Holistic causes of cancer—finally the end.
Toxicants and detoxification dysfunction
Toxins and Toxicants are words often used interchangeably. However, they are not the same. Toxins are something the body produces. The body is constantly bombarded to Toxicants. Toxins are from within (endogenous), and toxicants are from outside (exogenous). According to Merriam-Webster, Toxins are “a poisonous substance that is a specific product of the metabolic activities of a living organism and is usually very unstable, notably toxic…”. Hormone metabolites can be the perfect example of an endogenous toxin. The estrone metabolite, 4-OH estrone, damages DNA, has a high affinity and binds tightly to estrogen receptors, and increases cancer risk; yet, the body can produce these estrogen metabolites. A simple look at estrogen receptor status or estradiol (most biologically active estrogen) levels constitutes tunnel vision and will miss other endogenous toxins, such as estrogen metabolites.
Other Endotoxins, such as Lipopolysaccharide (LPS), are produced from bacteria in the gut and is also another example of an endogenous toxin that can increase cancer recurrence and metastatic risk. Lipopolysaccharide is an endotoxin produced from gram-negative bacteria. An increase in systemic LPS is often the result of an imbalanced gut microbiome, called dysbiosis [i] [ii]. And just how does the endotoxin LPS increase cancer risk, recurrent, and metastasis? I am so glad you asked. Research points to a direct link between LPS and the up-regulation of Toll-Like Receptor 4 (TLR-4) on cancer cells [iii]. An increase in TLR-4 is one of the mechanisms by which chemotherapy causes chemoresistance and metastasis [iv]. You did read that right. Chemotherapy, just like radiation and surgery, can cause metastasis of the very cancer it is intended to treat. I will discuss this a little more in the gut section below.
In contrast to toxins, toxicants are an exogenous toxic substance. Unfortunately, there are too many examples to choose from here. Politics, both left and right, have corrupted this scientific debate. Mycotoxins (fungal toxins), heavy metals, pesticides… are all examples of toxicants. The interesting thing about toxicants is that they don’t just damage DNA and compromise detoxification to contribute to cancer; many of them can contribute to cancer with their hormonal activity. The heavy metal cadmium (Cd) is referred to as a metalloestrogen because of its high estrogenic activity. Mycotoxins, fungal toxins are also very estrogenic. They are also known as xenoestrogens. They may also be referred to as exogenous estrogens or toxicant estrogens. So, let me set the table, in estrogen receptor positive (ER+) breast cancer patients, I have seen estrogen levels (estradiol and estrone) low, yet estrogenic mycotoxins or cadmium are significantly elevated. This scenario doesn’t even include the possible impact of hormone metabolites discussed in the previous post. That is what a holistic approach to toxins, toxicants, and detoxification looks like. It must encompass the whole of possibilities.
Infections, including viruses, bacteria, parasites, and fungi, are all linked to cancer. The most common link is between viruses and cancer. Current estimates are that viruses directly cause 15% of cancers. Common viruses implicated in cancer include the Epstein-Barr virus (EBV) in lymphomas (Hodgkin’s, non-Hodgkin’s, Burkitt’s), stomach, leiomyosarcomas, and nasopharyngeal carcinoma [v]; Human Papillomavirus (HPV) in specific certain cancer types including esophageal, laryngeal, head and neck, cervical, penile, vaginal, and rectal cancers [vi]; hepatitis B, C and D (HBV, HCV, HDV) in liver cancer [vii] [viii] [ix]; HIV in cervical cancer, Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and colorectal carcinoma [x] [xi]; Human T-lymphotropic virus-1 (HTLV-1) in leukemia and lymphoma [xii]. Not just one virus and not only one cancer type.
Parasites are not as common in the U.S. as in other parts of the world, but not as common does not translate to not at all. As a result, the connection between parasites and cancer is over-looked. Despite the oversight, the link between parasites and cancer is a strong one. The most common relationship is with the fluke parasites. The liver flukes, Opisthorchis viverrini and Clonorchis sinensis can cause cholangiocarcinoma [xiii] [xiv]. The blood flukes are not to be left overshadowed [xv] [xvi] [xvii]. These flukes include Schistosoma japonicum, Schistosoma mansoni, and Schistosoma haematobium. Schistosoma haematobium can cause bladder cancer, but also has been implicated in other adenocarcinomas and squamous cell carcinomas. Schistosoma japonicum can cause colorectal and squamous cell cancer. Schistosoma mansoni can cause liver and colorectal cancer. Not to be outdone, Plasmodium falciparum, one of the causes of malaria, is linked to the development of Burkett’s lymphoma [xviii]. Even tapeworms are implicated in human cancer [xix].
