Novel perspectives on the link between obesity and cancer risk: from mechanisms to clinical implications

Abstract

Existing epidemiologic and clinical studies have demonstrated that obesity is associated with the risk of a variety of cancers. In recent years, an increasing number of experimental and clinical studies have unraveled the complex relationship between obesity and cancer risk and the underlying mechanisms. Obesity-induced abnormalities in immunity and biochemical metabolism, including chronic inflammation, hormonal disorders, dysregulation of adipokines, and microbial dysbiosis, may be important contributors to cancer development and progression. These contributors play different roles in cancer development and progression at different sites. Lifestyle changes, weight loss medications, and bariatric surgery are key approaches for weight-centered, obesity-related cancer prevention. Treatment of obesity-related inflammation and hormonal or metabolic dysregulation with medications has also shown promise in preventing obesity-related cancers. In this review, we summarize the mechanisms through which obesity affects the risk of cancer at different sites and explore intervention strategies for the prevention of obesity-associated cancers, concluding with unresolved questions and future directions regarding the link between obesity and cancer. The aim is to provide valuable theoretical foundations and insights for the in-depth exploration of the complex relationship between obesity and cancer risk and its clinical applications.

Keywords

obesity / obesity-associated cancers / cancer risk / carcinogenesis / cancer prevention

References

[1] Conway B , Rene A . Obesity as a disease: no lightweight matter. Obes Rev 2004; 5(3): 145–151

[2] Williams EP , Mesidor M , Winters K , Dubbert PM , Wyatt SB . Overweight and obesity: prevalence, consequences, and causes of a growing public health problem. Curr Obes Rep 2015; 4(3): 363–370

[3] World Health Organization. Obesity and overweight. 2024. Available at the website of World Health Organization

[4] Jin X , Qiu T , Li L , Yu R , Chen X , Li C , Proud CG , Jiang T . Pathophysiology of obesity and its associated diseases. Acta Pharm Sin B 2023; 13(6): 2403–2424

[5] GBD 2015 Obesity Collaborators; Afshin A , Forouzanfar MH , Reitsma MB , Sur P , Estep K , Lee A , Marczak L , Mokdad AH , Moradi-Lakeh M , Naghavi M , Salama JS , Vos T , Abate KH , Abbafati C , Ahmed MB , Al-Aly Z , Alkerwi A , Al-Raddadi R , Amare AT , Amberbir A , Amegah AK , Amini E , Amrock SM , Anjana RM , Ärnlöv J , Asayesh H , Banerjee A , Barac A , Baye E , Bennett DA , Beyene AS , Biadgilign S , Biryukov S , Bjertness E , Boneya DJ , Campos-Nonato I , Carrero JJ , Cecilio P , Cercy K , Ciobanu LG , Cornaby L , Damtew SA , Dandona L , Dandona R , Dharmaratne SD , Duncan BB , Eshrati B , Esteghamati A , Feigin VL , Fernandes JC , Fürst T , Gebrehiwot TT , Gold A , Gona PN , Goto A , Habtewold TD , Hadush KT , Hafezi-Nejad N , Hay SI , Horino M , Islami F , Kamal R , Kasaeian A , Katikireddi SV , Kengne AP , Kesavachandran CN , Khader YS , Khang YH , Khubchandani J , Kim D , Kim YJ , Kinfu Y , Kosen S , Ku T , Defo BK , Kumar GA , Larson HJ , Leinsalu M , Liang X , Lim SS , Liu P , Lopez AD , Lozano R , Majeed A , Malekzadeh R , Malta DC , Mazidi M , McAlinden C , McGarvey ST , Mengistu DT , Mensah GA , Mensink GBM , Mezgebe HB , Mirrakhimov EM , Mueller UO , Noubiap JJ , Obermeyer CM , Ogbo FA , Owolabi MO , Patton GC , Pourmalek F , Qorbani M , Rafay A , Rai RK , Ranabhat CL , Reinig N , Safiri S , Salomon JA , Sanabria JR , Santos IS , Sartorius B , Sawhney M , Schmidhuber J , Schutte AE , Schmidt MI , Sepanlou SG , Shamsizadeh M , Sheikhbahaei S , Shin MJ , Shiri R , Shiue I , Roba HS , Silva DAS , Silverberg JI , Singh JA , Stranges S , Swaminathan S , Tabarés-Seisdedos R , Tadese F , Tedla BA , Tegegne BS , Terkawi AS , Thakur JS , Tonelli M , Topor-Madry R , Tyrovolas S , Ukwaja KN , Uthman OA , Vaezghasemi M , Vasankari T , Vlassov VV , Vollset SE , Weiderpass E , Werdecker A , Wesana J , Westerman R , Yano Y , Yonemoto N , Yonga G , Zaidi Z , Zenebe ZM , Zipkin B , Murray CJL . Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017; 377(1): 13–27

