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Modifiable Host Factors in Melanoma: Emerging Evidence for Obesity, Diet, Exercise, and the Microbiome

  • Melanoma (RJ Sullivan, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

We discuss how potentially modifiable factors including obesity, the microbiome, diet, and exercise may impact melanoma development, progression, and therapeutic response.

Recent Findings

Obesity is unexpectedly associated with improved outcomes with immune and targeted therapy in melanoma, with early mechanistic data suggesting leptin as one mediator. The gut microbiome is both a biomarker of response to immunotherapy and a potential target. As diet is a major determinant of the gut microbiome, ongoing studies are examining the interaction between diet, the gut microbiome, and immunity. Data are emerging for a potential role of exercise in reducing hypoxia and enhancing anti-tumor immunity, though this has not yet been well-studied in the context of contemporary therapies.

Summary

Recent data suggests energy balance may play a role in the outcomes of metastatic melanoma. Further studies are needed to demonstrate mechanism and causality as well as the feasibility of targeting these factors.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9. https://doi.org/10.1056/NEJMoa1412690.

    Article  CAS  PubMed  Google Scholar 

  3. Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, et al. Overall survival and durable responses in patients with BRAF V600–mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016;34(8):871–8. https://doi.org/10.1200/jco.2015.62.9345.

    Article  CAS  PubMed  Google Scholar 

  4. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16. https://doi.org/10.1056/NEJMoa1103782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. https://doi.org/10.1056/NEJMoa1503093.

    Article  CAS  PubMed  Google Scholar 

  6. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. https://doi.org/10.1056/NEJMoa1302369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kugel CH, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, et al. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res. 2018;24:5347–56. https://doi.org/10.1158/1078-0432.ccr-18-1116.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ecker BL, Kaur A, Douglass SM, Webster MR, Almeida FV, Marino GE, et al. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov. 2019;9(1):82–95. https://doi.org/10.1158/2159-8290.cd-18-0168.

    Article  PubMed  Google Scholar 

  9. Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH 3rd, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532(7598):250–4. https://doi.org/10.1038/nature17392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McQuade JL, Daniel CR, Hess KR, Davies MA. Sex as a predictor of response to cancer immunotherapy. Lancet Oncol. 2018;19(8):e376. https://doi.org/10.1016/s1470-2045(18)30483-2.

    Article  PubMed  Google Scholar 

  11. • Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K. Body fatness and cancer — viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794–8. https://doi.org/10.1056/NEJMsr1606602 Review of the evidence for obesity and cancer risk.

    Article  PubMed  Google Scholar 

  12. Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat Rev Cancer. 2015;15(8):484–98. https://doi.org/10.1038/nrc3967.

    Article  CAS  PubMed  Google Scholar 

  13. Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer. 2011;11(12):886–95. https://doi.org/10.1038/nrc3174.

    Article  CAS  PubMed  Google Scholar 

  14. Goodwin PJ, Stambolic V. Impact of the obesity epidemic on cancer. Annu Rev Med. 2015;66:281–96. https://doi.org/10.1146/annurev-med-051613-012328.

    Article  CAS  PubMed  Google Scholar 

  15. Lee CH, Woo YC, Wang Y, Yeung CY, Xu A, Lam KS. Obesity, adipokines and cancer: an update. Clin Endocrinol. 2015;83(2):147–56. https://doi.org/10.1111/cen.12667.

    Article  CAS  Google Scholar 

  16. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomark Prev. 2002;11(12):1531–43.

    CAS  Google Scholar 

  17. Suzuki R, Orsini N, Saji S, Key TJ, Wolk A. Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis. Int J Cancer. 2009;124(3):698–712. https://doi.org/10.1002/ijc.23943.

    Article  CAS  PubMed  Google Scholar 

  18. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8(12):915–28. https://doi.org/10.1038/nrc2536.

    Article  CAS  PubMed  Google Scholar 

  19. Iyengar NM, Gucalp A, Dannenberg AJ, Hudis CA. Obesity and cancer mechanisms: tumor microenvironment and inflammation. J Clin Oncol. 2016;34(35):4270–6.