Not all mischief is between viruses and parasites. There is a strong link between bacteria and cancer. Helicobacter pylori is the bacteria that can cause stomach ulcers. Current research points to the presence of Helicobacter pylori and the development of stomach cancer [xx] and lymphoma [xxi]. Helicobacter pylori is what is called a pathogenic bacteria. Not all bacteria are pathogenic. Bacteria can be opportunistic pathogens or not pathogenic at all—called commensal bacteria. Collectively, commensal bacteria is the gut microbiome. There is a powerful connection between the balance of the gut and the health of the individual. It is vital to point out the fact that one of the most significant influences on the gut microbiome is diet. It is known science that the balance or the imbalance of the gut microbiome can favor either health or dis-ease. How? The research into the gut, the gut microbiome, and health versus dis-ease is early. Still, LPS is highlighted as an essential connection between the gut, gut microbiome, and cancer.
Could this be where it all begins? Could the environment of the gut, including the gut microbiome, be key in the development of cancer and essential in the future of cancer treatment? Could diet influence healing versus dis-ease potential through its effects on the gut? Research is early here, but the sunrise view is looking like yes.
A recent study on the question found that diet does influence the toxicity potential of chemotherapy by up to 100 fold [xxii]. The mechanism is through the alteration of the gut microbiome. Now, it is important to realize that this was a human gut microbiome model in earthworms, but the implications are enormous. If diet increases chemotherapy toxicity through the gut microbiome, then it makes sense that the opposite can be true. Of course, this connection is known to be true [xxiii]. Simply stated, diet is the first treatment that dictates treatment toxicity and likely treatment response. Of course, the same would apply to health versus dis-ease potential.
We are at a Galileo threshold moment on cancer. The evidence is leading away from the old paradigm in the causes and treatment of cancer. Whether because of willful or un-willful ignorance, there will be those that are ignorant resistance. The historical perspective has been to look at the solid tumor as the problem. Maybe that is just a distraction or a diversion. The diet, the gut microbiome, the immune system, the TME, and their interrelated connections discussed are the actual frontier in the fight against cancer and the battle for healing.
But how? Is it just theory, yet unproven? Is it an application? Is it evidence-based? A recent study helps to answer these questions. This study highlights the link between the gut, inflammation, and cancer. In this study, the gut microbiome in the presence of a leaky gut was shown to increase LPS endotoxins (gram-negative bacterial toxin) that stimulate increases in TLR4 expression in colorectal cancer. The result is an increase in growth signaling through a significant and heavily utilized cancer growth pathway, the Akt/PI3k/mTOR pathway. The result is an increase in liver metastasis [xxiv]. Bam! Remember, metastasis is linked to a 90% cause of mortality in cancer. This is the same TLR4 receptor mechanism by which chemotherapy [xxv] [xxvi] [xxvii] [xxviii] and surgery [xxix] cause cancer recurrence and metastasis. But, there is so much more. Lipopolysaccharide borne out of an altered gut microbiome and associated leaky gut are linked to insulin resistance [xxx] [xxxi], diabetes [xxxii] [xxxiii], and Alzheimer’s disease [xxxiv]. This effect shows that it is not just about cancer, but many chronic diseases of aging.
The easiest way to change the gut microbiome is not probiotics, but diet. The best probiotic and the best prebiotic is diet. In contrast, the worst probiotic is diet. Diet is a love language with your gut microbiome. Weird, I know. Feed the gut and gut microbiome healthy food, and it will love you back. Feed it junk, don’t be surprised when it gives you trash back.
Is there any evidence that links diet directly to cancer? I have heard many patients recount their Oncologists claim that diet has no connection to cancer. Not only is there a connection, but the mechanism how is described in the published science. This direct connection can be found between Diet—> LPS—> TLR4—> cancer. This direct connection occurs in prostate cancer [xxxv]. This connection has also been implicated in breast cancer development [xxxvi] and colorectal cancer development [xxxvii]and recurrence [xxxviii].
Other associated deficiencies
Cancer is a dis-ease of many different deficiencies. These deficiencies include vitamins and minerals. For example, cancer is a vitamin C deficient state [xxxix], a vitamin D deficient state [xl] [xli], and a vitamin A deficient state [xlii] [xliii]. In addition, cancer is a zinc [xliv] [xlv] and selenium [xlvi] [xlvii] deficiency state. All these deficiencies contribute to immune system compromise, which favors cancer immune escape that is so critical to cancer initiation, survival and spread [xlviii] [xlix] [l] [li] [lii] [liii].