[6] Bjørge T , Häggström C , Ghaderi S , Nagel G , Manjer J , Tretli S , Ulmer H , Harlid S , Rosendahl AH , Lang A , Stattin P , Stocks T , Engeland A . BMI and weight changes and risk of obesity-related cancers: a pooled European cohort study. Int J Epidemiol 2019; 48(6): 1872–1885

[7] Neuhouser ML , Aragaki AK , Prentice RL , Manson JE , Chlebowski R , Carty CL , Ochs-Balcom HM , Thomson CA , Caan BJ , Tinker LF , Urrutia RP , Knudtson J , Anderson GL . Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the women’s health initiative randomized clinical trials. JAMA Oncol 2015; 1(5): 611–621

[8] Yang P , Zhou Y , Chen B , Wan HW , Jia GQ , Bai HL , Wu XT . Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur J Cancer 2009; 45(16): 2867–2873

[9] Dai Z , Xu YC , Niu L . Obesity and colorectal cancer risk: a meta-analysis of cohort studies. World J Gastroenterol 2007; 13(31): 4199–4206

[10] Larsson SC , Wolk A . Obesity and risk of non-Hodgkin’s lymphoma: a meta-analysis. Int J Cancer 2007; 121(7): 1564–1570

[11] 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 2008; 371(9612): 569–578

[12] Larsson SC , Wolk A . Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 2007; 97(7): 1005–1008

[13] Zhang Y , Liu H , Yang S , Zhang J , Qian L , Chen X . Overweight, obesity and endometrial cancer risk: results from a systematic review and meta-analysis. Int J Biol Markers 2014; 29(1): e21–e29

[14] Yang Y , Dong J , Sun K , Zhao L , Zhao F , Wang L , Jiao Y . Obesity and incidence of lung cancer: a meta-analysis. Int J Cancer 2013; 132(5): 1162–1169

[15] Kaaks R , Lukanova A , Kurzer MS . Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev 2002; 11(12): 1531–1543

[16] Yoshimoto S , Loo TM , Atarashi K , Kanda H , Sato S , Oyadomari S , Iwakura Y , Oshima K , Morita H , Hattori M , Honda K , Ishikawa Y , Hara E , Ohtani N . Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499(7456): 97–101

[17] Naaman SC , Shen S , Zeytinoglu M , Iyengar NM . Obesity and breast cancer risk: the oncogenic implications of metabolic dysregulation. J Clin Endocrinol Metab 2022; 107(8): 2154–2166

[18] Matsui S , Okabayashi K , Tsuruta M , Shigeta K , Seishima R , Ishida T , Kondo T , Suzuki Y , Hasegawa H , Shimoda M , Sugimoto S , Sato T , Kitagawa Y . Interleukin-13 and its signaling pathway is associated with obesity-related colorectal tumorigenesis. Cancer Sci 2019; 110(7): 2156–2165

[19] Shi D , Wu J , Wu Y , Lin X , Xu C , Lian X . High-fat diet-related obesity promotes urethane-induced lung tumorigenesis in C57BL/6J mice. Front Oncol 2021; 11: 620993

[20] Wunderlich FT , Luedde T , Singer S , Schmidt-Supprian M , Baumgartl J , Schirmacher P , Pasparakis M , Brüning JC . Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci USA 2008; 105(4): 1297–1302

[21] Venkatesh N , Martini A , McQuade JL , Msaouel P , Hahn AW . Obesity and renal cell carcinoma: biological mechanisms and perspectives. Semin Cancer Biol 2023; 94: 21–33

[22] Eibl G , Rozengurt E . Obesity and pancreatic cancer: insight into mechanisms. Cancers (Basel) 2021; 13(20): 5067

[23] Wilson RL , Taaffe DR , Newton RU , Hart NH , Lyons-Wall P , Galvão DA . Obesity and prostate cancer: a narrative review. Crit Rev Oncol Hematol 2022; 169: 103543

[24] Zhao C , Hu W , Xu Y , Wang D , Wang Y , Lv W , Xiong M , Yi Y , Wang H , Zhang Q , Wu Y . Current landscape: the mechanism and therapeutic impact of obesity for breast cancer. Front Oncol 2021; 11: 704893

[25] Kolb R , Sutterwala FS , Zhang W . Obesity and cancer: inflammation bridges the two. Curr Opin Pharmacol 2016; 29: 77–89

