organ systems. As such, treatments are likely to come as a shotgun strategy rather than one silver bullet. No single cause, no single cure. But of course, this does not imply that each and every piece of research literature thus conducted is promising towards this end. Research promoting a theory best substantiating a disease is far more likely to translate to clinical significance than research operating on the assumptions of a fundamentally flawed one.
The current predominating research focus that has seduced the scientific community for decades has been the somatic mutation theory (SMT) of cancer. This theory maintains that the ultimate driver of carcinogenesis is an accumulation of mutations in oncogenes (or cancer promoting genes) and tumor suppressor genes occurring during DNA replication. While widely accepted as irrefutable, even by the National Cancer Institute (2) and more indirectly by the WHO (3), this theory has numerous inconsistencies. Some cancers have no identifiable genetic mutations (4), while normal non-tumor cells can often possess these mutations (5), evidence which should not exist in the face of genetic absolutism. Some of the most damning evidence arises from nuclear transfer experiments (6), in which normal cells infected with a tumor nucleus produced normal cells despite having tumorigenic mutations. In contrast, cells infected with tumor mitochondria produced more tumor cells. An elaborate collection of SMT inconsistencies occur further in several of Seyfried’s papers, the following references not exhaustive: (7–10).
In fact, Seyfried and others propose an alternative to the SMT – the mitochondrial metabolic theory (MMT) of cancer. This theory poses the aforementioned mutations as downstream phenomena of mitochondrial damage to oxidative phosphorylation (OxPhos). This is substantiated by studies showing mitochondrial dyscoupling giving rise to the Warburg effect (11), as well as others showing malignancy regression following restoration of mitochondrial bioenergetics (12). In addition, either numerical, structural or functional mitochondrial abnormalities have been observed in at least 17 different cancer types (13) Cancer is characterized by reactive oxygen species (ROS) accumulation, which is a principal effect of mitochondrial dysfunction and has been shown to induce DNA mutations (14,15). Despite the accumulating evidence of mitochondrial damage in cancer, there remain investigators who dissent with the Warburg theory on the basis that OxPhos/respiration appears to be uncompromised in certain cancers (16,17), though the studies observing this effect either a) often occur in vitro and contradict in vivo observations (18), or b) have unreliable or flawed biomarker assays for mitochondrial function, such as phosphate/oxygen ratios, or even observing relative oxygen consumption rates (OCR) through the Seahorse instrument as a direct marker for ATP synthesis through OxPhos, when bioenergetics paint a more complicated role of oxygen (13,19). The close coupling of mitochondrial health and carcinogenesis, especially in light of its precedence over mutation, is thus worth further investigation, as the SMT has not resulted in significant treatment advances.
In the face of treatment and preventions
How has the MMT translated to treatment? By positing the mitochondria as the center of the problem, researchers can focus on the hallmark metabolic dysregulations in cancers and develop exploitations whether in the form of pharmaceuticals, metabolic therapies, or a combination of both, depending on cancer type, location, progression, and patient considerations. The ketogenic diet is emerging as a surprisingly powerful adjuvant to fulfill this end, though usually supplemented with additional dietary modifications to enhance the anti-tumorigenic effect, such as caloric restriction, fasting, and specific macronutrient formulations (20). Many studies exist in cell lines or rodent models, though clinical evidence is becoming equally pervasive across many cancer types, with many patients showing significant cancer reduction or even elimination with the ketogenic diet, sometimes in addition to current standards of care (21–24) and occasionally performing better than adjunct therapies (though not advised as a monotherapy in most cases (24,25)). Importantly, while peer-reviewed published literature is still fledging, hundreds of informal online testimonials from real patients vouch for the efficacy of carbohydrate restriction in improving their outcomes with cancer, which should feed the demand for formal clinical trials (26).
As we understand the global physiological and social impact of cancer, clinicians are wise to keep therapeutic carbohydrate restriction as a tool in their toolbox of treatment options. Other management strategies are likely to be of need especially when considering individual patient circumstances, such as the cancer type and stage as well as the patient’s capability to follow treatment protocols. The Cancer chapter of the Nutrition Network textbook, Ketogenics: The Science of Therapeutic Carbohydrate Restriction in Human Health, provides further insight on clinical applications of metabolic therapy as adjunct to standards of care, as well as an extensive reference library for the justifications of said therapy, expanding upon those cited here.
