Phoenix Rising

After half a century of extensive (and wildly expensive) research, and vast numbers of clinical trials – ClinicalTrials.gov currently lists 433,955 studies (1) – cancer remains the second-leading cause of death in the United States, after heart disease. It is first or second cause in all developed countries, and it’s getting worse; over the last few decades, the incidence of cancer in adults under 50 years of age has steadily increased in those countries (2). We currently experience a 50% and rising lifetime risk (3, 4).

Shuji Ogino is a professor at Harvard Chan School and Harvard Medical School, and a physician-scientist in the Department of Pathology at the Brigham and Women’s Hospital (2). “The risk is increasing with each generation,’ says Ogino. ‘People born in 1960 experienced higher cancer risk before they turn 50 than people born in 1950, and we predict that this risk level will continue to climb.”

It is not just a matter of a single cancer, which might possibly be attributed to a specific stressor. This is a very general problem, involving cancers of the breast, colorectum, endometrium, esophagus, extrahepatic bile duct, gallbladder, head and neck, kidney, liver, bone marrow, pancreas, prostate, stomach and thyroid. (Cervical cancer, which is significantly prevented by the HPV vaccine, is a notable exception).  

Colorectal cancer is a particular concern; diagnoses in young adults doubled from 11% in 1995 to 20% in 2019 (5).

The fact that so many cancers are increasing in young adults tells us that causative factors are in play from a very early age. The trend also implies that our many defenses against cancer, which we share with most multi-cellular organisms, are being progressively eroded. It is obviously our diet and lifestyle that is doing the damage, but public health today is effectively owned by the pharmaceutical industry. This is why prevention lags behind cancer treatments, which are far more profitable.

This is unfortunate. Despite significant and ongoing advances in cancer survival and treatment success rates, chemotherapeutic drugs generally reach a point of failure.

In some cases they fail in the short to medium term, because the patient dies with overwhelming infection enabled by immunosuppression or from some acute iatrogenic effect. Mostly, however, this approach fails in the longer term because it induces resistance. Initially positive results are generally followed by resurgence, and very often increased malignancy^6-9. Currently, 90% of chemotherapy failure is due to the growth and metastasis of cancers related to drug resistance^{9, 10}.

Solid cancers contain many different types of cancer cells, which function in a coordinated and collective manner. In this sense a tumor is very like an organ, or perhaps even an organism.These different cells are genetically diverse with differing functions, genomes and epigenomes, and hence different susceptibilities^10-12.

Due to this genetic diversity some cancer cells are better able to avoid, sequester, metabolize or excrete drugs, have enhanced repair/increased tolerance to DNA damage or higher antiapoptotic potential. 

The cancer collective responds and attempts to adapt to its microenvironment^{10, 11}, as all living entities do. Apply chemo, and standard Darwinian rules apply. Vulnerable cells die, cells more able to withstand the drug survive and the cancer mass eventually becomes drug-resistant. 

This is like antibiotic resistance, but worse. When treating infection, antibiotics do not kill all the pathogenic bacteria but reduce their numbers to the point where the immune system can take over. Chemo degrades immune function and makes it less able to complete the process, so now the balance of power shifts further to the cancer.

A recent review put it like this: ‘A brief review of the history of cancer research makes one wonder if modern strategies for treating patients with solid tumors may sometimes cause more harm than benefit’¹².

And it gets more complicated. 

In common with all life forms, cancer is driven to survive by a sort of imperative to live, an impulse to grow, continue and breed. This not only occurs at the cellular level, but also at the level of the whole cancer. There is a bewildering interplay of information within the cancer, with multiple mediators exchanging information between different populations of cancer cells and between cancer cells and host cells including connective and immune cells^9-12.

If (when) treatment doesn’t kill all cancer cells outright but leaves a few at the verge of death, some of those cells coopt intracellular machinery normally involved in physiological healing, and rebound into life. This is termed anastasis, Greek for ‘rising to life’^13-23. 