    Article  CAS  Google Scholar 

  20. Andersen CJ, Murphy KE, Fernandez ML. Impact of obesity and metabolic syndrome on immunity. Adv Nutr. 2016;7(1):66–75. https://doi.org/10.3945/an.115.010207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sergentanis TN, Antoniadis AG, Gogas HJ, Antonopoulos CN, Adami HO, Ekbom A, et al. Obesity and risk of malignant melanoma: a meta-analysis of cohort and case-control studies. Eur J Cancer. 2013;49(3):642–57. https://doi.org/10.1016/j.ejca.2012.08.028.

    Article  PubMed  Google Scholar 

  22. Skowron F, Berard F, Balme B, Maucort-Boulch D. Role of obesity on the thickness of primary cutaneous melanoma. J Eur Acad Dermatol Venereol. 2014;29:262–9. https://doi.org/10.1111/jdv.12515.

    Article  PubMed  Google Scholar 

  23. Brandon EL, Gu JW, Cantwell L, He Z, Wallace G, Hall JE. Obesity promotes melanoma tumor growth: role of leptin. Cancer Biol Ther. 2009;8(19):1871–9.

    Article  CAS  Google Scholar 

  24. Amjadi F, Javanmard SH, Zarkesh-Esfahani H, Khazaei M, Narimani M. Leptin promotes melanoma tumor growth in mice related to increasing circulating endothelial progenitor cells numbers and plasma NO production. J Exp Clin Cancer Res. 2011;30:21. https://doi.org/10.1186/1756-9966-30-21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gogas H, Trakatelli M, Dessypris N, Terzidis A, Katsambas A, Chrousos GP, et al. Melanoma risk in association with serum leptin levels and lifestyle parameters: a case-control study. Ann Oncol. 2008;19(2):384–9. https://doi.org/10.1093/annonc/mdm464.

    Article  CAS  PubMed  Google Scholar 

  26. Oba J, Wei W, Gershenwald JE, Johnson MM, Wyatt CM, Ellerhorst JA, et al. Elevated serum leptin levels are associated with an increased risk of sentinel lymph node metastasis in cutaneous melanoma. Medicine (Baltimore). 2016;95(11):e3073. https://doi.org/10.1097/MD.0000000000003073.

    Article  CAS  Google Scholar 

  27. Zhang M, Di Martino JS, Bowman RL, Campbell NR, Baksh SC, Simon-Vermot T, et al. Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Discov. 2018;8(8):1006–25. https://doi.org/10.1158/2159-8290.cd-17-1371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fang S, Wang Y, Dang Y, Gagel A, Ross MI, Gershenwald JE, et al. Association between body mass index, C-reactive protein levels, and melanoma patient outcomes. J Invest Dermatol. 2017;137(8):1792–5. https://doi.org/10.1016/j.jid.2017.04.007.

    Article  CAS  PubMed  Google Scholar 

  29. Gopal YNV, Rizos H, Chen G, Deng W, Frederick DT, Cooper ZA, et al. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Cancer Res. 2014;74(23):7037–47. https://doi.org/10.1158/0008-5472.can-14-1392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202–16. https://doi.org/10.1158/2159-8290.CD-15-0283.

    Article  CAS  PubMed  Google Scholar 

  31. •• McQuade J, Daniel C, Hess K, Mak C, Wang D, Rai R, et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 2018;19(3):310–22 First demonstration that obesity associated with improved outcomes with immune and targeted therapy in melanoma in >1900 patients in 6 independent cohorts.

    Article  Google Scholar 

  32. Greenlee H, Unger JM, LeBlanc M, Ramsey S, Hershman DL. Association between body mass index and cancer survival in a pooled analysis of 22 clinical trials. Cancer Epidemiol Biomark Prev. 2017;26(1):21–9. https://doi.org/10.1158/1055-9965.EPI-15-1336.

    Article  Google Scholar 

  33. Kroenke CH, Neugebauer R, Meyerhardt J, Prado CM, Weltzien E, Kwan ML, et al. Analysis of body mass index and mortality in patients with colorectal cancer using causal diagrams. JAMA Oncol. 2016;2(9):1137–45. https://doi.org/10.1001/jamaoncol.2016.0732.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Albiges L, Hakimi AA, Xie W, McKay RR, Simantov R, Lin X, et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations. J Clin Oncol. 2016;34:3655–63. https://doi.org/10.1200/JCO.2016.66.7311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Caan BJ, Meyerhardt JA, Kroenke CH, Alexeeff S, Xiao J, Weltzien E, et al. Explaining the obesity paradox: the association between body composition and colorectal cancer survival (C-SCANS Study). Cancer Epidemiol Biomark Prev. 2017;26(7):1008–15. https://doi.org/10.1158/1055-9965.EPI-17-0200.