The pathology in perspective
In spite of this emerging evidence, mainstream medical and research perspectives, and by consequence, the majority of doctors and patients whom they inform, remain staunchly plant-based (and by extension, carbohydrate-based), and anti-meat (which is high in fat, and part of a ketogenic diet). The Union for International Cancer Control on the official World Cancer Day website actively recommend the viewers to consume diets high in fruits, whole grains, and vegetables, but little to no red meat or salt, as these purportedly increase cancer risk. Their sourcing extends to the World Cancer Research Fund’s 2018 Diet and Cancer Report and colorectal cancer report (of which meat is infamously implicated)(27). Upon further analysis of this report, actual associations of meat and colorectal cancer were more conflicted across studies, with statistical significance in some demographics, but not in others. Egregiously, all of the studies included in this report are of epidemiological data based on a highly fallible questionnaire system, replete with risk ratios below 2 (compare to the causal relationship between tobacco and lung cancer – the risk ratio of which is upwards of 20 (28)) reflecting exceptionally weak risk association that are often replicated in “joke” epidemiology to highlight this shortcoming (29)). By the same token, evidence to support the consumption of whole grains, fruits, and vegetables is of similar caliber, in contrast to clinical trials like the Women’s Health Initiative which found the converse to be true through low fat dietary interventions (by consequence replacement of these foods with fruits, vegetables, and grains). (30) The report explicitly acknowledges the relative weakness of the data presented, and even findings of no statistical significance were largely undermined. Similar pathology is observed in other mainstream research resources when concerning cancer, such as the infamous 2015 International Agency for Research on Cancer (IARC) report in the Lancet Journal of Oncology (31), whose data points are endlessly recycled and regurgitated through these research organization websites despite widespread criticism of similar data flaws used to make sweeping health generalizations for the public. The purported link of red meat and cancer is not only erroneous, but extrapolated to all other cancers via general dietary recommendations both for patients with cancer and others seeking to prevent it.
Similar anti-meat narratives can be found in NCI and WHO informational pages, whose sourcing is equally traceable to this mediocre epidemiology (2,3). Meanwhile, clinical trials, one of the more rigorous forms of evidence, are discounted when results are contrary to this narrative (30,32). It is worth noting that continued advancement of this poorly substantiated dietary hypothesis is the major roadblock to acquire funding for therapeutic carbohydrate restriction in clinical trials, based upon the demonstrably false preconceptions of major cancer-based organizations championing the association of red meat, saturated fat, and cancer through the mainstream echo chambers, convincing funding agencies that a high-fat ketogenic diet is not the treatment, but rather a suicide mission.
Considering this degree of misinformation at stake, and the dire global consequences it is evidently manifesting, this year’s World Cancer Awareness Day at the Nutrition Network should be but a single step in the lifelong pursuit of returning the world of medicine and research back to the metabolic roots from which it stemmed, though mistakenly abandoned. The current approaches to cancer research, treatment, and prevention, though worth bank-breaking amounts, are but pretty pennies compared to the pricelessness of patient lives, which are only being poured down the drain despite the presumably good intentions of those behind these strategies. Moreover, the controlled clinical research desperately needed to counteract this narrative is being subordinated to flawed epidemiology that decides the health of the world instead. It rests upon our shoulders, compelled by Hippocratic virtue and objectivity as good physicians, researchers, coordinators, and scientists, to affront the narrative for the sake of human life, no matter the power and influence of organizations above us.
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- Cancer Facts & Figures 2022. 1930;
- What Is Cancer? – NCI [Internet]. 2007 [cited 2023 Jan 31]. Available from: https://www.cancer.gov/about-cancer/understanding/what-is-cancer
- Cancer [Internet]. [cited 2023 Jan 31]. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer
- Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153–8.
- Yizhak K, Aguet F, Kim J, Hess JM, Kübler K, Grimsby J, et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science. 2019 Jun 7;364(6444):eaaw0726.
- Singh KK, Kulawiec M, Still I, Desouki MM, Geradts J, Matsui SI. Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis. Gene. 2005 Jul 18;354:140–6.
- Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014 Mar;35(3):515–27.
- Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab. 2010 Jan 27;7(1):7.
