Exclusive Report from the American Association for Cancer Research Conference

Most forms of cancer are almost entirely preventable. No more than 10% of cancer cases can be attributed to inherited genetic factors, while 90%-95% are caused by lifestyle and environmental factors.¹

Tobacco alone accounts for 25%-30% of cancer deaths, diet for 30%-35%, infections for 15%-20%, and radiation (including ultraviolet light) up to 10%.¹ Being overweight or obese is estimated to cause 4%-20% of cancer deaths.² All of these factors create or lead to chronic inflammation,³ the most common cause of cancer.^1,4

Cells in body tissues are normally “good citizens” that cooperate with other cells to facilitate body function. Cancer cells, by contrast, have no purpose other than to grow and multiply, contributing nothing to body function.

Many cancers are based on abnormal DNA or chromosomes, usually due to lifestyle or environmental DNA damage, but some are the result of inherited mutations.⁵ For example, although mutations in the BRCA1 gene are not common for the general population,^6,7 for those having it, the risk of breast or ovarian cancer before the age of 70 is 65% or 39%, respectively.⁸ (It’s possible that lifestyle differences have some bearing on which BRCA1 carriers do or do not get cancer, but this has not been well studied.)

The two broad classes of genetic defects underlying cancer are (1) overactive oncogenes (genes that accelerate growth and multiplication), and (2) inactivated tumor suppressor genes (genes that normally prevent cancer).

Two of the most common oncogenes are PIK3CA (which promotes cell growth, survival, and motility)⁹ and KRAS (which greatly increases cell glucose uptake).¹⁰ The most common tumor suppressor gene is p53 (which causes cells with defective DNA to self-destruct or stop replicating).¹¹

Cancer begins with gene mutations that increase abnormal growth and replication. Factors that assist these processes enable cancer cells to immortalize, or promote the formation of new blood vessels to nourish the tumor. In more advanced stages, mutations allow cancer to spread to other organs, a process called metastasis. More than 90% of cancer deaths are due to metastasis.¹² To reach the metastatic stage typically requires at least several mutations.¹³ The risk of cancer before age 40 is only about 2%, but by age 80 the risk increases to 50%.¹⁴

In the United States, the six most frequently diagnosed cancers are, in decreasing order: breast, lung, prostate, colorectal, bladder, and skin. The six most common causes of cancer death in the United States are, in decreasing order: lung, colorectal, pancreas, breast, prostate, and liver.¹⁵ Thanks to aggressive efforts to detect breast and prostate cancer in early stages, they are often cured. Pancreatic cancer, by contrast, is usually only detected in more advanced stages.

Normal cells generate most of their energy from glucose and oxygen in the mitochondria. Cancer cells, however, obtain their energy by glucose metabolism outside the mitochondria through glycolysis. Although it is 18 times more efficient to derive energy from glucose in mitochondria,¹⁶ cancer cells compensate by absorbing massive amounts of glucose, with rates of glycolysis up to 200 times greater than normal cells.¹⁷

Cancer cells use glucose primarily as a source of material for building cellular components, rather than for energy.^17,18 High glucose utilization is so characteristic of cancer that cancer imaging with PET scans is based on detection of high glucose utilization.¹⁹

Dichloroacetate (DCA), a non-patented compound, counteracts a protective mechanism used by cancer cells that prevents glucose products from entering mitochondria, which would send the mitochondria into overdrive, resulting in cell death.¹⁸ Life Extension Foundation^® is funding clinical trials to treat cancer patients with DCA.

With this background, let’s review the American Association for Cancer Research annual meeting, which was held April 18-22, 2015, in Philadelphia.