    Article  Google Scholar 

  36. Lennon H, Sperrin M, Badrick E, Renehan AG. The obesity paradox in cancer: a review. Curr Oncol Rep. 2016;18(9):56. https://doi.org/10.1007/s11912-016-0539-4.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Renehan AG, Sperrin M. The obesity paradox and mortality after colorectal cancer: a causal conundrum. JAMA Oncol. 2016;2(9):1127–9. https://doi.org/10.1001/jamaoncol.2016.0868.

    Article  PubMed  Google Scholar 

  38. McQuade JL, Daniel CR, Davies MA. Body-mass index and metastatic melanoma outcomes - authors’ reply. Lancet Oncol. 2018;19(5):e227–e8. https://doi.org/10.1016/s1470-2045(18)30266-3.

    Article  PubMed  Google Scholar 

  39. Joosse A, Collette S, Suciu S, Nijsten T, Lejeune F, Kleeberg UR, et al. Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials. J Clin Oncol. 2012;30(18):2240–7. https://doi.org/10.1200/JCO.2011.38.0584.

    Article  PubMed  Google Scholar 

  40. Joosse A, Collette S, Suciu S, Nijsten T, Patel PM, Keilholz U, et al. Sex is an independent prognostic indicator for survival and relapse/progression-free survival in metastasized stage III to IV melanoma: a pooled analysis of five European organisation for research and treatment of cancer randomized controlled trials. J Clin Oncol. 2013;31(18):2337–46. https://doi.org/10.1200/jco.2012.44.5031.

    Article  PubMed  Google Scholar 

  41. Naik GS, Waikar SS, Johnson AEW, Buchbinder EI, Haq R, Hodi FS, et al. Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition. J Immunother Cancer. 2019;7(1):89. https://doi.org/10.1186/s40425-019-0512-5.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979;48(4):633–8. https://doi.org/10.1210/jcem-48-4-633.

    Article  CAS  PubMed  Google Scholar 

  43. Natale CA, Duperret EK, Zhang J, Sadeghi R, Dahal A, O'Brien KT, et al. Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors. Elife. 2016;5. https://doi.org/10.7554/eLife.15104.

  44. Natale CA, Li J, Zhang J, Dahal A, Dentchev T, Stanger BZ, et al. Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade. Elife. 2018;7. https://doi.org/10.7554/eLife.31770.

  45. McQuade JL, Davies MA. Estrogen returns to the stage in melanoma. Pigment Cell Melanoma Res. 2018;31:554–5. https://doi.org/10.1111/pcmr.12706.

    Article  PubMed  Google Scholar 

  46. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–38. https://doi.org/10.1038/nri.2016.90.

    Article  CAS  PubMed  Google Scholar 

  47. Daly LE, Power DG, O'Reilly A, Donnellan P, Cushen SJ, O'Sullivan K, et al. The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. Br J Cancer. 2017;116(3):310–7. https://doi.org/10.1038/bjc.2016.431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cortellini A, Bersanelli M, Buti S, Cannita K, Santini D, Perrone F, et al. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable. J Immunother Cancer. 2019;7(1):57. https://doi.org/10.1186/s40425-019-0527-y.

    Article  PubMed  PubMed Central  Google Scholar 

  49. •• Wang Z, Aguilar EG, Luna JI, Dunai C, Khuat LT, Le CT, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med. 2019;25(1):141–51. https://doi.org/10.1038/s41591-018-0221-5 First mechanistic study of "obesity paradox" in immunotherapy demonstrating that obesity induces T cell exhaustion which can be overcome with PD1 immunotherapy.

    Article  CAS  PubMed  Google Scholar 

  50. Li S, Wang Z, Huang J, Fan J, Du H, Liu L, et al. Systematic review of prognostic roles of body mass index for patients undergoing lung cancer surgery: does the 'obesity paradox' really exist? European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic. Surgery. 2017;51(5):817–28. https://doi.org/10.1093/ejcts/ezw386.

    Article  Google Scholar 

  51. Research WCRFAIfC. Diet, nutrition, physical activity and cancer: a global perspective. 2018.

    Google Scholar 

  52. Yang K, Fung TT, Nan H. An epidemiological review of diet and cutaneous malignant melanoma. Cancer Epidemiol Biomark Prev. 2018;27(10):1115–22. https://doi.org/10.1158/1055-9965.epi-18-0243.