Those cells that do come back are more invasive than before^{12, 13}, and they drive other cancer cells towards compensatory proliferation^{18, 19}. They do so via activation of Caspase-3, a protein normally linked to apoptosis in damaged cells but which can take on an opposite role^17-18, promoting carcinogenesis, metastasis and therapy resistance.

These proliferation-stimulating and pro-survival pathways have been referred to as ‘Phoenix Rising’^{16, 19-23}, with cancer rising from the ashes of the tumor that was targeted by chemo or radiotherapy.  The cancer emerges more ‘determined’ than ever to succeed. This is an important cause of treatment failure.

Next generation immune-modulatory therapies undoubtedly present with improved therapeutic indices. 

Tigilanol tiglate, a small molecule isolated from the seed of the Australian plant Fontainea picrosperma, is generating positive results in animal cancer²⁴. Injected directly into tumors, it promotes a localized immune response which frequently results in complete remission. It has recently been synthesized²⁵, and is currently undergoing clinical trials²⁶.

Generalised immune responses stimulated by various cancer vaccines also look very promising, and Flt3L-NDV combinations and other variants are generating extremely positive results^{ie 27, 28}. 

If they can be made available within reasonable pricing systems the vaccines, tigilanol tiglate and its analogues will likely change the treatment landscape. However, it will be some time before they are available for general use.

All the above makes cancer prevention an attractive option. If we could optimize it and standardize it, we could theoretically reduce the numbers of cancer patients who eventually require treatment. If, perhaps, we could learn the lessons of the past.

In mid-Victorian England cancer was recorded as a relatively minor cause of death, this in a population with an average life expectancy (after age 5) comparable to today’s social classes C and D, which most closely resemble the mid-Victorian population²⁹.

This is reasonably similar to the situation that prevails in contemporary vestigial groups^ie30. Among the Bolivian Tsimane endometrial, ovarian, breast, prostate, lung and colorectal cancers appear to be rare; although cancers with a more infectious etiology, such as cervical cancer, are more common³¹.

It is worth reviewing those factors which might have protected our ancestors, and now appear to be leaving us vulnerable. The Victorian exposome was very different to ours, as represented in the following, far from comprehensive table²⁹:

List of Terms
*MetS = Metabolic Syndrome, NIDDM = Non Insulin-Dependent Diabetes
*Beta-glucuronidase = enzyme produced in higher levels during dysbiosis, leading to release of free estrogen in the gut, re-uptake and higher plasma levels of estrogen
*LPS = Lipopolysaccharides. Produced in higher levels during dysbiosis, cause chronic inflammation in gut, leaky gut and chronic inflammation in other tissues
*Phytonutrients (polyphenols, carotenoids etc) induce cancer cell redifferentiation, mid-cell cycle arrest and apoptosis. They also stabilize the ECM (extra-cellular matrix), slowing angiogenesis, tumorigenesis and metastasis.
*Phase 2 inducers. Detoxifying (conjugating) enzymes, primarily in the liver, that accelerate excretion of carcinogens
*AMPK = AMP-activated protein kinase. Known as the energy master-switch.
*mTORC = Mammalian target of rapamycin. mTORC 1 and 2 promote cell growth, proliferation and survival.

In summary, the mid-Victorian metabolism was very unlike ours, and was cancer-hostile
where ours is cancer-permissive.

Cancer cells were likely being formed in the bodies of Victorians at the same rate as today, but they were emerging in a well-defended environment. The cancer statistics of the period³², while imperfect, suggest that relatively few of those cancers achieved clinical significance. 

The Victorian diet consisted almost exclusively of basic produce with low calorific / high phytonutrient density²⁹, and contained none of the ultra-processed foods which dominate today’s diet and are increasingly linked to cancer^33-35. Their cooking techniques were generally low temperature ie below 100C, spirits were seldom consumed and tobacco seldom smoked, although taken as snuff²⁹.

In an age before IT and the internal combustion engine, men and women were also physically very active²⁹. Type 2 Diabetes, a leading cause of cancer deaths today³⁶, was rare ³⁷, as was obesity. 