Colorectal Cancer

Grivennikov

Sergei Grivennikov, PhD, assistant professor, Fox Chase Cancer Center, Philadelphia, is a specialist in cancers of the large intestine and rectum. He provided insights on the most frequently mutated gene in colorectal cancer, the adenomatous polyposis coli (APC) gene. This defect is seen in 75% of sporadic colorectal cancers, but is due to an inherited mutation in less than 1% of cases.²⁰

Chronic inflammation, characterized by the release of inflammatory cytokines (proteins) and DNA-damaging oxidants is typically the cause of colorectal gene mutations. Chronic inflammation not only contributes to the initiation of cancer mutations, but to tumor growth and metastasis.¹² Inflammation leads to infiltration of bacteria into tumors, which enhances the inflammation by releasing endotoxins.^21-23 A high-fat diet can result in excessive pro-inflammatory bile acids, which can increase cancer-causing bacteria.²⁴ Calcium can help remove toxic bile acids.^25,26

Trinchieri

Giorgio Trinchieri, MD, director for the Cancer and Inflammation Program, National Cancer Institute, Bethesda, Maryland, is concerned with the fact that inflammation contributes to abnormal bacteria in the gut, and that the abnormal bacteria interfere with anticancer chemotherapy.²⁷ Dr. Trinchieri would like to alter the gut microbiota to improve cancer treatment.²⁸ He recommends the use of probiotics, prebiotics, and transplantation of feces from healthy persons into cancer patients.²⁹ The FDA has been blocking fecal transfer by insisting that human stools are a drug which will require FDA approval before it can be given to patients.³⁰

Jobin

Christian Jobin, PhD, professor of medicine, University of Florida, Gainesville, is concerned with how inflammation induces colorectal cancer. Death from colorectal cancer is at least twice as high in persons with ulcerative colitis or Crohn’s Disease as for the general population.³¹ Dr. Jobin suggests that inflammation encourages expansion of gut microorganisms that can induce cancer,³² including more toxic strains of E. coli bacteria.³³ Even without increasing the number of E. coli, inflammation can increase the propensity of E. coli to induce colorectal cancer.³⁴ Dr. Jobin wants to develop bacteria-killing viruses that are specific for the toxic strains of E. coli most responsible for inflammation and cancer.

Aspirin against Colorectal Cancer

Andrew Chan, MD, program director, Gastroenterology, Massachusetts General Hospital, Boston, has investigated the use of aspirin to prevent colorectal cancer and to improve survival in colorectal cancer patients. Dr. Chan found that women who took the largest amounts of aspirin (325 mg more than 14 times per week) had the greatest (53%) reduction in risk of colorectal cancer.³⁵ But he also found that those women had the highest risk of gastrointestinal bleeding.³⁶ Dr. Chan discovered that aspirin increased survival in colorectal cancer patients with a PIK3CA mutation, but not in patients lacking this mutation.³⁷ Dr. Chan has done genetic screening to better identify colorectal cancer patients who would or would not benefit from aspirin.³⁸ Editor’s note: Studies using lower dose aspirin reduce cancer risk, but not as effectively (by 53%) as reported by Dr. Chan.^98,99

Cervical Cancer

Douglas Lowy, MD, acting director, National Cancer Institute, Bethesda, Maryland, works on vaccination against human papillomavirus (HPV). HPV is nearly always the cause of cervical cancer,³⁹ which is the second most common cause of cancer in women worldwide.⁴⁰ HPV is almost twice as common in less developed countries compared to developed countries,⁴¹ and is the most common sexually transmitted infection, although symptoms are not usually manifest.⁴² A school HPV vaccination program for girls aged 12-17 was introduced in Australia in 2007. Prevalence of the types of HPV vaccinated against dropped to less than a quarter of the initial value in young women by 2011,⁴³ and genital warts among women under 21 dropped from over 11% to less than 1%.⁴⁴ DNA testing for HPV provides 60%- 70% better screening than Pap smears.⁴⁵

The PIK3CA Oncogene Mutation

Vanhaesebroeck

Bart Vanhaesebroeck, PhD, professor, University College London Cancer Institute, London, England, is interested in the PIK3CA subset of PI3K ( PhosphoInositide 3-kinase) as one of the most frequently mutated genes in cancer, occurring in up to 40% of breast cancer cases, more than a third of cancers of the uterus, up to a third of colon cancers, and about a quarter of stomach cancers (among other cancers).⁴⁶ These mutations in PIK3CA result in excessive cell growth, multiplication, metastasis, and inhibition of apoptosis (cell suicide).⁹ PIK3CA mutations are one of the most common oncogene mutations in breast cancer (especially cases associated with increased estrogen response).⁴⁷ PIK3CA-inhibiting substances can not only reduce PIK3CA activity,⁴⁸ but normalize blood vessels, thereby facilitating delivery of other chemotherapeutic agents.⁴⁹