[26] Cleary MP , Grossmann ME . Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 2009; 150(6): 2537–2542

[27] Booth A , Magnuson A , Fouts J , Foster M . Adipose tissue, obesity and adipokines: role in cancer promotion. Horm Mol Biol Clin Investig 2015; 21(1): 57–74

[28] Zhang Z , Zhou D , Lai Y , Liu Y , Tao X , Wang Q , Zhao G , Gu H , Liao H , Zhu Y , Xi X , Feng Y . Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. Cancer Lett 2012; 319(1): 89–97

[29] Edvardsson K , Strom A , Jonsson P , Gustafsson JA , Williams C . Estrogen receptor beta induces antiinflammatory and antitumorigenic networks in colon cancer cells. Mol Endocrinol 2011; 25(6): 969–979

[30] Song M , Chan AT , Sun J . Influence of the gut microbiome, diet, and environment on risk of colorectal cancer. Gastroenterology 2020; 158(2): 322–340

[31] Socol CT , Chira A , Martinez-Sanchez MA , Nunez-Sanchez MA , Maerescu CM , Mierlita D , Rusu AV , Ruiz-Alcaraz AJ , Trif M , Ramos-Molina B . Leptin signaling in obesity and colorectal cancer. Int J Mol Sci 2022; 23(9): 4713

[32] Endo H , Hosono K , Uchiyama T , Sakai E , Sugiyama M , Takahashi H , Nakajima N , Wada K , Takeda K , Nakagama H , Nakajima A . Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis. Gut 2011; 60(10): 1363–1371

[33] Hotamisligil GS . Inflammation and metabolic disorders. Nature 2006; 444(7121): 860–867

[34] Shoelson SE , Herrero L , Naaz A . Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132(6): 2169–2180

[35] Deng T , Lyon CJ , Bergin S , Caligiuri MA , Hsueh WA . Obesity, inflammation, and cancer. Annu Rev Pathol 2016; 11(1): 421–449

[36] McTiernan A , Wu L , Chen C , Chlebowski R , Mossavar-Rahmani Y , Modugno F , Perri MG , Stanczyk FZ , Van Horn L , Wang CY; Women’s Health Initiative Investigators . Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity (Silver Spring) 2006; 14(9): 1662–1677

[37] Renehan AG , Frystyk J , Flyvbjerg A . Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 2006; 17(8): 328–336

[38] Chung KM , Singh J , Lawres L , Dorans KJ , Garcia C , Burkhardt DB , Robbins R , Bhutkar A , Cardone R , Zhao X , Babic A , Vayrynen SA , Dias Costa A , Nowak JA , Chang DT , Dunne RF , Hezel AF , Koong AC , Wilhelm JJ , Bellin MD , Nylander V , Gloyn AL , McCarthy MI , Kibbey RG , Krishnaswamy S , Wolpin BM , Jacks T , Fuchs CS , Muzumdar MD . Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma. Cell 2020; 181(4): 832–847.e18

[39] Tschöp M , Weyer C , Tataranni PA , Devanarayan V , Ravussin E , Heiman ML . Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50(4): 707–709

[40] Carlson MJ , Thiel KW , Yang S , Leslie KK . Catch it before it kills: progesterone, obesity, and the prevention of endometrial cancer. Discov Med 2012; 14(76): 215–222

[41] Fasshauer M , Blüher M . Adipokines in health and disease. Trends Pharmacol Sci 2015; 36(7): 461–470

[42] Steppan CM , Lazar MA . Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 2002; 13(1): 18–23

[43] Buechler C , Feder S , Haberl EM , Aslanidis C . Chemerin isoforms and activity in obesity. Int J Mol Sci 2019; 20(5): 1128

[44] Sethi JK , Vidal-Puig A . Visfatin: the missing link between intra-abdominal obesity and diabetes. Trends Mol Med 2005; 11(8): 344–347

[45] Yang J , Liu S , Li Y , Fan Z , Meng Y , Zhou B , Zhang G , Zhan H . FABP4 in macrophages facilitates obesity-associated pancreatic cancer progression via the NLRP3/IL-1β axis. Cancer Lett 2023; 575: 216403

[46] El-Serag HB , Tran T , Richardson P , Ergun G . Anthropometric correlates of intragastric pressure. Scand J Gastroenterol 2006; 41(8): 887–891

[47] Springer NL , Iyengar NM , Bareja R , Verma A , Jochelson MS , Giri DD , Zhou XK , Elemento O , Dannenberg AJ , Fischbach C . Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage Phenotype Similar to Tumor-Associated Macrophages. Am J Pathol 2019; 189(10): 2019–2035

