Crossroad between Obesity and Gastrointestinal Cancers: A Review of Molecular Mechanisms and Interventions

Mitra Moodi, Tahmineh Tavakoli, Zoya Tahergorabi

Abstract


The burden of gastrointestinal (GI) cancer is increasing worldwide, and in the past decade, cancer had entered the list of chronic debilitating diseases whose risk is substantially increased by hypernutrition. Obesity may increase the risk of cancer by the imbalance of various mechanisms including insulin and insulin‑like growth factor1 (IGF‑I) signaling, systemic inflammation, immune dysregulation, tumor angiogenesis, adipokines secretion, and intestinal microbiota that usually act interdependently. An increased understanding of the mechanisms underlying obesity‑GI cancer link can provide multiple opportunities for cancer prevention. This review discusses various mechanisms involved molecular mechanisms linking obesity with GI cancers including esophagus, stomach, colorectal and hepatocellular. Furthermore, an optional intervention such as diet restriction and exercise is described, which may be preventive or therapeutic in GI cancer.

Keywords


Gastrointestinal tract; molecular mechanisms; neoplasms; obesity

Full Text:

PDF

References


Blüher M. Obesity: Global epidemiology and pathogenesis. Nat

Rev Endocrinol 2019;15:288‑98.

Organization WH. Obesity and overweight World Health

Organization Website. World Health Organization Website; 2018.

Lauby‑Secretan B, Scoccianti C, Loomis D, Grosse Y,

Bianchini F, Straif K. Body fatness and cancer—Viewpoint of

the IARC Working Group. N Eng J Med 2016;375:794‑8.

Tahergorabi Z, Moodi M, Zardast M, Ghayravani Z, Tavakoli T.

Metabolic syndrome and the risk of gastrointestinal cancer:

A case‑control study. Asian Pac J Cancer Prev 2018;19:2205‑10.

Nock NL, Thompson CL, Tucker TC, Berger NA, Li L.

Associations between obesity and changes in adult BMI over

time and colon cancer risk. Obesity 2008;16:1099‑104.

Alemán JO, Eusebi LH, Ricciardiello L, Patidar K, Sanyal AJ,

Holt PR. Mechanisms of obesity‑induced gastrointestinal

neoplasia. Gastroenterology 2014;146:357‑73.

sadat Yousefi M, Sharifi‑Esfahani M, Pourgholam‑Amiji N,

Afshar M, Sadeghi‑Gandomani H, Otroshi O, et al. Esophageal

cancer in the world: Incidence, mortality and risk factors.

Biomed Res Ther 2018;5:2504‑17.

Bird‑Lieberman EL, Fitzgerald RC. Early diagnosis of

oesophageal cancer. Br J Cancer 2009;101:1‑6.

Pourhoseingholi MA, Vahedi M, Baghestani AR. Burden of

gastrointestinal cancer in Asia; an overview. Gastroenterol

Hepatol Bed Bench 2015;8:19‑27.

Kubo A, Corley DA. Body mass index and adenocarcinomas

of the esophagus or gastric cardia: A systematic review

and meta‑analysis. Cancer Epidemiol Biomarkers Prev

;15:872‑8.

Solaymani‑Dodaran M, Logan R, West J, Card T, Coupland C.

Risk of oesophageal cancer in Barrett’s oesophagus and

gastro‑oesophageal reflux. Gut 2004;53:1070‑4.

Chak A, Falk G, Grady WM, Kinnard M, Elston R, Mittal S,

et al. Assessment of familiality, obesity, and other risk factors

for early age of cancer diagnosis in adenocarcinomas of the

esophagus and gastroesophageal junction. Am J Gastroenterol

;104:1913‑21.

Zheng J, Zhao M, Li J, Lou G, Yuan Y, Bu S, et al.

Obesity‑associated digestive cancers: A review of mechanisms

and interventions. Tumor Biol 2017;39:1010428317695020.

Tahergorabi Z, Khazaei M. The relationship between

inflammatory markers, angiogenesis, and obesity. ARYA

Atheroscler 2013;9:247‑53.

Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF

system in cancer growth and metastasis: Overview and recent

insights. Endocr Rev 2007;28:20‑47.

Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R. Insulin

receptor isoforms and insulin receptor/insulin‑like growth

factor receptor hybrids in physiology and disease. Endocr Rev

;30:586‑623.

El Yafi F, Winkler R, Delvenne P, Boussif N, Belaiche J,

Louis E. Altered expression of type I insulin-like growth factor

receptor in Crohn’s disease. Clin Exp Immunol 2005;139:526‑33.

Gallagher EJ, LeRoith D. Minireview: IGF, insulin, and cancer.

Endocrinology 2011;152:2546‑51.

Doyle SL, Donohoe CL, Finn SP, Howard JM, Lithander FE,

Reynolds JV, et al. IGF‑1 and its receptor in esophageal cancer:

Association with adenocarcinoma and visceral obesity. Am J

Gastroenterol 2012;107:196‑204.

Francois F, Roper J, Goodman AJ, Pei Z, Ghumman M,

Mourad M, et al. The association of gastric leptin with

oesophageal inflammation and metaplasia. Gut 2008;57:16‑24.

Howard J, Beddy P, Ennis D, Keogan M, Pidgeon G,

Reynolds J. Associations between leptin and adiponectin receptor

upregulation, visceral obesity and tumour stage in oesophageal

and junctional adenocarcinoma. Br J Surg 2010;97:1020‑7.

Duggan C, Onstad L, Hardikar S, Blount PL, Reid BJ,

Vaughan TL. Association between markers of obesity

and progression from Barrett’s esophagus to esophageal

adenocarcinoma. Clin Gastroenterol Hepatol 2013;11:934‑43.

Unger RH, Scherer PE. Gluttony, sloth and the metabolic

syndrome: A roadmap to lipotoxicity. Trends Endocrinol Metab

;21:345‑52.

Rubenstein JH, Kao JY, Madanick RD, Zhang M, Wang M,

Spacek MB, et al. Association of adiponectin multimers with

Barrett’s oesophagus. Gut 2009;58:1583‑9.

Ogunwobi O, Beales I. Leptin stimulates the proliferation of

human oesophageal adenocarcinoma cells via HB‑EGF and

TGFα mediated transactivation of the epidermal growth factor

receptor. Br J Biomed Sci 2008;65:121‑7.

Thompson OM, Beresford SA, Kirk EA, Bronner MP,

Vaughan TL. Serum leptin and adiponectin levels and

risk of Barrett’s esophagus and intestinal metaplasia of

the gastroesophageal junction. Obesity (Silver Spring)

;18:2204‑11.

Nasrollahzadeh D, Malekzadeh R, Ploner A, Shakeri R,

Sotoudeh M, Fahimi S, et al. Variations of gastric corpus

microbiota are associated with early esophageal squamous cell

carcinoma and squamous dysplasia. Sci Rep 2015;5:8820.

Patel T, Bhattacharya P, Das S. Gut microbiota: An indicator

to gastrointestinal tract diseases. J Gastrointest Cancer

;47:232‑8.

Yang L, Francois F, Pei Z. Molecular pathways: Pathogenesis

and clinical implications of microbiome alteration in esophagitis

and Barrett esophagus. Clin Cancer Res 2012;18:2138‑44.

Lee S‑J, Park H, Chang JH, Conklin JL. Generation of nitric

oxide in the opossum lower esophageal sphincter during

physiological experimentation. Yonsei Med J 2006;47:223‑9.

Farhood B, Geraily G, Alizadeh A. Incidence and mortality of

various cancers in Iran and compare to other countries: A review

article. Iran J Public Health 2018;47:309‑16.

Chow W‑H, Blot WJ, Vaughan TL, Risch HA, Gammon MD,

Stanford JL, et al. Body mass index and risk of adenocarcinomas

of the esophagus and gastric cardia. J Natl Cancer Inst

;90:150‑5.

Crew KD, Neugut AI. Epidemiology of gastric cancer. World J

Gastroenterol 2006;12:354‑62.

Lagergren J, Bergström R, Nyrén O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia. Ann Intern Med 1999;130:883‑90.

Rastaghi S, Jafari‑Koshki T, Mahaki B, Bashiri Y, Mehrabani K,

Soleimani A. Trends and risk factors of gastric cancer in Iran

(2005–2010). Int J Prev Med 2019;10:79.