Cancer Stem Cells

Kolev

Vihren Kolev, PhD, senior scientist, Verastem, Inc., Cambridge, Massachusetts, is attempting to eliminate cancer by targeting cancer stem cells. These cells are hard to eliminate. Often, apparently successful eradication of tumors by chemotherapy ultimately ends in failure because surviving cancer stem cells create a new, more resistant tumor. He described markers of cancer stem cells, such as focal adhesion kinase⁵⁰ and aldehyde dehydrogenase 1,^51,52 which have the possibility of making stem cells easier to locate and identify, and thus eliminate.

Mostoslavsky

Raul Mostoslavsky, MD, PhD, associate professor of Medicine, Harvard Medical School, is an expert in sirtuin proteins,⁵³ the most well-known of which is SIRT1. SIRT1 extends the lifespan of yeast, worms, and flies when stimulated by resveratrol.⁵⁴ Dr. Mostoslavsky, however, is most interested in the effect of SIRT6 on cancer. SIRT6 is localized at the telomeres at the end of chromosomes. It helps to maintain genetic stability, and prevents cellular aging.⁵⁵ Dr. Mostoslavsky has demonstrated that SIRT6 maintains genetic stability by assisting with repair of damaged DNA.⁵⁶ Cancer cells are greatly dependent on glycolysis to support rapid growth and multiplication. Dr. Mostoslavsky has shown that SIRT6 opposes this process, that reduction of SIRT6 fosters glycolysis, and that many cancers repress SIRT6.⁵⁷ Life Extension Foundation is funding Dr. Vera Gorbunova to find SIRT6-activating therapies.

Enhancing the Immune System against Cancer

Schumacher

Ton Schumacher, PhD, professor, Netherlands Cancer Institute, Amsterdam, Netherlands, works on using the immune system to fight cancer. The role of the immune system in preventing cancer is apparent from the fact that AIDS victims and transplant recipients taking immune suppressant drugs have an increased risk of cancer.^58,59 Cancer cells are able to evade or suppress the immune system. The journal Science called cancer immunotherapy the “breakthrough of the year” in 2013 because of the discovery of ways to prevent cancer from blocking the immune system.⁶⁰ Cancer that has spread from its tissue of origin (metastatic cancer) is generally incurable. Metastatic melanoma has shown rapid tumor regression in nearly a third of patients receiving these kinds of immunotherapies (checkpoint inhibitors) that prevent cancer from blocking the immune system.⁶⁰ Dr. Schumacher was part of a team that analyzed nearly five million mutations in over 7,000 cancers. Melanoma and lung cancer were found to have the highest frequency of mutations.⁶¹ Cancer cells that have the highest number of mutations, such as melanoma, are the most vulnerable to this type of (checkpoint inhibitor) immunotherapy.⁶²

CRISPR Gene Editing to Fight Cancer

 

Tyler Jacks, PhD, director, Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, has been using the new CRISPR/Cas9 technology, which was developed for editing the human genome in 2013.^63,64 CRISPR/Cas9 is based on a system used by bacteria to defend themselves against viruses. When bacteria are invaded by viruses, the bacteria store part of the virus’s DNA in the genome of their cell, called CRISPR. RNA copied from the CRISPR is attached to a Cas9 cutting enzyme. The RNA then guides the Cas9 enzyme to the virus to cut (and thereby destroy) the virus. CRISPR/Cas9 has been applied to gene editing by designing guide RNAs for specific DNA locations to be edited.⁶³

Dr. Jacks has worked on a team that used CRISPR/Cas9 to cure an inherited disease in a mouse.⁶⁵ He has also used CRISPR/Cas9 to create a mouse model of cancer.⁶⁶ Such models can be used to study the features of many cancer types, and to experiment with potential therapies. Cancer cells can have a high mutation rate, although only a few of the mutations are thought to drive the cancer. CRISPR/Cas9 can be used to distinguish between mutations that drive cancer and mutations which do not. Dr. Jacks anticipates that CRISPR/Cas9 will be used to design immune system cells that target specific cancers.⁶⁷

Conclusions/Interpretations

 

It is an unfortunate fact that almost all of modern medicine is based on treatment of disease, rather than on prevention, most tragically exemplified by cancer, which is so highly preventable. The key to prevention is better lifestyle. Unconventional health practices have the potential to reduce cancer incidence even more than the lifestyle changes advocated by conventional medicine. As I wrote in the December 2015 issue of Life Extension Magazine^®, a low carbohydrate ketogenic diet can provide energy while depriving cancer cells of the amount of glucose they require.