[48] Castro BBA , Foresto-Neto O , Saraiva-Camara NO , Sanders-Pinheiro H . Renal lipotoxicity: insights from experimental models. Clin Exp Pharmacol Physiol 2021; 48(12): 1579–1588

[49] Lumeng CN , Bodzin JL , Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117(1): 175–184

[50] Weisberg SP , McCann D , Desai M , Rosenbaum M , Leibel RL , Ferrante AW Jr . Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112(12): 1796–1808

[51] Apostolopoulos V , de Courten MP , Stojanovska L , Blatch GL , Tangalakis K , de Courten B . The complex immunological and inflammatory network of adipose tissue in obesity. Mol Nutr Food Res 2016; 60(1): 43–57

[52] Kim DH , Kim HJ , Seong JK . UCP2 KO mice exhibit ameliorated obesity and inflammation induced by high-fat diet feeding. BMB Rep 2022; 55(10): 500–505

[53] Sun K , Kusminski CM , Scherer PE . Adipose tissue remodeling and obesity. J Clin Invest 2011; 121(6): 2094–2101

[54] Herrada AA , Olate-Briones A , Rojas A , Liu C , Escobedo N , Piesche M . Adipose tissue macrophages as a therapeutic target in obesity-associated diseases. Obes Rev 2021; 22(6): e13200

[55] Huh JY , Park YJ , Ham M , Kim JB . Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cells 2014; 37(5): 365–371

[56] Murano I , Barbatelli G , Parisani V , Latini C , Muzzonigro G , Castellucci M , Cinti S . Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res 2008; 49(7): 1562–1568

[57] Lee YS , Kim JW , Osborne O , Oh DY , Sasik R , Schenk S , Chen A , Chung H , Murphy A , Watkins SM , Quehenberger O , Johnson RS , Olefsky JM . Increased adipocyte O₂ consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity. Cell 2014; 157(6): 1339–1352

[58] Fischer-Posovszky P , Wang QA , Asterholm IW , Rutkowski JM , Scherer PE . Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages. Endocrinology 2011; 152(8): 3074–3081

[59] O’Rourke RW , White AE , Metcalf MD , Olivas AS , Mitra P , Larison WG , Cheang EC , Varlamov O , Corless CL , Roberts CT Jr , Marks DL . Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells. Diabetologia 2011; 54(6): 1480–1490

[60] Guerreiro VA , Carvalho D , Freitas P . Obesity, adipose tissue, and inflammation answered in questions. J Obes 2022; 2022: 2252516

[61] Quail DF , Dannenberg AJ . The obese adipose tissue microenvironment in cancer development and progression. Nat Rev Endocrinol 2019; 15(3): 139–154

[62] Nishimoto S , Fukuda D , Higashikuni Y , Tanaka K , Hirata Y , Murata C , Kim-Kaneyama JR , Sato F , Bando M , Yagi S , Soeki T , Hayashi T , Imoto I , Sakaue H , Shimabukuro M , Sata M . Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance. Sci Adv 2016; 2(3): e1501332

[63] Caspar-Bauguil S , Kolditz CI , Lefort C , Vila I , Mouisel E , Beuzelin D , Tavernier G , Marques MA , Zakaroff-Girard A , Pecher C , Houssier M , Mir L , Nicolas S , Moro C , Langin D . Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages. Diabetologia 2015; 58(11): 2627–2636

[64] Prieur X , Mok CY , Velagapudi VR , Nunez V , Fuentes L , Montaner D , Ishikawa K , Camacho A , Barbarroja N , O’Rahilly S , Sethi JK , Dopazo J , Oresic M , Ricote M , Vidal-Puig A . Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 2011; 60(3): 797–809

[65] Howe LR , Subbaramaiah K , Hudis CA , Dannenberg AJ . Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res 2013; 19(22): 6074–6083

[66] Hersoug LG , Moller P , Loft S . Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity. Obes Rev 2016; 17(4): 297–312

[67] Park EJ , Lee JH , Yu GY , He G , Ali SR , Holzer RG , Osterreicher CH , Takahashi H , Karin M . Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140(2): 197–208

[68] de Andrade CT , Rocha GZ , Zamuner M , Dos Reis RB , Reis LO . Obesity influence on bladder inflammation and cancer: a cystitis model. Int J Clin Exp Pathol 2022; 15(9): 373–379

[69] Hunter CA , Jones SA . IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015; 16(5): 448–457

[70] Niu G , Wright KL , Huang M , Song L , Haura E , Turkson J , Zhang S , Wang T , Sinibaldi D , Coppola D , Heller R , Ellis LM , Karras J , Bromberg J , Pardoll D , Jove R , Yu H . Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002; 21(13): 2000–2008