Cancer is a complex process. The last four posts have reviewed a holistic perspective on the causes of cancer. Medical narrow mindedness need not apply here. It is the evidence that applies here. Unfortunately, the story doesn’t end with the points presented in this series. There are many more known and yet to be known contributors to cancer. As a result, the holistic causes of cancer will expand with new knowledge. Stay tuned as we update this expanding arena of ideas on holistic causes and treatments of cancer.
[i] Wang J, Gu X, Yang J, Wei Y, Zhao Y. Gut Microbiota Dysbiosis and Increased Plasma LPS and TMAO Levels in Patients With Preeclampsia. Front Cell Infect Microbiol. 2019;9:409. Published 2019 Dec 3. doi:10.3389/fcimb.2019.00409
[ii] Salguero MV, Al-Obaide MAI, Singh R, Siepmann T, Vasylyeva TL. Dysbiosis of Gram-negative gut microbiota and the associated serum lipopolysaccharide exacerbates inflammation in type 2 diabetic patients with chronic kidney disease. Exp Ther Med. 2019;18(5):3461-3469. doi:10.3892/etm.2019.7943
[iii] Hsu RYC, Chan CHF, Spicer JD, Rousseau MC, Giannias B, Rousseau S, Ferri LE. LPS-Induced TLR4 Signaling in Human Colorectal Cancer Cells Increases β1 Integrin-Mediated Cell Adhesion and Liver Metastasis. Cancer Res. Mar 2011;71(5):1989-1998; DOI: 10.1158/0008-5472.CAN-10-2833
[iv] Rajput S, Volk-Draper LD, Ran S. TLR4 Is a Novel Determinant of the Response to Paclitaxel in Breast Cancer. Mol Cancer Ther. Aug 2013;12(8):1676-1687; DOI: 10.1158/1535-7163.MCT-12-1019
[v] Thompson MP, Kurzrock R. Epstein-Barr Virus and Cancer. Clin Cancer Res. Feb 2004;10(3):803-821;DOI: 10.1158/1078-0432.CCR-0670-3
[vi] Senkomago V, Henley SJ, Thomas CC, Mix JM, Markowitz LE, Saraiya M. Human Papillomavirus–Attributable Cancers — United States, 2012–2016. MMWR Morb Mortal Wkly Rep.2019;68:724–728. DOI: http://dx.doi.org/10.15585/mmwr.mm6833a3
[vii] Brownell J, Polyak SJ. Molecular Pathways: Hepatitis C Virus, CXCL10, and the Inflammatory Road to Liver Cancer. Clin Cancer Res. Mar 2013;19(6):1347-1352; DOI: 10.1158/1078-0432.CCR-12-0928
[viii] Wong Ch, Goh K. Chronic hepatitis B infection and liver cancer. Biomed Imaging Interv J. 2006;2(3):e7. doi:10.2349/biij.2.3.e7
[ix] Abbas Z, Abbas M, Abbas S, Shazi L. Hepatitis D and hepatocellular carcinoma. World J Hepatol. 2015;7(5):777-786. doi:10.4254/wjh.v7.i5.777
[x] Ford RM, McMahon MM, Wehbi MA. HIV/AIDS and Colorectal Cancer: A Review in the Era of Antiretrovirals. Gastroenterol Hepatol (N Y). 2008;4(4):274-278.