Due to the mid-Victorian exposome, the mid-Victorian milieu interieur was anti-inflammatory, euglycemic and eubiotic. It was more immune-competent than ours, with b-glucan mediated up-regulated innate immunity^38-40 and an enhanced TH1/TH2 Ratio⁴¹. It was replete with polyphenols, carotenoids and a range of other phytonutrients which inter alia promote cancer cell re-differentiation, cell-cycle arrest, apoptosis and ferroptosis, cell contact inhibition, enhanced innate immune functions and ECM stabilisation^42-51.

Cancer cells emerging in this terrain were confronted with multiple barriers to survival and growth.

In marked contrast the modern milieu tends to be pro-inflammatory, immune-compromised, hyper-glycemic, dysbiotic and depleted in chemo-preventive phytonutrients. It is exposed to higher intakes of cooked meat and similar carcinogens, and the industrial diet’s reduced content of phase 2-inducing phytochemicals likely extends their half-life.

Our lower intakes of prebiotic fiber create an unhealthier colonic microbiota⁵², with shifts in estrogen and estrogen metabolites linked to an increased risk of breast cancer^52-54.  Prostate cancer risk may also be affected, although the data are diverse. Our lower levels of physical activity lead inter alia to increased obesity, Type 2 diabetes and mTOR signalling⁵⁵. 

The multiple lines of defense that eukaryotes like ourselves had to develop in order to win the prisoners’ dilemma posed by our single cell prokaryote ancestors, have been degraded by the modern lifestyle; and the evidence that these changes have made our bodies more cancer-friendly can be clearly seen in current public health trends.

It will be objected that many micro- and phytonutrients have been tried as single agents in cancer models, and found wanting. This is entirely unsurprising, and is more of a reflection of today’s mono-therapeutic / pharmaceutical mind-set than of the way in which a pre-transitional diet and lifestyle operate to provide very many obstacles to cancer progression. This resembles antimicrobial or chemotherapeutic polypharmacy, where multiple agents are co-administered to make it more difficult for the target to acquire resistance.

This cancer-hobbling is hinted at in mid-Victorian cancer statistics^{32, 56}. 

Daniel McLachlan was Principal Medical Officer of the Royal Chelsea Hospital in London between 1840 and 1863, with ongoing responsibility for over 500 patients. His magnum opus ‘A Practical Treatise on the Diseases and Infirmities of Advanced Life’, published in 1863, was a leading geriatric medicine textbook of the time.

In 800 pages of detailed clinical observations he makes only a few references to cancer (primarily of the GI tract), and describes a series of 854 death records which included only 47 cases of cancer⁵⁶.

At a 5.5% incidence, mid-Victorian overall cancer rates were approximately 10% of ours, if McLachlan’s figures are accurate. Given the technology of the time, how much weight can we put on them?

While he and his colleagues’ ability to detect cancer at an early stage was considerably less advanced than our own, the data noted here are based on autopsies conducted by physicians who recorded cancer without prejudice, and who were certainly able to identify gross tumors post mortem. The leukemias, too, were already well characterised by that time⁵⁷.

The mid-Victorian autopsy data may therefore reflect, however imperfectly, the 10% of cancer subjects in whom a genetic risk factor can be identified. McLachlan alludes to this, noting a strong familial disposition to ie stomach cancer⁵⁶. He could see a link that is today largely obscured by the larger numbers of cancers occurring in individuals without genetic risk, but subject to a cancer-promoting exosome. 

There is another apparent key point of difference between ourselves and the mid-Victorians. 

We expect the incidence of cancer to rise exponentially with age, in line with the declining ability of our many checkpoint systems. I believe that this pattern may in fact be an artefact, due to the extensive disrepair of our multiple cancer defenses. Cancer cells arriving at any age are likely to survive and, over time, present as clinical disease. Given a similar number of cancer cells being added to the total per unit of time, the rate of clinical emergence will undoubtedly increase as we age and our immune systems decline.