[71] Alzahrani B , Iseli TJ , Hebbard LW . Non-viral causes of liver cancer: does obesity led inflammation play a role. Cancer Lett 2014; 345(2): 223–229

[72] Bergmann J , Muller M , Baumann N , Reichert M , Heneweer C , Bolik J , Lucke K , Gruber S , Carambia A , Boretius S , Leuschner I , Becker T , Rabe B , Herkel J , Wunderlich FT , Mittrucker HW , Rose-John S , Schmidt-Arras D . IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology 2017; 65(1): 89–103

[73] Liu Z , Brooks RS , Ciappio ED , Kim SJ , Crott JW , Bennett G , Greenberg AS , Mason JB . Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer. J Nutr Biochem 2012; 23(10): 1207–1213

[74] Olivo-Marston SE , Hursting SD , Perkins SN , Schetter A , Khan M , Croce C , Harris CC , Lavigne J . Effects of calorie restriction and diet-induced obesity on murine colon carcinogenesis, growth and inflammatory factors, and microRNA expression. PLoS One 2014; 9(4): e94765

[75] Li J , Tang Y , Lin TC , Zeng H , Mason JB , Liu Z . Tumor necrosis factor-alpha knockout mitigates intestinal inflammation and tumorigenesis in obese Apc(1638N) mice. J Nutr Biochem 2023; 117: 109355

[76] Martínez-Chacón G , Yatkin E , Polari L , Deniz Dinc D , Peuhu E , Hartiala P , Saarinen N , Makela S . CC chemokine ligand 2 (CCL2) stimulates aromatase gene expression in mammary adipose tissue. FASEB J 2021; 35(5): e21536

[77] Gonçalves RM , Delgobo M , Agnes JP , das Neves RN , Falchetti M , Casagrande T , Garcia APV , Vieira TC , Somensi N , Bruxel MA , Mendes DAGB , Rafacho A , Báfica A , Gelain DP , Moreira JCF , Cassali GD , Bishop AJR , Zanotto-Filho A . COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice. Cancer Lett 2021; 502: 44–57

[78] Dushnicky MJ , Nazarali S , Mir A , Portwine C , Samaan MC . Is there a causal relationship between childhood obesity and acute lymphoblastic leukemia? A review. Cancers (Basel) 2020; 12(11): 3082

[79] Rehman J , Traktuev D , Li J , Merfeld-Clauss S , Temm-Grove CJ , Bovenkerk JE , Pell CL , Johnstone BH , Considine RV , March KL . Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109(10): 1292–1298

[80] Kilroy GE , Foster SJ , Wu X , Ruiz J , Sherwood S , Heifetz A , Ludlow JW , Stricker DM , Potiny S , Green P , Halvorsen YD , Cheatham B , Storms RW , Gimble JM . Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol 2007; 212(3): 702–709

[81] Xue B , Wu S , Sharkey C , Tabatabaei S , Wu CL , Tao Z , Cheng Z , Strand D , Olumi AF , Wang Z . Obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland. Prostate Cancer Prostatic Dis 2020; 23(3): 465–474

[82] Wang X , Simpson ER , Brown KA . Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer. J Steroid Biochem Mol Biol 2015; 153: 35–44

[83] Campbell KL , Foster-Schubert KE , Alfano CM , Wang CC , Wang CY , Duggan CR , Mason C , Imayama I , Kong A , Xiao L , Bain CE , Blackburn GL , Stanczyk FZ , McTiernan A . Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial. J Clin Oncol 2012; 30(19): 2314–2326

[84] Bhardwaj P , Au CC , Benito-Martin A , Ladumor H , Oshchepkova S , Moges R , Brown KA . Estrogens and breast cancer: mechanisms involved in obesity-related development, growth and progression. J Steroid Biochem Mol Biol 2019; 189: 161–170

[85] Santen RJ , Song RX , McPherson R , Kumar R , Adam L , Jeng MH , Yue W . The role of mitogen-activated protein (MAP) kinase in breast cancer. J Steroid Biochem Mol Biol 2002; 80(2): 239–256

[86] Fernandez SV , Russo IH , Russo J . Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells. Int J Cancer 2006; 118(8): 1862–1868

[87] Cavalieri EL , Stack DE , Devanesan PD , Todorovic R , Dwivedy I , Higginbotham S , Johansson SL , Patil KD , Gross ML , Gooden JK , Ramanathan R , Cerny RL , Rogan EG . Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci USA 1997; 94(20): 10937–10942