[xi] Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol. 2016;7(1):54-86. doi:10.5306/wjco.v7.i1.54
[xii] Mahieux, R., Gessain, A. Adult T-cell leukemia/lymphoma and HTLV-1. Curr Hematol Malig Rep. 2007;2:257–264. https://doi.org/10.1007/s11899-007-0035-x
[xiii] Prueksapanich P, Piyachaturawat P, Aumpansub P, Ridtitid W, Chaiteerakij R, Rerknimitr R. Liver Fluke-Associated Biliary Tract Cancer. Gut Liver. 2018;12(3):236-245. doi:10.5009/gnl17102
[xiv] Sripa B, Kaewkes S, Sithithaworn P, et al. Liver fluke induces cholangiocarcinoma. PLoS Med. 2007;4(7):e201. doi:10.1371/journal.pmed.0040201
[xv] Feng M, Cheng X. Parasite-Associated Cancers (Blood Flukes/Liver Flukes). Adv Exp Med Biol. 2017;1018:193-205. doi:10.1007/978-981-10-5765-6_12
[xvi] Palumbo, Emilio MD. Association Between Schistosomiasis and Cancer: A Review, Infectious Diseases in Clinical Practice. May 2007;15(3):145-148. doi: 10.1097/01.idc.0000269904.90155.ce
[xvii] Lodhia J, Mremi A, Pyuza JJ, Bartholomeo N, Herman AM. Schistosomiasis and cancer: Experience from a zonal hospital in Tanzania and opportunities for prevention. Journal of Surgical Case Reports. May 2020;2020(5). rjaa144, https://doi.org/10.1093/jscr/rjaa144
[xviii] Thorley-Lawson D, Deitsch KW, Duca KA, Torgbor C. The Link between Plasmodium falciparum Malaria and Endemic Burkitt’s Lymphoma-New Insight into a 50-Year-Old Enigma. PLoS Pathog. 2016;12(1):e1005331. doi:10.1371/journal.ppat.1005331
[xix] Muehlenbachs A, Bhatnagar J, Agudelo CA, et al. Malignant Transformation of Hymenolepis nana in a Human Host. N Engl J Med. 2015;373(19):1845‐1852. doi:10.1056/NEJMoa1505892
[xx] Polk DB, Peek RM Jr. Helicobacter pylori: gastric cancer and beyond [published correction appears in Nat Rev Cancer. 2010 Aug;10(8):593]. Nat Rev Cancer. 2010;10(6):403-414. doi:10.1038/nrc2857
[xxi] Nakamura S, Yao T, Aoyagi K, Iida M, Fujishima M, Tsuneyoshi M. Helicobacter pylori and primary gastric lymphoma. Cancer. 1997;79:3-11. doi:10.1002/(SICI)1097-0142(19970101)79:1<3::AID-CNCR2>3.0.CO;2-P
[xxii] Ke, W., Saba, J.A., Yao, C. et al. Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion. Nat Commun 11, 2587 (2020). https://doi.org/10.1038/s41467-020-16220-w
[xxiii] Alexander, J., Wilson, I., Teare, J. et al. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 14, 356–365 (2017). https://doi.org/10.1038/nrgastro.2017.20
[xxiv] Hsu RYC, Chan CHF, Spicer JD, Rousseau MC, Giannias B, Rousseau S, Ferri LE. LPS-Induced TLR4 Signaling in Human Colorectal Cancer Cells Increases β1 Integrin-Mediated Cell Adhesion and Liver Metastasis. Cancer Res. March 2011;71(5):1989-1998; DOI: 10.1158/0008-5472.CAN-10-2833
[xxv] Sun Z, Luo Q, Ye D, Chen W, Chen F. Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis. Mol Cancer. 2012;11:33. Published 2012 May 14. doi:10.1186/1476-4598-11-33
[xxvi] Ran S. The Role of TLR4 in Chemotherapy-Driven Metastasis. Cancer Res. 2015;75(12):2405-2410. doi:10.1158/0008-5472.CAN-14-3525
[xxvii] Wang AC, Su QB, Wu FX, Zhang XL, Liu PS. Role of TLR4 for paclitaxel chemotherapy in human epithelial ovarian cancer cells. Eur J Clin Invest. 2009;39(2):157-164. doi:10.1111/j.1365-2362.2008.02070.x
[xxviii] Volk-Draper L, Hall K, Griggs C, et al. Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res. 2014;74(19):5421-5434. doi:10.1158/0008-5472.CAN-14-0067
[xxix] O’Leary DP, Bhatt L, Woolley JF, et al. TLR-4 signalling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1. PLoS One. 2012;7(10):e44176. doi:10.1371/journal.pone.0044176
[xxx] Pedro, M.N., Magro, D.O., da Silva, E.U.P.P. et al. Plasma levels of lipopolysaccharide correlate with insulin resistance in HIV patients. Diabetol Metab Syndr 10, 5 (2018). https://doi.org/10.1186/s13098-018-0308-7
[xxxi] Liang H, Hussey SE, Sanchez-Avila A, Tantiwong P, Musi N (2013) Effect of Lipopolysaccharide on Inflammation and Insulin Action in Human Muscle. PLoS ONE 8(5): e63983. https://doi.org/10.1371/journal.pone.0063983
[xxxii] Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761-1772. doi:10.2337/db06-1491
[xxxiii] Hawkesworth, S., Moore, S., Fulford, A. et al. Evidence for metabolic endotoxemia in obese and diabetic Gambian women. Nutr & Diabetes 3, e83 (2013). https://doi.org/10.1038/nutd.2013.24
[xxxiv] Zhan X, Stamova B, Sharp FR. Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review. Front Aging Neurosci. 2018;10:42. Published 2018 Feb 22. doi:10.3389/fnagi.2018.00042
[xxxv] Parsons JK, Zahrieh D, Mohler JL, et al. Effect of a Behavioral Intervention to Increase Vegetable Consumption on Cancer Progression Among Men With Early-Stage Prostate Cancer: The MEAL Randomized Clinical Trial. JAMA. 2020;323(2):140‐148. doi:10.1001/jama.2019.20207
[xxxvi] Seol MA, Park JH, Jeong JH, Lyu J, Han SY, Oh SM. Role of TOPK in lipopolysaccharide-induced breast cancer cell migration and invasion. Oncotarget. 2017;8(25):40190-40203. doi:10.18632/oncotarget.15360
[xxxvii] Cammarota R, Bertolini V, Pennesi G, Bucci EO, Gottardi O, Garlanda C, et al. The tumor microenvironment of colorectal cancer: stromal TLR-4 expression as a potential prognostic marker. J Transl Med. 2010;8:112.