Helicobacter and Cancer Collaborative Group. Gastric cancer

and Helicobacter pylori: A combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49:347‑53.

De Ostrovich KK, Lambertz I, Colby JK, Tian J, Rundhaug JE,

Johnston D, et al. Paracrine overexpression of insulin‑like

growth factor‑1 enhances mammary tumorigenesis in vivo. Am J

Pathol 2008;173:824‑34.

Huang YF, Shen MR, Hsu KF, Cheng YM, Chou CY. Clinical

implications of insulin‑like growth factor 1 system in early‑stage

cervical cancer. Br J Cancer 2008;99:1096‑102.

Zhao R, DeCoteau JF, Geyer CR, Gao M, Cui H, Casson AG.

Loss of imprinting of the insulin‑like growth factor II (IGF2)

gene in esophageal normal and adenocarcinoma tissues.

Carcinogenesis 2009;30:2117‑22.

Wang HB, Zhou CJ, Song SZ, Chen P, Xu WH, Liu B,

et al. Evaluation of Nrf2 and IGF‑1 expression in benign,

premalignant and malignant gastric lesions. Pathol Res Pract

;207:169‑73.

Liu W, Yu R, Zhou G. Expression and significance of IGF‑1R

and VEGF in gastric carcinoma. Xi Bao Yu Fen Zi Mian Yi Xue

Za Zhi 2009;25:529‑30.

Matsubara J, Yamada Y, Nakajima TE, Kato K, Hamaguchi T,

Shirao K, et al. Clinical significance of insulin‑like growth factor

type 1 receptor and epidermal growth factor receptor in patients

with advanced gastric cancer. Oncology 2008;74:76‑83.

Zhao X, Huang K, Zhu Z, Chen S, Hu R. Correlation between

expression of leptin and clinicopathological features and

prognosis in patients with gastric cancer. J Gastroenterol Hepatol

;22:1317‑21.

Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol

;207:12‑22.

Tahergorabi Z, Khazaei M. Leptin and its cardiovascular effects:

Focus on angiogenesis. Adv Biomed Res 2015;4:79.

Zhao L, Vogt PK. Class I PI3K in oncogenic cellular

transformation. Oncogene 2008;27:5486‑96.

Ericksen RE, Rose S, Westphalen CB, Shibata W, Muthupalani S,

Tailor Y, et al. Obesity accelerates Helicobacter felis‑induced

gastric carcinogenesis by enhancing immature myeloid cell

trafficking and TH17 response. Gut 2014;63:385‑94.

Kai H, Kitadai Y, Kodama M, Cho S, Kuroda T, Ito M, et al.

Involvement of proinflammatory cytokines IL‑1β and IL‑6

in progression of human gastric carcinoma. Anticancer Res

;25:709‑13.

Kuroda T, Kitadai Y, Tanaka S, Yang X, Mukaida N,

Yoshihara M, et al. Monocyte chemoattractant protein‑1

transfection induces angiogenesis and tumorigenesis of gastric

carcinoma in nude mice via macrophage recruitment. Clin

Cancer Res 2005;11:7629‑36.

Peng L, Zhan P, Zhou Y, Fang W, Zhao P, Zheng Y, et al.

Prognostic significance of vascular endothelial growth

factor immunohistochemical expression in gastric cancer:

A meta‑analysis. Mol Biol Rep 2012;39:9473‑84.

McCarthy T, O'Neil BH. Angiogenesis inhibitors in gastric

cancer. J Orphan Drugs: Res Rev. 2014;4:55-61.

Gandomani HS, Aghajani M, Mohammadian‑Hafshejani A,

Tarazoj AA, Pouyesh V, Salehiniya H. Colorectal cancer in the

world: Incidence, mortality and risk factors. Biomed Res Ther

;4:1656‑75.

Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M.

Body‑mass index and incidence of cancer: A systematic review

and meta‑analysis of prospective observational studies. Lancet

;371:569‑78.

Ouban A, Muraca P, Yeatman T, Coppola D. Expression and

distribution of insulin‑like growth factor‑1 receptor in human

carcinomas. Hum Pathol 2003;34:803‑8.