[88] Wolin KY , Carson K , Colditz GA . Obesity and cancer. Oncologist 2010; 15(6): 556–565

[89] Chen J , Iverson D . Estrogen in obesity-associated colon cancer: friend or foe? Protecting postmenopausal women but promoting late-stage colon cancer. Cancer Causes Control 2012; 23(11): 1767–1773

[90] Barzi A , Lenz AM , Labonte MJ , Lenz HJ . Molecular pathways: estrogen pathway in colorectal cancer. Clin Cancer Res 2013; 19(21): 5842–5848

[91] Bhardwaj P , Ikeda T , Zhou XK , Wang H , Zheng XE , Giri DD , Elemento O , Verma A , Miyazawa M , Mukherjee S , Falcone DJ , Wendel NK , Scherr DS , Dannenberg AJ . Supplemental estrogen and caloric restriction reduce obesity-induced periprostatic white adipose inflammation in mice. Carcinogenesis 2019; 40(7): 914–923

[92] Graham JD , Clarke CL . Physiological action of progesterone in target tissues. Endocr Rev 1997; 18(4): 502–519

[93] Kariagina A , Doseff AI . Anti-inflammatory mechanisms of dietary flavones: tapping into nature to control chronic inflammation in obesity and cancer. Int J Mol Sci 2022; 23(24): 15753

[94] Yang S , Thiel KW , Leslie KK . Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab 2011; 22(4): 145–152

[95] Barazzoni R , Gortan Cappellari G , Ragni M , Nisoli E . Insulin resistance in obesity: an overview of fundamental alterations. Eat Weight Disord 2018; 23(2): 149–157

[96] Kalupahana NS , Moustaid-Moussa N , Claycombe KJ . Immunity as a link between obesity and insulin resistance. Mol Aspects Med 2012; 33(1): 26–34

[97] Moodi M , Tavakoli T , Tahergorabi Z . Crossroad between obesity and gastrointestinal cancers: a review of molecular mechanisms and interventions. Int J Prev Med 2021; 12(1): 18

[98] Huang XF , Chen JZ . Obesity, the PI3K/Akt signal pathway and colon cancer. Obes Rev 2009; 10(6): 610–616

[99] Yu J , Shen J , Sun TT , Zhang X , Wong N . Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol 2013; 23(6 Pt B): 483–491

[100] Pugeat M , Crave JC , Elmidani M , Nicolas MH , Garoscio-Cholet M , Lejeune H , Dechaud H , Tourniaire J . Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. J Steroid Biochem Mol Biol 1991; 40(4–6): 841–849

[101] Rose DP , Gracheck PJ , Vona-Davis L . The Interactions of obesity, inflammation and insulin resistance in breast cancer. Cancers (Basel) 2015; 7(4): 2147–2168

[102] Kawaguchi M , Kanemaru A , Fukushima T , Yamamoto K , Tanaka H , Haruyama Y , Itoh H , Matsumoto N , Kangawa K , Nakazato M , Kataoka H . Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice. Cancer Sci 2015; 106(9): 1130–1136

[103] Davis TR , Pierce MR , Novak SX , Hougland JL . Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling. Open Biol 2021; 11(7): 210080

[104] Chandra R , Liddle RA . Cholecystokinin. Curr Opin Endocrinol Diabetes Obes 2007; 14(1): 63–67

[105] Shiiya T , Nakazato M , Mizuta M , Date Y , Mondal MS , Tanaka M , Nozoe S , Hosoda H , Kangawa K , Matsukura S . Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002; 87(1): 240–244

[106] Cui H , Lopez M , Rahmouni K . The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol 2017; 13(6): 338–351

[107] Pereira J , da Silva FC , de Moraes-Vieira PMM . The impact of ghrelin in metabolic diseases: an immune perspective. J Diabetes Res 2017; 2017: 4527980

[108] Guzzardi MA , Pugliese G , Bottiglieri F , Pelosini C , Muscogiuri G , Barrea L , Savastano S , Colao A . Obesity-related gut hormones and cancer: novel insight into the pathophysiology. Int J Obes 2021; 45(9): 1886–1898

[109] Breton J , Galmiche M , Déchelotte P . Dysbiotic gut bacteria in obesity: an overview of the metabolic mechanisms and therapeutic perspectives of next-generation probiotics. Microorganisms 2022; 10(2): 452

[110] Ley RE , Turnbaugh PJ , Klein S , Gordon JI . Human gut microbes associated with obesity. Nature 2006; 444(7122): 1022–1023

[111] Cani PD , Jordan BF . Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat Rev Gastroenterol Hepatol 2018; 15(11): 671–682