In a mid-Victorian, cancer cells emerging at any age were subject to multiple barriers to progress, and generally failed to thrive. Among the mid-Victorians this reportedly produced a different temporal frequency of clinical cancers, with an average age of presentation of circa 40^58-60 compared to 60 today.

This suggests that a significant number of these cases may have been genetically susceptible ones, as suggested above; and if this is indeed the case, it would then follow that mid-Victorians without genetic risk factors were substantially less at risk than their counterparts today.  

Finally, and for comparative purposes, it is interesting to consider cancer rates in other animals. Among 42 species of primates kept in controlled and optimised conditions (ie without predation and with minimal risk of trauma), the cancer mortality rate is circa 5%⁶¹. This more closely resembles vestigial and reported mid-Victorian rates than our own, and appears to make contemporary Homo sapiens an outlier.

A strategy to reduce exposure to carcinogenic factors, up-regulate all of our many anti-cancer defenses and perhaps restore or at least move towards mid-Victorian rates of cancer, starts with abstention from tobacco and alcoholic spirits, and minimization or avoidance of ultra-processed foods.

The second step adds weight maintenance and talking part in some form of physical activity for at least an hour a day⁶².

A third step may eventually involve nutritional enhancement via functional foods and supplements designed specifically to recreate a pre-transitional metabolome. This could be achieved by combining an omega-3 HUFA / amphiphile polyphenol combination, a blend of different length prebiotic fibers and a comprehensive micro- and phytonutrient support program designed to reproduce the mid-Victorian profile.

This strategy may not only help reduce the numbers of patients requiring cancer treatment, but also provide support to those who have been treated and are now in remission, a group for which we currently have no substantive recommendations. Its efficacy will theoretically be measurable via pending blood pre-cancer blood tests Galleri, PanSeer, CancerSEEk et al, and eventually by clinical cancer rates.

The entrée to such a program depends on the food industry developing healthier products than the foods they currently sell. With their help, we might have a chance to set a global preventive program in place, and raise our public health from the ashes where it currently languishes.

It is not, however, exclusively about food. 

Whereas a sedentary lifestyle increases the risk of cancer by up to 80%⁶², small amounts of physical activity (less than an hour a day) reduces the risk of 13 different cancers^{63, 64}. Low levels of physical activity were associated in these studies with the largest reduction in mortality risk, with increasing physical activity producing progressively less benefit; which is odd, because other scientists have found that high levels of aerobic activity inhibit metastasis⁶⁵. 

The risk reduction at low levels of activity is said to be mediated via reduction of insulin, inflammation and body weight, with some immune enhancement. Higher levels of activity may protect against metastasis via nutrient competition (‘starving the cancer’) and via induced changes in AMPK and mTOR activation^{65, 66}. 

A recent meta-analysis, which indicated that up to 70% of premature cancer deaths world-wide were theoretically preventable via lifestyle change⁶⁷, supports my general thesis.

Choose life.

Next week: Caution, I’m Hot.

• An amended version of this post was published as a scientific paper. ‘Back to the Future: a 19^th century Perspective on Cancer.’ Chandra-Khan A, Clayton P. Medical Research Archives, European Society of Medicine. [online] 11(10), October 31st, 2023