Valentinis B, Baserga R. IGF‑I receptor signalling in

transformation and differentiation. Mol Pathol 2001;54:133‑7.

Guo YS, Narayan S, Yallampalli C, Singh P. Characterization

of insulinlike growth factor I receptors in human colon cancer.

Gastroenterology 1992;102:1101‑8.

Singh P, Rubin N. Insulinlike growth factors and binding proteins

in colon cancer. Gastroenterology 1993;105:1218‑37.

Rinaldi S, Cleveland R, Norat T, Biessy C, Rohrmann S,

Linseisen J, et al. Serum levels of IGF-I, IGFBP-3 and colorectal

cancer risk: Results from the EPIC cohort, plus a meta-analysis

of prospective studies. Int J Cancer 2010;126:1702‑15.

Karczewski J, Begier‑Krasińska B, Staszewski R, Popławska E,

Gulczynska‑Elhadi K, Dobrowolska A. Obesity and the risk of

gastrointestinal cancers. Dig Dis Sci 2019;64:2740‑9.

Donohoe C, Pidgeon G, Lysaght J, Reynolds J. Obesity and

gastrointestinal cancer. Br J Surg 2010;97:628‑42.

Tsilidis KK, Branchini C, Guallar E, Helzlsouer KJ, Erlinger TP,

Platz EA. C-reactive protein and colorectal cancer risk:

A systematic review of prospective studies. Int J Cancer

;123:1133‑40.

Tahergorabi Z, Khazaei M, Moodi M, Chamani E. From obesity

to cancer: A review on proposed mechanisms. Cell Biochem

Funct 2016;34:533‑45.

Ho GY, Wang T, Gunter MJ, Strickler HD, Cushman M,

Kaplan RC, et al. Adipokines linking obesity with colorectal

cancer risk in postmenopausal women. Cancer Res

;72:3029‑37.

Endo H, Hosono K, Uchiyama T, Sakai E, Sugiyama M,

Takahashi H, et al. Leptin acts as a growth factor for colorectal

tumours at stages subsequent to tumour initiation in murine

colon carcinogenesis. Gut 2011;60:1363‑71.

Drew JE. Molecular mechanisms linking adipokines to

obesity‑related colon cancer: Focus on leptin. Proc Nutr Soc

;71:175‑80.

Padidar S, Farquharson AJ, Williams LM, Kelaiditi E,

Hoggard N, Arthur JR, et al. Leptin up-regulates

pro-inflammatory cytokines in discrete cells within mouse colon.

J Cell Physiol 2011;226:2123‑30.

Sugiyama M, Takahashi H, Hosono K, Endo H, Kato S,

Yoneda K, et al. Adiponectin inhibits colorectal cancer cell

growth through the AMPK/mTOR pathway. Int J Oncol

;34:339‑44.

Kim AY, Lee YS, Kim KH, Lee JH, Lee HK, Jang S‑H, et al.

Adiponectin represses colon cancer cell proliferation via

AdipoR1‑and‑R2‑mediated AMPK activation. Mol Endocrinol

;24:1441‑52.

Saxena A, Baliga MS, Ponemone V, Kaur K, Larsen B,

Fletcher E, et al. Mucus and adiponectin deficiency: Role in

chronic inflammation‑induced colon cancer. Int J Colorectal Dis

;28:1267‑79.

Konda B, Shum H, Rajdev L. Anti‑angiogenic agents in

metastatic colorectal cancer. World J Gastrointest Oncol

;7:71‑86.

Bendardaf R, El‑Serafi A, Syrjänend K, Collan Y, Pyrhönen S.

The effect of vascular endothelial growth factor‑1 expression on

survival of advanced colorectal cancer patients. Libyan J Med

;12:1290741.

Nandikolla AG, Rajdev L. Targeting angiogenesis in

gastrointestinal tumors: Current challenges. Transl Gastroenterol

Hepatol 2016;1:67.

Tahergorabi Z, Rashidi B, Khazaei M. Ghrelin does not modulate angiogenesis in matrigel plug in normal and diet‑induced obese mice. J Res Med Sci 2013;18:939‑42.