[112] Xiao S , Zhao L . Gut microbiota-based translational biomarkers to prevent metabolic syndrome via nutritional modulation. FEMS Microbiol Ecol 2014; 87(2): 303–314

[113] He Y , Fu L , Li Y , Wang W , Gong M , Zhang J , Dong X , Huang J , Wang Q , Mackay CR , Fu YX , Chen Y , Guo X . Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8⁺ T cell immunity. Cell Metab 2021; 33(5): 988–1000.e7

[114] Cani PD , Bibiloni R , Knauf C , Waget A , Neyrinck AM , Delzenne NM , Burcelin R . Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57(6): 1470–1481

[115] Saus E , Iraola-Guzman S , Willis JR , Brunet-Vega A , Gabaldon T . Microbiome and colorectal cancer: roles in carcinogenesis and clinical potential. Mol Aspects Med 2019; 69: 93–106

[116] Sears CL , Geis AL , Housseau F . Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. J Clin Invest 2014; 124(10): 4166–4172

[117] Goodwin AC , Destefano Shields CE , Wu S , Huso DL , Wu X , Murray-Stewart TR , Hacker-Prietz A , Rabizadeh S , Woster PM , Sears CL , Casero RA Jr . Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci USA 2011; 108(37): 15354–15359

[118] McLeod A , Wolf P , Chapkin RS , Davidson LA , Ivanov I , Berbaum M , Williams LR , Gaskins HR , Ridlon J , Sanchez-Flack J , Blumstein L , Schiffer L , Hamm A , Cares K , Antonic M , Bernabe BP , Fitzgibbon M , Tussing-Humphreys L . Design of the Building Research in CRC prevention (BRIDGE-CRC) trial: a 6-month, parallel group Mediterranean diet and weight loss randomized controlled lifestyle intervention targeting the bile acid-gut microbiome axis to reduce colorectal cancer risk among African American/Black adults with obesity. Trials 2023; 24(1): 113

[119] Gupta H , Youn GS , Shin MJ , Suk KT . Role of gut microbiota in hepatocarcinogenesis. Microorganisms 2019; 7(5): 121

[120] Loo TM , Kamachi F , Watanabe Y , Yoshimoto S , Kanda H , Arai Y , Nakajima-Takagi Y , Iwama A , Koga T , Sugimoto Y , Ozawa T , Nakamura M , Kumagai M , Watashi K , Taketo MM , Aoki T , Narumiya S , Oshima M , Arita M , Hara E , Ohtani N . Gut microbiota promotes obesity-associated liver cancer through PGE(2)-mediated suppression of antitumor immunity. Cancer Discov 2017; 7(5): 522–538

[121] Ohtani N . Microbiome and cancer. Semin Immunopathol 2015; 37(1): 65–72

[122] Kessoku T , Kobayashi T , Imajo K , Tanaka K , Yamamoto A , Takahashi K , Kasai Y , Ozaki A , Iwaki M , Nogami A , Honda Y , Ogawa Y , Kato S , Higurashi T , Hosono K , Yoneda M , Okamoto T , Usuda H , Wada K , Kobayashi N , Saito S , Nakajima A . Endotoxins and non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2021; 12: 770986

[123] Kwa M , Plottel CS , Blaser MJ , Adams S . The intestinal microbiome and estrogen receptor-positive female breast cancer. J Natl Cancer Inst 2016; 108(8): djw029

[124] Alpuim Costa D , Nobre JG , Batista MV , Ribeiro C , Calle C , Cortes A , Marhold M , Negreiros I , Borralho P , Brito M , Cortes J , Braga SA , Costa L . Human microbiota and breast cancer—is there any relevant link? A literature review and new horizons toward personalised medicine. Front Microbiol 2021; 12: 584332

[125] Li S , Li X . Leptin in normal physiology and leptin resistance. Sci Bull (Beijing) 2016; 61(19): 1480–1488

[126] Bullwinkle EM , Parker MD , Bonan NF , Falkenberg LG , Davison SP , DeCicco-Skinner KL . Adipocytes contribute to the growth and progression of multiple myeloma: unraveling obesity related differences in adipocyte signaling. Cancer Lett 2016; 380(1): 114–121

[127] Lönnqvist F , Arner P , Nordfors L , Schalling M . Overexpression of the obese (ob) gene in adipose tissue of human obese subjects. Nat Med 1995; 1(9): 950–953

[128] Stemmer K , Perez-Tilve D , Ananthakrishnan G , Bort A , Seeley RJ , Tschop MH , Dietrich DR , Pfluger PT . High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney. Dis Model Mech 2012; 5(5): 627–635