References

1. https://clinicaltrials.gov/ct2/resources/trends  Accessed December 9^th 2022
2. Ugai T, Sasamoto N, Lee HY, Ando M, Song M, Tamimi RM, Kawachi I, Campbell PT, Giovannucci EL, Weiderpass E, Rebbeck TR, Ogino S. Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat Rev Clin Oncol. 2022 Oct;19(10):656-673.
3. NIH National Cancer Institute ‘21. https://www.cancer.gov/about-cancer/understanding/statistics#:~:text=Approximately%2039.5%25%20of%20men%20and,will%20die%20of%20the%20disease.  Accessed December 11^th, 2022
4. Cancer Research UK ’21. https://www.cancerresearchuk.org/health-professional/cancer-statistics/risk/lifetime-risk#heading-Zero     Accessed December 11^th, 2022
5. Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023 May-Jun;73(3):233-254.
6. Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, Xue EA, Cheng E, D’Alfonso TM, Jones JG, Anampa J, Rohan TE, Sparano JA, Condeelis JS, Oktay MH. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med. 2017 Jul 5;9(397):eaan0026.
7. Hughes R, Qian BZ, Rowan C, Muthana M, Keklikoglou I, Olson OC, Tazzyman S, Danson S, Addison C, Clemons M, Gonzalez-Angulo AM, Joyce JA, De Palma M, Pollard JW, Lewis CE. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 2015;75:3479–3491.
8. Roodhart JML, He H, Daenen LGM, Monvoisin A, Barber CL, van Amersfoort M, Hofmann JJ, Radtke F, Lane TF, Voest EE, Iruela-Arispe ML. Notch1 regulates angio-supportive bone marrow–derived cells in mice: Relevance to chemoresistance. Blood. 2013;122:143–153.
9. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull. 2017 Sep;7(3):339-348.
10. Mirzayans R., Murray D. Intratumor heterogeneity and therapy resistance: Contributions of dormancy, apoptosis reversal (anastasis) and cell fusion to disease recurrence. Int. J. Mol. Sci. 2020;21:1308.
11. Herbein G, Nehme Z. Polyploid giant cancer cells, a hallmark of oncoviruses and a new therapeutic challenge. Front. Oncol. 2020;10:567116.
12. Mirzayans R, Murray D. What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit? Int J Mol Sci. 2022 Oct 30;23(21):13217.
13. Zaitceva V, Kopeina GS, Zhivotovsky B. Anastasis: Return journey from cell death. Cancers. 2021;13:3671.
14. Tang HM, Tang HL. Anastasis: Recovery from the brink of cell death. R. Soc. Open Sci. 2018;5:180442.
15. Mohammed RN, Khosravi M, Rahman HS, Adili A, Kamali N, Soloshenkov PP, Thangavelu L, Saeedi H, Shomali N, Tamjidifar R, Isazadeh A, Aslaminabad R, Akbari M. Anastasis: cell recovery mechanisms and potential role in cancer. Cell Commun Signal. 2022 Jun 3;20(1):81.
16. Seervi M, Sumi S, Chandrasekharan A, Sharma AK, Santhosh Kumar TR. Molecular profiling of anastatic cancer cells: Potential role of the nuclear export pathway. Cell Oncol. 2019;42:645–661.
17. Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, Li CY. Apoptotic cells activate the ‘‘phoenix rising’’ pathway to promote wound healing and tissue regeneration. Sci. Signal. 2010;3:ra13.
18. Ng W-L, Huang Q, Liu X, Zimmerman M, Li F, Li C-Y. Molecular mechanisms involved in tumor repopulation after radiotherapy. Transl. Cancer Res. 2013;2:442–448.
19. Cheng J, Tian L, Ma J, Gong Y, Zhang Z, Chen Z, Xu B, Xiong H, Li C, Huang Q. Dying tumor cells stimulate proliferation of living tumor cells via caspase-dependent protein kinase Cδ activation in pancreatic ductal adenocarcinoma. Mol. Oncol. 2015;9:105–114.