Conventional medicine too often discounts the value of supplements, but many scientific studies demonstrate that supplements can substantially reduce cancer incidence.¹

The key to more curative treatment is early detection. Good breast and prostate examination practices explain why the diagnosis rate for these cancers greatly exceeds the rate of fatality. Colon cancer would be more effectively treated if more people had regular colon examinations. Liver cancer is often due to chronic inflammation resulting from hepatitis. The hepatitis B virus can be prevented by vaccination.⁶⁸ Hepatitis C virus is usually transmitted by unsafe intravenous drug or transfusion practices and unprotected sex, but is now controlled in over 90% of cases.^69,70 Pancreatic cancer has been difficult to detect in early stages, which is why it is so often fatal. Cancer cells often release DNA into the bloodstream, which means that detecting cancer through blood tests (“liquid biopsies”) may be done in the future if standardized techniques can be developed.⁷¹

Notes on Cancer Prevention

There appears to be a link between salt intake and the bacterium Helicobacter pylori, which is associated with stomach cancer. It is possible that these two factors contribute to the development of the disease. In addition, salt intake and other dietary components are likely to damage the stomach mucosal lining, increasing the risk of stomach cancer.⁷² Risk of stomach cancer, colon cancer, and rectal cancer is probably increased by damage to mucous membranes from iron or N-nitroso compounds (NOCs) in red or processed meat.^73-75 Further damage is caused when cooking at high temperatures as this contributes to the formation of cancer-causing heterocyclic amines.⁷⁶ Mucosal damage is also a reason why consuming more than two drinks of alcohol daily increases colorectal cancer risk.⁷⁷ Any amount of alcohol consumption increases the risk of breast cancer in women because alcohol can convert estrogen into carcinogenic forms.^78-81 For women with a BRCA1 mutation, surgical removal of the breasts can result in a reduced breast cancer risk.^82,83

Animals that eat plants and fish that eat fish have increased concentrations of toxic metals in their flesh^84,85 and increased concentrations of organic toxins in their fat.^86-88 Organic toxins like PCBs (polychlorinated biphenyls) persist in the environment and thus accumulate in fat tissue, increasing by many times the risk of melanoma skin cancer (for example).⁸⁹ Because these toxins can damage DNA and cause cancer, a plant-based diet is safer than an animal-based diet. Chlorophyllin supplements can reduce the cancer-causing potential of toxin exposure.^90,91 (See the December 2015 issue of Life Extension Magazine for more details.)

Selenium supplementation has been shown to reduce cancer incidence.⁹² A double-blind, randomized study showed that zinc supplements improved survival of cancer patients receiving radiation therapy.⁹³ Vitamin D supplementation has been shown to reduce breast cancer incidence.⁹⁴ Curcumin has been shown to inhibit breast cancer metastasis in mice.⁹⁵ Higher quercetin intake is associated with reduced lung cancer incidence.⁹⁶ A randomized, placebo-controlled trial of omega-3 fatty acid (EPA) supplementation showed significantly reduced polyp formation in subjects having an inherited predisposition to colon cancer.⁹⁷ Life Extension Magazine has published many articles about nutrients which can reduce DNA damage by preventing inflammation and adverse gene expression changes, so the above is merely a sampling.

If you have any questions on the scientific content of this article, please call a Life Extension^® Wellness Specialist at 1-866-864-3027.