    Article  CAS  Google Scholar 

  53. Soldati L, Di Renzo L, Jirillo E, Ascierto PA, Marincola FM, De Lorenzo A. The influence of diet on anti-cancer immune responsiveness. J Transl Med. 2018;16(1):75. https://doi.org/10.1186/s12967-018-1448-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. 2012;62(4):242–74. https://doi.org/10.3322/caac.21142.

    Article  Google Scholar 

  55. Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Hu FB, Mayer RJ, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007;298(7):754–64. https://doi.org/10.1001/jama.298.7.754.

    Article  CAS  PubMed  Google Scholar 

  56. Kwan ML, Weltzien E, Kushi LH, Castillo A, Slattery ML, Caan BJ. Dietary patterns and breast cancer recurrence and survival among women with early-stage breast cancer. J Clin Oncol. 2009;27(6):919–26. https://doi.org/10.1200/jco.2008.19.4035.

    Article  PubMed  Google Scholar 

  57. Gregg JR, Zheng J, Lopez DS, Reichard C, Browman G, Chapin B, et al. Diet quality and Gleason grade progression among localised prostate cancer patients on active surveillance. Br J Cancer. 2019;120(4):466–71. https://doi.org/10.1038/s41416-019-0380-2.

    Article  PubMed  Google Scholar 

  58. • O'Keefe SJ, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015;6:6342. https://doi.org/10.1038/ncomms7342 Controlled feeding study demonstrating that diet change can rapidly and reproducibly change gut microbiota.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Demark-Wahnefried W, Polascik TJ, George SL, Switzer BR, Madden JF, Ruffin MT, et al. Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery. Cancer Epidemiol Biomark Prev. 2008;17(12):3577–87. https://doi.org/10.1158/1055-9965.epi-08-0008.

    Article  CAS  Google Scholar 

  60. Pierce JP, Natarajan L, Caan BJ, Parker BA, Greenberg ER, Flatt SW, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women’s Healthy Eating and Living (WHEL) randomized trial. Jama. 2007;298(3):289–98. https://doi.org/10.1001/jama.298.3.289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro A, Hoy MK, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst. 2006;98(24):1767–76. https://doi.org/10.1093/jnci/djj494.

    Article  PubMed  Google Scholar 

  62. Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature. 2016;535(7610):75–84. https://doi.org/10.1038/nature18848.

    Article  CAS  PubMed  Google Scholar 

  63. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84. https://doi.org/10.1126/science.aad1329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–9. https://doi.org/10.1126/science.aac4255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia. 2017;19(10):848–55. https://doi.org/10.1016/j.neo.2017.08.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103. https://doi.org/10.1126/science.aan4236.

    Article  CAS  PubMed  Google Scholar 

  67. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359(6371):104–8. https://doi.org/10.1126/science.aao3290.

    Article  CAS  PubMed  Google Scholar 

  68. Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28(6):1368–79. https://doi.org/10.1093/annonc/mdx108.

    Article  CAS  PubMed  Google Scholar 

  69. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7. https://doi.org/10.1126/science.aan3706.

    Article  CAS  PubMed  Google Scholar 

  70. • McQuade JL, Daniel CR, Helmink BA, Wargo JA. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 2019;20(2):e77–91. https://doi.org/10.1016/s1470-2045(18)30952-5 Review of the evidence on role for microbiome in cancer as well as potential for modulation to change outcomes.

    Article  PubMed  Google Scholar 

  71. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;555(7695):210–5. https://doi.org/10.1038/nature25973.

    Article  CAS  PubMed  Google Scholar 

  72. Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell. 2016;167(5):1339–53 e21. https://doi.org/10.1016/j.cell.2016.10.043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Luu M, Weigand K, Wedi F, Breidenbend C, Leister H, Pautz S, et al. Regulation of the effector function of CD8(+) T cells by gut microbiota-derived metabolite butyrate. Sci Rep. 2018;8(1):14430. https://doi.org/10.1038/s41598-018-32860-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. McQuade JL, Gopalakrishnan V, Spencer C, Andrews MA, Helmink BA, Cogdill AP, et al. SMR Congress 2018 Abstracts: the gut microbiome of melanoma patients is distinct from that of healthy individuals and is impacted by probiotic and antibiotic use. Pigment Cell Melanoma Res. 2018;31(1):138–9.