20. Huang Q, Li F, Liu X, Li W, Shi W, Liu FF, O’Sullivan B, He Z, Peng Y, Tan AC and 10 others. Caspase3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 2011;17:860–866.
21. Zhao R, Kaakati R, Lee AK, Liu X, Li F, Li C-Y. Novel roles of apoptotic caspases in tumor repopulation, epigenetic reprogramming, carcinogenesis, and beyond. Cancer Metastasis Rev. 2018;37:227–236.
22. Corsi F, Capradossi F, Pelliccia A, Briganti S, Bruni E, Traversa E, Torino F, Reichle A, Ghibelli L. Apoptosis as driver of therapy-induced cancer repopulation and acquired cell-resistance (CRAC): A simple in vitro model of Phoenix Rising in prostate cancer. Int. J. Mol. Sci. 2022;23:1152.
23. Liu C, Li CY, Yuan F. Mathematical modeling of the Phoenix Rising pathway. PLoS Comput Biol. 2014 Feb 6;10(2):e1003461.
24. De Ridder TR, Campbell JE, Burke-Schwarz C, Clegg D, Elliot EL, Geller S, Kozak W, Pittenger ST, Pruitt JB, Riehl J, White J, Wiest ML, Johannes CM, Morton J, Jones PD, Schmidt PF, Gordon V, Reddell P. Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC-46). J Vet Intern Med. 2021 Jan;35(1):415-429.
25. Wender PA, Gentry ZO, Fanelli DJ, Luu-Ngoyen QH, McAteer OD, Njoo E. Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues. Nat. Chem. (2022). https://doi.org/10.1038/s41557-022-01048-2
26. Panizza BJ, de Souza P, Cooper A, Roohullah A, Karapetis CS, Lickliter JD. Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46). EBioMedicine. 2019 Dec;50:433-441.
27. Marron TU, Schwartz M, Corbett V, Merad M. Neoadjuvant Immunotherapy for Hepatocellular Carcinoma. J Hepatocell Carcinoma. 2022 Jun 30;9:571-581.
28. Svensson-Arvelund J, Cuadrado-Castano S, Pantsulaia G, Kim K, Aleynick M, Hammerich L, Upadhyay R, Yellin M, Marsh H, Oreper D, Jhunjhunwala S, Moussion C, Merad M, Brown BD, García-Sastre A, Brody JD. Expanding cross-presenting dendritic cells enhances oncolytic virotherapy and is critical for long-term anti-tumor immunity. Nat Commun. 2022 Nov 22;13(1):7149.
29. Clayton P, Rowbotham J. How the mid-Victorians worked, ate and died. Int J Environ Res Public Health. 2009 Mar;6(3):1235-53.
30. Gurven M, Kaplan H, Zelada Supa A. 2007. Mortality experience of Tsimanen Amerindians of Bolivia: regional variation and temporal trends. Am J Hum Biol 19: 376-398.
31. Stieglitz J, Blackwell AD, Gutierrez, RQ, Linares, EC, Gurven M, Kaplan H. (2012). Modernization, sexual risk-taking, and gynecological morbidity among Bolivian forager-horticulturalists. PLoS ONE, 7, e50384.
32. Charlton J, Murphy M, editors. The Health of Adult Britain 1841–1994. 2 volumes. London: National Statistics; 2004.
33. Fiolet T, Srour B, Sellem L, Kesse-Guyot E, Allès B, Méjean C, Deschasaux M, Fassier P, Latino-Martel P, Beslay M, Hercberg S, Lavalette C, Monteiro CA, Julia C, Touvier M. Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort. BMJ. 2018 Feb 14;360:k322.
34. Srour B, Fezeu LK, Kesse-Guyot E, Allès B, Méjean C, Andrianasolo RM, Chazelas E, Deschasaux M, Hercberg S, Galan P, Monteiro CA, Julia C, Touvier M. Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Santé). BMJ. 2019 May 29;365:l1451.
35. Chang K, Gunter MJ, Rauber F, Levy RB, Huybrechts I, Kliemann N, Millett C, Vamos EP. Ultra-processed food consumption, cancer risk and cancer mortality: a large-scale prospective analysis within the UK Biobank. eClinical Med. Published: January 31, 2023DOI:https://doi.org/10.1016/j.eclinm.2023.101840