References

1. Anand P, Kunnumakkara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008;25(9):2097-116.
2. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-38.
3. Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol. 2009;9(4):351-69.
4. Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science. 2013;339(6117):286-91.
5. Salk JJ, Fox EJ, Loeb LA. Mutational heterogeneity in human cancers: origin and consequences. Annu Rev Pathol. 2010;5:51-75.
6. Balmaña J, Díez O, Castiglione M, et al. BRCA in breast cancer: ESMO Clinical Recommendations. Annals of Oncology. 2009;20(suppl 4):iv19-iv20.
7. Available at: https://www.knowbrca.org/provider/fna/about-brca1-brca2-and-hereditary-breast-and-ovarian-cancers. Accessed June 15, 2016.
8. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-30.
9. Ligresti G, Militello L, Steelman LS, et al. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Cell Cycle. 2009;8(9):1352-8.
10. Yun J, Rago C, Cheong I, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325(5947):1555-9.
11. Dashzeveg N, Yoshida K. Cell death decision by p53 via control of the mitochondrial membrane. Cancer Lett. 2015;367(2):108-12.
12. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-99.
13. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339(6127):1546-58.
14. Martincorena I, Campbell PJ. Somatic mutation in cancer and normal cells. Science. 2015;349(6255):1483-9.
15. Available at: http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. Accessed June 8, 2016.
16. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-33.
17. Agnihotri S, Zadeh G. Metabolic reprogramming in glioblastoma: the influence of cancer metabolism on epigenetics and unanswered questions. Neuro Oncol. 2016;18(2):160-72.
18. Lu J, Tan M, Cai Q. The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett. 2015;356(2 Pt A):156-64.
19. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
20. Hinoi T, Akyol A, Theisen BK, et al. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res. 2007;67(20):9721-30.
21. Li Y, Kundu P, Seow SW, et al. Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice. Carcinogenesis. 2012;33(6):1231-8.
22. Grivennikov SI, Wang K, Mucida D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 2012;491(7423):254-8.
23. Kostic AD, Chun E, Meyerson M, et al. Microbes and inflammation in colorectal cancer. Cancer Immunol Res. 2013;1(3):150-7.
24. Sears CL, Garrett WS. Microbes, microbiota, and colon cancer. Cell Host Microbe. 2014;15(3):317-28.
25. Govers MJ, Termont DS, Lapre JA, et al. Calcium in milk products precipitates intestinal fatty acids and secondary bile acids and thus inhibits colonic cytotoxicity in humans. Cancer Res. 1996;56(14):3270-5.
26. Grau MV, Baron JA, Sandler RS, et al. Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. J Natl Cancer Inst. 2007;99(2):129-36.
27. Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967-70.
28. Goldszmid RS, Dzutsev A, Viaud S, et al. Microbiota modulation of myeloid cells in cancer therapy. Cancer Immunol Res. 2015;3(2):103-9.
29. Viaud S, Daillere R, Boneca IG, et al. Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ. 2015;22(2):199-214.
30. Megerlin F, Fouassier E, Lopert R, et al. Faecal microbiota transplantation: a sui generis biological drug, not a tissue. Ann Pharm Fr. 2014;72(4):217-20.
31. Herrinton LJ, Liu L, Levin TR, et al. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology. 2012;143(2):382-9.
32. Arthur JC, Perez-Chanona E, Muhlbauer M, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338(6103):120-3.
33. Buc E, Dubois D, Sauvanet P, et al. High prevalence of mucosa-associated E. coli producing cyclomodulin and genotoxin in colon cancer. PLoS One. 2013;8(2):e56964.
34. Arthur JC, Gharaibeh RZ, Muhlbauer M, et al. Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer. Nat Commun. 2014;5:4724.
35. Chan AT, Giovannucci EL, Meyerhardt JA, et al. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. Jama. 2005;294(8):914-23.
36. Huang ES, Strate LL, Ho WW, et al. Long-term use of aspirin and the risk of gastrointestinal bleeding. Am J Med. 2011;124(5):426-33.
37. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596-606.