[xxxviii] Lu CC, Kuo HC, Wang FS, Jou MH, Lee KC, Chuang JH. Upregulation of TLRs and IL-6 as a marker in human colorectal cancer. Int J Mol Sci. 2014;16:159-77.
[xxxix] Maryland CR, Bennett MI, Allan K. Vitamin C deficiency in cancer patients. Palliative Medicine. Jan 2005;19(1):17-20. https://doi.org/10.1191%2F0269216305pm970oa
[xl] Young MRI, Xiong Y. Influence of vitamin D on cancer risk and treatment: Why the variability?. Trends Cancer Res. 2018;13:43‐53.
[xli] Dev R, Del Fabbro E, Schwartz GG, et al. Preliminary report: vitamin D deficiency in advanced cancer patients with symptoms of fatigue or anorexia. Oncologist. 2011;16(11):1637‐1641. doi:10.1634/theoncologist.2011-0151
[xlii] Doldo E, Costanza G, Agostinelli S, et al. Vitamin A, cancer treatment and prevention: the new role of cellular retinol binding proteins. Biomed Res Int. 2015;2015:624627. doi:10.1155/2015/624627
[xliii] Niles R. M. Signaling pathways in retinoid chemoprevention and treatment of cancer. Mutation Research. 2004;555(1-2):81–96. doi: 10.1016/j.mrfmmm.2004.05.020.
[xliv] Prasad AS, Beck FW, Snell DC, Kucuk O. Zinc in cancer prevention. Nutr Cancer. 2009;61(6):879‐887. doi:10.1080/01635580903285122
[xlv] Dhawan DK, Chadha VD. Zinc: a promising agent in dietary chemoprevention of cancer. Indian J Med Res. 2010;132(6):676‐682.
[xlvi] Hughes DJ et al. Prediagnostic selenium status and hepatobiliary cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. The American Journal of Clinical Nutrition, Volume 104, Issue 2, August 2016, Pages 406–414, https://doi.org/10.3945/ajcn.116.131672
[xlvii] Hughes DJ, Fedirko V, Jenab M, et al. Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort. Int J Cancer. 2015;136(5):1149‐1161. doi:10.1002/ijc.29071
[xlviii] Skrajnowska D, Bobrowska-Korczak B. Role of Zinc in Immune System and Anti-Cancer Defense Mechanisms. Nutrients. 2019;11(10):2273. Published 2019 Sep 22. doi:10.3390/nu11102273
[xlix] Rolles B, Maywald M, Rink L. Influence of zinc deficiency and supplementation on NK cell cytotoxicity. J Functional Foods. Sept 2018;48:322-328.
[l] Yildiz A, Kaya Y, Tanriverdi O. Effect of the Interaction Between Selenium and Zinc on DNA Repair in Association With Cancer Prevention. J Cancer Prev. 2019;24(3):146-154. doi:10.15430/JCP.2019.24.3.146
[li] Ferencík M, Ebringer L. Modulatory effects of selenium and zinc on the immune system. Folia Microbiol (Praha). 2003;48(3):417-426. doi:10.1007/BF02931378
[lii] Mikirova N, Riordan N, Casciari J. Modulation of Cytokines in Cancer Patients by Intravenous Ascorbate Therapy. Med Sci Monit. 2016;22:14-25. Published 2016 Jan 3. doi:10.12659/msm.895368