36. Ling S, Zaccardi F, Issa E, Davies MJ, Khunti K, Brown K. Inequalities in cancer mortality trends in people with type 2 diabetes: 20 year population-based study in England. Diabetologia. 2023 Jan 24. doi: 10.1007/s00125-022-05854-8.
37. Osler W: The Principles and Practice of Medicine. New York, D. Appleton and Company,1892
38. LeBlanc BW, Albina JE, Reichner JS. The effect of PGG-beta-glucan on neutrophil chemotaxis in vivo. J Leukoc Biol. 2006 Apr;79(4):667-75.
39. Lee YJ, Paik DJ, Kwon DY, Yang HJ, Park Y. Agrobacterium sp.-derived β-1,3-glucan enhances natural killer cell activity in healthy adults: a randomized, double-blind, placebo-controlled, parallel-group study. Nutr Res Pract. 2017 Feb;11(1):43-50.
40. Hong F, Yan J, Baran JT, Allendorf DJ, Hansen RD, Ostroff GR, Xing PX, Cheung NK, Ross GD. Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models. J Immunol. 2004 Jul 15;173(2):797-806.
41. Kirmaz C, Bayrak P, Yilmaz O, Yuksel H. Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis: a double-blind placebo-controlled study. Eur Cytokine Netw. 2005 Jun;16(2):128-34.
42. Kang HJ, Youn YK, Hong MK, Kim LS. Antiproliferation and redifferentiation in thyroid cancer cell lines by polyphenol phytochemicals. J Korean Med Sci. 2011 Jul;26(7):893-9.
43. Barth TJ, Zöller J, Kübler A, Born IA, Osswald H. Redifferentiation of oral dysplastic mucosa by the application of the antioxidants beta-carotene, alpha-tocopherol and vitamin C. Int J Vitam Nutr Res. 1997;67(5):368-76.
44. Marzocco S, Singla RK, Capasso A. Multifaceted Effects of Lycopene: A Boulevard to the Multitarget-Based Treatment for Cancer. Molecules. 2021 Sep 2;26(17):5333.
45. Teodoro AJ, Oliveira FL, Martins NB, Maia Gde A, Martucci RB, Borojevic R. Effect of lycopene on cell viability and cell cycle progression in human cancer cell lines. Cancer Cell Int. 2012;12:36.
46. Palozza P, Simone R.E, Catalano A, Mele MC. Tomato lycopene and lung cancer prevention: From experimental to human studies. Cancers. 2011;3:2333–2357.
47. Kotake-Nara E, Kushiro M, Zhang H, Sugawara T, Miyashita K, Nagao A. Carotenoids affect proliferation of human prostate cancer cells. J. Nutr. 2001;131:3303–3306.
48. Bajalia EM, Azzouz FB, Chism DA, Giansiracusa DM, Wong CG, Plaskett KN, Bishayee A. Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms. Cancers (Basel). 2022 Jul 4;14(13):3278.
49. Bilgin S, Erden Tayhan S, Yıldırım A, Koç E. Investigation of the effects of isoeugenol-based phenolic compounds on migration and proliferation of HT29 colon cancer cells at cellular and molecular level. Bioorg Chem. 2022 Nov 8;130:106230.
50. Renke G, Baesso T, Paes R, Renke A. β-Glucan “Trained Immunity” Immunomodulatory Properties Potentiate Tissue Wound Management and Accelerate Fitness Recovery. Immunotargets Ther. 2022 Oct 17;11:67-73.
51. De Marco Castro E, Calder PC, Roche HM. β-1,3/1,6-Glucans and Immunity: State of the Art and Future Directions. Mol Nutr Food Res. 2021 Jan;65(1):e1901071.
52. Zengul AG, Demark-Wahnefried W, Barnes S, Morrow CD, Bertrand B, Berryhill TF, Frugé AD. Associations between Dietary Fiber, the Fecal Microbiota and Estrogen Metabolism in Postmenopausal Women with Breast Cancer. Nutr Cancer. 2021;73(7):1108-1117.
53. Kwa M, Plottel CS, Blaser MJ, Adams S. The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. J Natl Cancer Inst. 2016 Apr 22;108(8):djw029.