- Seyfried T. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. John Wiley & Sons; 2012. 482 p.
- Seyfried TN, Chinopoulos C. Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory? Metabolites. 2021 Sep;11(9):572.
- Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol. 2008 Apr 1;18(4):165–73.
- Fosslien E. Cancer morphogenesis: role of mitochondrial failure. Ann Clin Lab Sci. 2008;38(4):307–29.
- Seyfried TN, Arismendi-Morillo G, Mukherjee P, Chinopoulos C. On the Origin of ATP Synthesis in Cancer. iScience. 2020 Nov;23(11):101761.
- Degtyareva NP, Heyburn L, Sterling J, Resnick MA, Gordenin DA, Doetsch PW. Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines. Nucleic Acids Res. 2013 Oct;41(19):8995–9005.
- Galadari S, Rahman A, Pallichankandy S, Thayyullathil F. Reactive oxygen species and cancer paradox: To promote or to suppress? Free Radic Biol Med. 2017 Mar;104:144–64.
- Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011 May;11(5):325–37.
- Sun H, Chen L, Cao S, Liang Y, Xu Y. Warburg Effects in Cancer and Normal Proliferating Cells: Two Tales of the Same Name. Genomics Proteomics Bioinformatics. 2019 Jun 1;17(3):273–86.
- Momcilovic M, Jones A, Bailey ST, Waldmann CM, Li R, Lee JT, et al. In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer. Nature. 2019 Nov;575(7782):380–4.
- Pacini N, Borziani F. Oncostatic-Cytoprotective Effect of Melatonin and Other Bioactive Molecules: A Common Target in Mitochondrial Respiration. Int J Mol Sci. 2016 Mar;17(3):341.
- Li J, Zhang H, Dai Z. Cancer Treatment With the Ketogenic Diet: A Systematic Review and Meta-analysis of Animal Studies. Front Nutr [Internet]. 2021 [cited 2023 Feb 1];8. Available from: https://www.frontiersin.org/articles/10.3389/fnut.2021.594408
- Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, et al. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutr Metab. 2010 Apr 22;7(1):33.
- Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports.: Journal of the American College of Nutrition: Vol 14, No 2 [Internet]. [cited 2023 Feb 1]. Available from: https://www.tandfonline.com/doi/abs/10.1080/07315724.1995.10718495
- Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, et al. Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab. 2015 Mar 25;3(1):3.
- Dr. David Harper – “Ketogenic Diets to Prevent and Treat Cancer (and maybe COVID19)” [Internet]. 2020 [cited 2023 Feb 1]. Available from: https://www.youtube.com/watch?v=DlI6DMZxgBY
- Dr. Dawn Lemanne – “Carbohydrate Restriction in Cancer Therapy” [Internet]. 2017 [cited 2023 Feb 1]. Available from: https://www.youtube.com/watch?v=8RvByLXyoYk
- Cancer Archives [Internet]. Carnivore Diet. [cited 2023 Feb 1]. Available from: https://carnivore.diet/category/success-stories/cancer/
- Diet, nutrition, physical activity and colorectal cancer. 2017;
- Pesch B, Kendzia B, Gustavsson P, Jöckel KH, Johnen G, Pohlabeln H, et al. Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer J Int Cancer. 2012 Sep 1;131(5):1210–9.
- Moosa IA. Blaming suicide on NASA and divorce on margarine: the hazard of using cointegration to derive inference on spurious correlation. Appl Econ. 2017 Mar 28;49(15):1483–90.
- Women’s Health Initiative (WHI) | NHLBI, NIH [Internet]. [cited 2023 Feb 2]. Available from: https://www.nhlbi.nih.gov/science/womens-health-initiative-whi
- Bouvard V, Loomis D, Guyton KZ, Grosse Y, Ghissassi FE, Benbrahim-Tallaa L, et al. Carcinogenicity of consumption of red and processed meat. Lancet Oncol. 2015 Dec 1;16(16):1599–600.
- BARANG. Analysis of colorectal cancer occurrence during surveillance colonoscopy in the dietary Polyp Prevention Trial – Gastrointestinal Endoscopy [Internet]. BARANG LIVE. 2023 [cited 2023 Feb 2]. Available from: https://www.structhome.com/cara-https-www.giejournal.org/article/S0016-5107(04)02765-8/pdf