38. Nan H, Hutter CM, Lin Y, et al. Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants. Jama. 2015;313(11):1133-42.
39. Arbyn M, Castellsague X, de Sanjose S, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011;22(12):2675-86.
40. Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer. 2004;111(2):278-85.
41. Adegoke O, Kulasingam S, Virnig B. Cervical cancer trends in the United States: a 35-year population-based analysis. J Womens Health (Larchmt). 2012;21(10):1031-7.
42. Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirus among females in the United States, the National Health And Nutrition Examination Survey, 2003-2006. J Infect Dis. 2011;204(4):566-73.
43. Tabrizi SN, Brotherton JM, Kaldor JM, et al. Fall in human papillomavirus prevalence following a national vaccination program. J Infect Dis. 2012;206(11):1645-51.
44. Ali H, Donovan B, Wand H, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. Bmj. 2013;346:f2032.
45. Ronco G, Dillner J, Elfstrom KM, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383(9916):524-32.
46. Samuels Y, Waldman T. Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol. 2010;347:21-41.
47. Zardavas D, Phillips WA, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res. 2014;16(1):201.
48. Foukas LC, Berenjeno IM, Gray A, et al. Activity of any class IA PI3K isoform can sustain cell proliferation and survival. Proc Natl Acad Sci U S A. 2010;107(25):11381-6.
49. Qayum N, Im J, Stratford MR, et al. Modulation of the tumor microvasculature by phosphoinositide-3 kinase inhibition increases doxorubicin delivery in vivo. Clin Cancer Res. 2012;18(1):161-9.
50. Luo M, Fan H, Nagy T, et al. Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells. Cancer Res. 2009;69(2):466-74.
51. Sakakibara M, Fujimori T, Miyoshi T, et al. Aldehyde dehydrogenase 1-positive cells in axillary lymph node metastases after chemotherapy as a prognostic factor in patients with lymph node-positive breast cancer. Cancer. 2012;118(16):3899-910.
52. Alamgeer M, Ganju V, Kumar B, et al. Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer. Breast Cancer Res. 2014;16(2):R44.
53. Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009;460(7255):587-91.
54. Bhullar KS, Hubbard BP. Lifespan and healthspan extension by resveratrol. Biochim Biophys Acta. 2015;1852(6):1209-18.
55. Zhong L, D’Urso A, Toiber D, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140(2):280-93.
56. Toiber D, Erdel F, Bouazoune K, et al. SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell. 2013;51(4):454-68.
57. Sebastian C, Zwaans BM, Silberman DM, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012;151(6):1185-99.
58. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59-67.
59. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565-70.
60. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432-3.
61. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-21.
62. Jacob JA. Cancer Immunotherapy Researchers Focus on Refining Checkpoint Blockade Therapies. Jama. 2015;314(20):2117-9.
63. Mali P, Esvelt KM, Church GM. Cas9 as a versatile tool for engineering biology. Nat Methods. 2013;10(10):957-63.
64. Ledford H. CRISPR: gene editing is just the beginning. Nature. 2016;531(7593):156-9.
65. Yin H, Xue W, Chen S, et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol. 2014;32(6):551-3.
66. Xue W, Chen S, Yin H, et al. CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature. 2014;514(7522):380-4.
67. Sanchez-Rivera FJ, Jacks T. Applications of the CRISPR-Cas9 system in cancer biology. Nat Rev Cancer. 2015;15(7):387-95.
68. Seto WK, Fung J, Yuen MF, et al. Future prevention and treatment of chronic hepatitis B infection. J Clin Gastroenterol. 2012;46(9):725-34.
69. Leleu H, Blachier M, Rosa I. Cost-effectiveness of sofosbuvir in the treatment of patients with hepatitis C. Journal of Viral Hepatitis. 2015;22(4):376-83.
70. Maheshwari A, Thuluvath PJ. Management of acute hepatitis C. Clin Liver Dis. 2010;14(1):169-76; x.
71. Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472-84.
72. Wang XQ, Terry PD, Yan H. Review of salt consumption and stomach cancer risk: epidemiological and biological evidence. World J Gastroenterol. 2009;15(18):2204-13.