    Google Scholar 

  75. • Spencer C, Gopalakrishnan V, McQuade J, Andrews M, Helmink B, Khan M, et al., editors. The gut microbiome (GM) and immunotherapy response are influenced by host lifestyle factors. Atlanta: American Association for Cancer Research; 2019. Abstract of cohort of melanoma patients treated with anti-PD1 showing that high dietary fiber intake associated with increased abundance of pro-response bacteria and improved response to immunotherapy.

    Google Scholar 

  76. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559–63. https://doi.org/10.1038/nature12820.

    Article  CAS  PubMed  Google Scholar 

  77. Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560:499–503. https://doi.org/10.1038/s41586-018-0343-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yennu Nanda VG, Hu Z, Thiele VM, Heffernan TP, DiFrancesco M, Masrszalek J, et al., editors. Targeting mitochondrial oxidative phosphorylation in de novo and acquired MAPK inhibitor-resistant melanomas. Metabolism and Cancer. Bellevue: AACR; 2015.

    Google Scholar 

  79. Xia S, Lin R, Jin L, Zhao L, Kang HB, Pan Y, et al. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 2017;25(2):358–73. https://doi.org/10.1016/j.cmet.2016.12.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Buffart LM, Kalter J, Sweegers MG, Courneya KS, Newton RU, Aaronson NK, et al. Effects and moderators of exercise on quality of life and physical function in patients with cancer: an individual patient data meta-analysis of 34 RCTs. Cancer Treat Rev. 2017;52:91–104. https://doi.org/10.1016/j.ctrv.2016.11.010.

    Article  PubMed  Google Scholar 

  81. Ballard-Barbash R, Friedenreich CM, Courneya KS, Siddiqi SM, McTiernan A, Alfano CM. Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104(11):815–40. https://doi.org/10.1093/jnci/djs207.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Irwin ML, Smith AW, McTiernan A, Ballard-Barbash R, Cronin K, Gilliland FD, et al. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol. 2008;26(24):3958–64. https://doi.org/10.1200/JCO.2007.15.9822.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kruk J, Aboul-Enein HY. Physical activity in the prevention of cancer. Asian Pac J Cancer Prev. 2006;7(1):11–21.

    PubMed  Google Scholar 

  84. Moore SC, Lee IM, Weiderpass E, Campbell PT, Sampson JN, Kitahara CM, et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med. 2016;176(6):816–25. https://doi.org/10.1001/jamainternmed.2016.1548.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Shors AR, Solomon C, McTiernan A, White E. Melanoma risk in relation to height, weight, and exercise (United States). Cancer Causes Control. 2001;12(7):599–606.

    Article  CAS  Google Scholar 

  86. Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91(3):1071–121. https://doi.org/10.1152/physrev.00038.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Giatromanolaki A, Sivridis E, Kouskoukis C, Gatter KC, Harris AL, Koukourakis MI. Hypoxia-inducible factors 1alpha and 2alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin. Melanoma Res. 2003;13(5):493–501. https://doi.org/10.1097/01.cmr.0000056268.56735.4c.

    Article  CAS  PubMed  Google Scholar 

  88. Loftus SK, Baxter LL, Cronin JC, Fufa TD, Program NCS, Pavan WJ. Hypoxia-induced HIF1alpha targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis. Pigment Cell Melanoma Res. 2017;30(3):339–52. https://doi.org/10.1111/pcmr.12579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lee JT, Herlyn M. Microenvironmental influences in melanoma progression. J Cell Biochem. 2007;101(4):862–72. https://doi.org/10.1002/jcb.21204.

    Article  CAS  PubMed  Google Scholar 

  90. Li H, Chen J, Wang X, He M, Zhang Z, Cen Y. Nodal induced by hypoxia exposure contributes to dacarbazine resistance and the maintenance of stemness in melanoma cancer stemlike cells. Oncol Rep. 2018;39(6):2855–64. https://doi.org/10.3892/or.2018.6387.