Strassburg S, Anker SD, Castaneda TR, Burget L, Perez‑Tilve D,

Pfluger PT, et al. Long‑term effects of ghrelin and ghrelin

receptor agonists on energy balance in rats. Am J Physiol

Endocrinol Metab 2008;295:E78‑84.

Waseem T, Duxbury M, Ashley SW, Robinson MK. Ghrelin

promotes intestinal epithelial cell proliferation through PI3K/Akt

pathway and EGFR trans‑activation both converging to ERK 1/2

phosphorylation. Peptides 2014;52:113‑21.

Yu H, Xu G, Fan X. The effect of ghrelin on cell proliferation

in small intestinal IEC‑6 cells. Biomed Pharmacother

;67:235‑9.

Kew MC. Hepatocellular carcinoma: Epidemiology and risk

factors. J Hepatocell Carcinoma 2014;1:115‑25.

Mittal S, El‑Serag HB. Epidemiology of HCC: Consider the

population. J Clin Gastroenterol 2013;47(Suppl):S2‑6.

Pourhoseingholi MA, Fazeli Z, Zali MR, Alavian SM. Burden of

hepatocellular carcinoma in Iran; Bayesian projection and trend

analysis. Asian Pac J Cancer Prev 2010;11:859‑62.

Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty

liver disease: Biochemical, metabolic, and clinical implications.

Hepatology 2010;51:679‑89.

Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk:

New mechanistic insights from epidemiology. Nat Rev Cancer

;15:484‑98.

Wong VWS, Wong GLH, Tsang SWC, Fan T, Chu WCW,

Woo J, et al. High prevalence of colorectal neoplasm in patients

with non‑alcoholic steatohepatitis. Gut 2011;60:829‑36.

Hwang ST, Cho YK, Park JH, Kim HJ, Park DI, Sohn CI, et al.

Relationship of non-alcoholic fatty liver disease to colorectal

adenomatous polyps. J Gastroenterol Hepatol 2010;25:562‑7.

Barash H, Gross ER, Edrei Y, Ella E, Israel A, Cohen I, et al.

Accelerated carcinogenesis following liver regeneration is

associated with chronic inflammation‑induced double‑strand

DNA breaks. Proc Natl Acad Sci 2010;107:2207‑12.

Muriel P. Role of free radicals in liver diseases. Hepatol Int

;3:526‑36.

Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in

non‑alcoholic fatty liver disease: An emerging menace. J Hepatol

;56:1384‑91.

Calle EE, Kaaks R. Overweight, obesity and cancer:

Epidemiological evidence and proposed mechanisms. Nat Rev

Cancer 2004;4:579‑91.

Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S,

Fukui K, et al. Hypoadiponectinemia accelerates hepatic tumor

formation in a nonalcoholic steatohepatitis mouse model.

J Hepatol 2007;47:556‑64.

Saxena NK, Fu PP, Nagalingam A, Wang J, Handy J,

Cohen C, et al. Adiponectin modulates C-jun N-terminal kinase

and mammalian target of rapamycin and inhibits hepatocellular

carcinoma. Gastroenterology. 2010;139:1762-73, 1773.e1-5.

Sharma D, Wang J, Fu PP, Sharma S, Nagalingam A, Mells J,

et al. Adiponectin antagonizes the oncogenic actions of leptin in

hepatocellular carcinogenesis. Hepatology 2010;52:1713‑22.

Aleksandrova K, Boeing H, Nöthlings U, Jenab M, Fedirko V,

Kaaks R, et al. Inflammatory and metabolic biomarkers and risk

of liver and biliary tract cancer. Hepatology 2014;60:858‑71.

Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M,

Niederegger H, et al. Visfatin, an adipocytokine with

proinflammatory and immunomodulating properties. J Immunol

;178:1748‑58.

Moschen AR, Molnar C, Wolf AM, Weiss H, Graziadei I,

Kaser S, et al. Effects of weight loss induced by

bariatric surgery on hepatic adipocytokine expression.

J Hepatol 2009;51:765‑77.

Adolph T, Grander C, Grabherr F, Tilg H. Adipokines and

non‑alcoholic fatty liver disease: Multiple interactions. Int J Mol

Sci 2017;18:1649.