73. Larsson SC, Wolk A. Meat consumption and risk of colorectal cancer: a meta-analysis of prospective studies. Int J Cancer. 2006;119(11):2657-64.
74. Zhu H, Yang X, Zhang C, et al. Red and processed meat intake is associated with higher gastric cancer risk: a meta-analysis of epidemiological observational studies. PLoS One. 2013;8(8):e70955.
75. Lewin MH, Bailey N, Bandaletova T, et al. Red meat enhances the colonic formation of the DNA adduct O6-carboxymethyl guanine: implications for colorectal cancer risk. Cancer Res. 2006;66(3):1859-65.
76. Abid Z, Cross AJ, Sinha R. Meat, dairy, and cancer. Am J Clin Nutr. 2014;100 Suppl 1:386s-93s.
77. Cho E, Smith-Warner SA, Ritz J, et al. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med. 2004;140(8):603-13.
78. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. Jama. 1998;279(7):535-40.
79. Boffetta P, Hashibe M. Alcohol and cancer. Lancet Oncol. 2006;7(2):149-56.
80. Hartman TJ, Sisti JS, Hankinson SE, et al. Alcohol Consumption and Urinary Estrogens and Estrogen Metabolites in Premenopausal Women. Horm Cancer. 2016 Feb;7(1):65-74.
81. Castro GD, Castro JA. Alcohol drinking and mammary cancer: Pathogenesis and potential dietary preventive alternatives. World J Clin Oncol. 2014 Oct 10;5(4):713-29.
82. Heemskerk-Gerritsen BAM, Brekelmans CTM, Menke-Pluymers MBE, et al. Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic. Annals of Surgical Oncology. 2007;14(12):3335-44.
83. Kaas R, Verhoef S, Wesseling J, et al. Prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers: very low risk for subsequent breast cancer. Ann Surg. 2010;251(3):488-92.
84. Ginsberg GL, Toal BF. Quantitative approach for incorporating methylmercury risks and omega-3 fatty acid benefits in developing species-specific fish consumption advice. Environ Health Perspect. 2009;117(2):267-75.
85. Poste AE, Muir DC, Guildford SJ, et al. Bioaccumulation and biomagnification of mercury in African lakes: the importance of trophic status. Sci Total Environ. 2015;506-507:126-36.
86. Crinnion WJ. Polychlorinated biphenyls: persistent pollutants with immunological, neurological, and endocrinological consequences. Altern Med Rev. 2011;16(1):5-13.
87. Webster L, Russell M, Walsham P, et al. Halogenated persistent organic pollutants in relation to trophic level in deep sea fish. Mar Pollut Bull. 2014;88(1-2):14-27.
88. Mrema EJ, Rubino FM, Brambilla G, et al. Persistent organochlorinated pesticides and mechanisms of their toxicity. Toxicology. 2013;307:74-88.
89. Gallagher RP, Macarthur AC, Lee TK, et al. Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: a preliminary study. Int J Cancer. 2011;128(8):1872-80.
90. John K, Divi RL, Keshava C, et al. CYP1A1 and CYP1B1 gene expression and DNA adduct formation in normal human mammary epithelial cells exposed to benzo[a]pyrene in the absence or presence of chlorophyllin. Cancer Lett. 2010;292(2):254-60.
91. Nagini S, Palitti F, Natarajan AT. Chemopreventive potential of chlorophyllin: a review of the mechanisms of action and molecular targets. Nutr Cancer. 2015;67(2):203-11.
92. Duffield-Lillico AJ, Reid ME, Turnbull BW, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev. 2002;11(7):630-9.
93. Lin LC, Que J, Lin KL, et al. Effects of zinc supplementation on clinical outcomes in patients receiving radiotherapy for head and neck cancers: a double-blinded randomized study. Int J Radiat Oncol Biol Phys. 2008;70(2):368-73.
94. Garland CF, Gorham ED, Mohr SB, et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103(3-5):708-11.
95. Aggarwal BB, Shishodia S, Takada Y, et al. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 2005;11(20):7490-8.
96. Knekt P, Kumpulainen J, Jarvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr. 2002;76(3):560-8.
97. West NJ, Clark SK, Phillips RK, et al. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut. 2010;59(7):918-25.
98. Friis S, Riis AH, Erichsen R, et al. Low-Dose Aspirin or Nonsteroidal Anti-inflammatory Drug Use and Colorectal Cancer Risk: A Population-Based, Case-Control Study. Ann Intern Med. 2015 Sep 1;163(5):347-55.
99. Ishikawa H, Mutoh M, Suzuki S, et al. The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut. 2014 Nov;63(11):1755-9.