    Article  CAS  PubMed  Google Scholar 

  91. Qin Y, Roszik J, Chattopadhyay C, Hashimoto Y, Liu C, Cooper ZA, et al. Hypoxia-driven mechanism of vemurafenib resistance in melanoma. Mol Cancer Ther. 2016;15(10):2442–54. https://doi.org/10.1158/1535-7163.MCT-15-0963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bedogni B, Powell MB. Hypoxia, melanocytes and melanoma - survival and tumor development in the permissive microenvironment of the skin. Pigment Cell Melanoma Res. 2009;22(2):166–74. https://doi.org/10.1111/j.1755-148X.2009.00553.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hanna SC, Krishnan B, Bailey ST, Moschos SJ, Kuan PF, Shimamura T, et al. HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases. J Clin Invest. 2013;123(5):2078–93. https://doi.org/10.1172/JCI66715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. • Betof AS, Lascola CD, Weitzel D, Landon C, Scarbrough PM, Devi GR, et al. Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise. J Natl Cancer Inst. 2015;107(5). https://doi.org/10.1093/jnci/djv040 . This paper was the first to demonstrate that exercise causes vascular normalization and augments chemotherapy-induced tumor growth delay in a preclinical model.

  95. Jones LW, Antonelli J, Masko EM, Broadwater G, Lascola CD, Fels D, et al. Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer. J Appl Physiol (1985). 2012;113(2):263–72. https://doi.org/10.1152/japplphysiol.01575.2011.

    Article  Google Scholar 

  96. Schadler KL, Thomas NJ, Galie PA, Bhang DH, Roby KC, Addai P, et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget. 2016;7(40):65429–40. https://doi.org/10.18632/oncotarget.11748.

    Article  PubMed  PubMed Central  Google Scholar 

  97. •• Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 2016;23(3):554–62. https://doi.org/10.1016/j.cmet.2016.01.011 This paper was the first to demonstrate exercise-induced growth delay in murine models of melanoma, with increased melanoma tumor NK cell infiltration, mediated by epinephrine and IL-6.

    Article  CAS  PubMed  Google Scholar 

  98. • Ashcraft KA, Peace RM, Betof AS, Dewhirst MW, Jones LW. Efficacy and mechanisms of aerobic exercise on cancer initiation, progression, and metastasis: a critical systematic review of in vivo preclinical data. Cancer Res. 2016;76(14):4032–50. https://doi.org/10.1158/0008-5472.CAN-16-0887 Systematic review of the literature of 53 preclinical studies on the effects of exercise on cancer prevention and progression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ashcraft KA, Warner AB, Jones LW, Dewhirst MW. Exercise as adjunct therapy in cancer. Semin Radiat Oncol. 2019;29(1):16–24. https://doi.org/10.1016/j.semradonc.2018.10.001.

    Article  PubMed  Google Scholar 

  100. Abdalla DR, Aleixo AA, Murta EF, Michelin MA. Innate immune response adaptation in mice subjected to administration of DMBA and physical activity. Oncol Lett. 2014;7(3):886–90. https://doi.org/10.3892/ol.2013.1774.

    Article  CAS  PubMed  Google Scholar 

  101. Lu Q, Ceddia MA, Price EA, Ye SM, Woods JA. Chronic exercise increases macrophage-mediated tumor cytolysis in young and old mice. Am J Phys. 1999;276(2):R482–9. https://doi.org/10.1152/ajpregu.1999.276.2.R482.

    Article  CAS  Google Scholar 

  102. Rooney BV, Bigley AB, LaVoy EC, Laughlin M, Pedlar C, Simpson RJ. Lymphocytes and monocytes egress peripheral blood within minutes after cessation of steady state exercise: a detailed temporal analysis of leukocyte extravasation. Physiol Behav. 2018;194:260–7. https://doi.org/10.1016/j.physbeh.2018.06.008.

    Article  CAS  PubMed  Google Scholar 

  103. LaVoy EC, Hussain M, Reed J, Kunz H, Pistillo M, Bigley AB, et al. T-cell redeployment and intracellular cytokine expression following exercise: effects of exercise intensity and cytomegalovirus infection. Phys Rep. 2017;5(1):e13070. https://doi.org/10.14814/phy2.13070.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave., Box 8, New York, NY, 10065, USA

    Allison Betof Warner

  2. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 430, Houston, TX, 77030, USA

    Jennifer L. McQuade

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Jennifer L. McQuade has received compensation from Merck for service as a consultant.

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Warner, A.B., McQuade, J.L. Modifiable Host Factors in Melanoma: Emerging Evidence for Obesity, Diet, Exercise, and the Microbiome. Curr Oncol Rep 21, 72 (2019). https://doi.org/10.1007/s11912-019-0814-2

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