Jamali R, Razavizade M, Arj A, Aarabi MH. Serum adipokines

might predict liver histology findings in non‑alcoholic fatty liver

disease. World J Gastroenterol 2016;22:5096‑103.

Yilmaz Y, Yonal O, Kurt R, Alahdab YO, Eren F, Ozdogan O,

et al. Serum levels of omentin, chemerin and adipsin in patients

with biopsy‑proven nonalcoholic fatty liver disease. Scand J

Gastroenterol 2011;46:91‑7.

Pohl R, Haberl EM, Rein-Fischboeck L, Zimny S, Neumann M,

Aslanidis C, et al. Hepatic chemerin mRNA expression is

reduced in human nonalcoholic steatohepatitis. Eur J Clin Invest

;47:7‑18.

Polyzos SA, Kountouras J, Anastasilakis AD, Geladari EV,

Mantzoros CS. Irisin in patients with nonalcoholic fatty liver

disease. Metabolism 2014;63:207‑17.

Hursting SD, DiGiovanni J, Dannenberg AJ, Azrad M,

LeRoith D, Demark‑Wahnefried W, et al. Obesity, energy

balance, and cancer: New opportunities for prevention. Cancer

Prev Res (Phila) 2012;5:1260‑72.

Lashinger LM, Ford NA, Hursting SD. Interacting inflammatory

and growth factor signals underlie the obesity‑cancer link. J Nutr

;144:109‑13.

Zahedi H, Djalalinia S, Asayesh H, Mansourian M, Abdar ZE,

Gorabi AM, et al. A higher dietary inflammatory index score

is associated with a higher risk of incidence and mortality of

cancer: A comprehensive systematic review and meta‑analysis.

Int J Prev Med 2020;11:15.

Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L,

Wener MH, et al. Effects of a caloric restriction weight loss diet

and exercise on inflammatory biomarkers in overweight/obese

postmenopausal women: A randomized controlled trial. Cancer

Res 2012;72:2314‑26.

Foster-Schubert KE, Alfano CM, Duggan CR, Xiao L,

Campbell KL, Kong A, et al. Effect of diet and exercise, alone

or combined, on weight and body composition in overweight-toobese postmenopausal women. Obesity 2012;20:1628‑38.

Quang N, Hien NQ, Quang NT, Chung NT. Active Lifestyle

Patterns Reduce the Risk of Colorectal Cancer in the North of

Vietnam: A Hospital-Based Case-Control Study. Cancer Control.

;26:1073274819864666.

Oruç Z, Kaplan MA. Effect of exercise on colorectal cancer

prevention and treatment. World J Gastrointest Oncol

;11:348‑66.

Harriss D, Atkinson G, Batterham A, George K,

Tim Cable N, Reilly T, et al. Lifestyle factors and colorectal

cancer risk (2): A systematic review and meta-analysis of

associations with leisure-time physical activity. Colorectal

Dis 2009;11:689‑701.

Kelly SA, Zhao L, Jung K‑C, Hua K, Threadgill DW, Kim Y,

et al. Prevention of tumorigenesis in mice by exercise is

dependent on strain background and timing relative to carcinogen exposure. Sci Rep 2017;7:1‑11. doi: 10.1038/srep43086.

Wang X, You T, Murphy K, Lyles MF, Nicklas BJ. Addition of

exercise increases plasma adiponectin and release from adipose

tissue. Med Sci Sports Exerc 2015;47:2450‑5.

Kelly KR, Navaneethan SD, Solomon TP, Haus JM, Cook M,

Barkoukis H, et al. Lifestyle‑induced decrease in fat mass

improves adiponectin secretion in obese adults. Med Sci Sports

Exerc 2014;46:920‑6.

Abbenhardt C, McTiernan A, Alfano CM, Wener MH, Campbell KL, Duggan C, et al. Effects of individual and

combined dietary weight loss and exercise interventions in

postmenopausal women on adiponectin and leptin levels. J Intern

Med 2013;274:163‑75.

Ulrich CM, Himbert C, Holowatyj AN, Hursting SD. Energy

balance and gastrointestinal cancer: Risk, interventions,

outcomes and mechanisms. Nat Rev Gastroenterol Hepatol

;15:683‑98.