54. Farvid MS, Spence ND, Holmes MD, Barnett JB. Fiber consumption and breast cancer incidence: A systematic review and meta-analysis of prospective studies. Cancer. 2020 Jul 1;126(13):3061-3075.
55. Agostini D, Natalucci V, Baldelli G, De Santi M, Donati Zeppa S, Vallorani L, Annibalini G, Lucertini F, Federici A, Izzo R, Stocchi V, Barbieri E. New Insights into the Role of Exercise in Inhibiting mTOR Signaling in Triple-Negative Breast Cancer. Oxid Med Cell Longev. 2018 Sep 30;2018:5896786.
56. McLauchlan D. A Practical Treatise on the Diseases and Infirmities of Advanced Life. Neill & Company, Edinburgh 1863. Page 31
57. Kampen KR. The discovery and early understanding of leukemia. Leuk Res. 2012 Jan;36(1):6-13.
58. ‘Cancer Hospital London’. Nottinghamshire Guardian, 2 August 1851: ‘The medical report stated that more than five females to one male were affected with the disease of cancer, predominantly breast cancer, and that about the age of 43 years was the average at which women were affected.’
59. ‘Cancer Hospital’. Oxford University and City Herald, 26 December 1863: ‘There were 1,481 rases in which the cancerous afflictions had reached the second stage of the malady. The average duration of the diseases previous to coming to the hospital was three years, and the average age the patients 43 years.’
60. ‘The Health of London During the Week’. Morning Post, 1 May 1850: ‘The deaths of 20 persons, of whom 18 were women, were the results of cancer, and all occurred between 35 years of age and 50.’
61. Vincze O, Colchero F, Lemaître JF, Conde DA, Pavard S, Bieuville M, Urrutia AO, Ujvari B, Boddy AM, Maley CC, Thomas F, Giraudeau M. Cancer risk across mammals. Nature. 2022 Jan;601(7892):263-267.
62. Watts EL, Matthews CE, Freeman JR, Gorzelitz JS, Hong HG, Liao LM, McClain KM, Saint-Maurice PF, Shiroma EJ, Moore SC. Association of Leisure Time Physical Activity Types and Risks of All-Cause, Cardiovascular, and Cancer Mortality Among Older Adults. JAMA Netw Open. 2022 Aug 1;5(8):e2228510.
63. Moore SC, Lee IM, Weiderpass E, Campbell PT, Sampson JN, Kitahara CM, Keadle SK, Arem H, Berrington de Gonzalez A, Hartge P, Adami HO, Blair CK, Borch KB, Boyd E, Check DP, Fournier A, Freedman ND, Gunter M, Johannson M, Khaw KT, Linet MS, Orsini N, Park Y, Riboli E, Robien K, Schairer C, Sesso H, Spriggs M, Van Dusen R, Wolk A, Matthews CE, Patel AV. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. JAMA Intern Med. 2016 Jun 1;176(6):816-25.
64. Minihan AK, Patel AV, Flanders WD, Sauer AG, Jemal A, Islami F. Proportion of Cancer Cases Attributable to Physical Inactivity by US State, 2013-2016. Med Sci Sports Exerc. 2022 Mar 1;54(3):417-423.
65. Sheinboim D, Parikh S, Manich P, Markus I, Dahan S, Parikh R, Stubbs E, Cohen G, Zemser-Werner V, Bell RE, Ruiz SA, Percik R, Brenner R, Leibou S, Vaknine H, Arad G, Gerber Y, Keinan-Boker L, Shimony T, Bikovski L, Goldstein N, Constantini K, Labes S, Mordechai S, Doron H, Lonescu A, Ziv T, Nizri E, Choshen G, Eldar-Finkelman H, Tabach Y, Helman A, Ben-Eliyahu S, Erez N, Perlson E, Geiger T, Ben-Zvi D, Khaled M, Gepner Y, Levy C. An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination. Cancer Res. 2022 Nov 15;82(22):4164-4178.
66. Run Away. Drpaulclayton.eu/blog/running-away/
67. Frick C, Rumgay H, Vignat J, Ginsburg O, Nolte E, Bray F, Soerjomataram I. Quantitative estimates of preventable and treatable deaths from 36 cancers worldwide: a population-based study. Lancet Glob Health. 2023 Nov;11(11):e1700-e1712.