[129] Shen L , Zhang C , Cui K , Liang X , Zhu G , Hong L . Leptin secreted by adipocytes promotes EMT transition and endometrial cancer progression via the JAK2/STAT3 signalling pathway. Adipocyte 2024; 13(1): 2293273

[130] Habib CN , Al-Abd AM , Tolba MF , Khalifa AE , Khedr A , Mosli HA , Abdel-Naim AB . Leptin influences estrogen metabolism and accelerates prostate cell proliferation. Life Sci 2015; 121: 10–15

[131] Catalano S , Mauro L , Marsico S , Giordano C , Rizza P , Rago V , Montanaro D , Maggiolini M , Panno ML , Ando S . Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Biol Chem 2004; 279(19): 19908–19915

[132] Zahid H , Subbaramaiah K , Iyengar NM , Zhou XK , Chen IC , Bhardwaj P , Gucalp A , Morrow M , Hudis CA , Dannenberg AJ , Brown KA . Leptin regulation of the p53-HIF1α/PKM₂-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity-breast cancer link. Int J Obes 2018; 42(4): 711–720

[133] Catalano S , Marsico S , Giordano C , Mauro L , Rizza P , Panno ML , Ando S . Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 2003; 278(31): 28668–28676

[134] Yoon YS , Kwon AR , Lee YK , Oh SW . Circulating adipokines and risk of obesity related cancers: a systematic review and meta-analysis. Obes Res Clin Pract 2019; 13(4): 329–339

[135] Maeda N , Funahashi T , Matsuzawa Y , Shimomura I . Adiponectin, a unique adipocyte-derived factor beyond hormones. Atherosclerosis 2020; 292: 1–9

[136] Chang E , Choi JM , Kim WJ , Rhee EJ , Oh KW , Lee WY , Park SE , Park SW , Park CY . Restoration of adiponectin expression via the ERK pathway in TNFα-treated 3T3-L1 adipocytes. Mol Med Rep 2014; 10(2): 905–910

[137] Sugiyama M , Takahashi H , Hosono K , Endo H , Kato S , Yoneda K , Nozaki Y , Fujita K , Yoneda M , Wada K , Nakagama H , Nakajima A . Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway. Int J Oncol 2009; 34(2): 339–344

[138] Xie L , Wang Y , Wang S , Wu N , Chen Y , Yan J . Adiponectin induces growth inhibition and apoptosis in cervical cancer HeLa cells. Biologia (Bratisl) 2011; 66(4): 712–720

[139] Srilatha M , Malla R , Adem MP , Foote JB , Nagaraju GP . Obesity associated pancreatic ductal adenocarcinoma: therapeutic challenges. Semin Cancer Biol 2023; 97: 12–20

[140] Jiang J , Fan Y , Zhang W , Shen Y , Liu T , Yao M , Gu J , Tu H , Gan Y . Adiponectin suppresses human pancreatic cancer growth through attenuating the β-catenin signaling pathway. Int J Biol Sci 2019; 15(2): 253–264

[141] Saxena NK , Fu PP , Nagalingam A , Wang J , Handy J , Cohen C , Tighiouart M , Sharma D , Anania FA . Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology 2010; 139(5): 1762–1673,1773.e1–5

[142] Gong WJ , Zheng W , Xiao L , Tan LM , Song J , Li XP , Xiao D , Cui JJ , Li X , Zhou HH , Yin JY , Liu ZQ . Circulating resistin levels and obesity-related cancer risk: a meta-analysis. Oncotarget 2016; 7(36): 57694–57704

[143] Conde J , Scotece M , Gómez R , López V , Gómez-Reino JJ , Lago F , Gualillo O . Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. Biofactors 2011; 37(6): 413–420

[144] Curat CA , Wegner V , Sengenes C , Miranville A , Tonus C , Busse R , Bouloumie A . Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 2006; 49(4): 744–747

[145] Tarkowski A , Bjersing J , Shestakov A , Bokarewa MI . Resistin competes with lipopolysaccharide for binding to toll-like receptor 4. J Cell Mol Med 2010; 14(6b 6B): 1419–1431

[146] Wang CH , Wang PJ , Hsieh YC , Lo S , Lee YC , Chen YC , Tsai CH , Chiu WC , Chu-Sung Hu S , Lu CW , Yang YF , Chiu CC , Ou-Yang F , Wang YM , Hou MF , Yuan SS . Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties. Oncogene 2018; 37(5): 589–600

[147] Helmink BA , Reddy SM , Gao J , Zhang S , Basar R , Thakur R , Yizhak K , Sade-Feldman M , Blando J , Han G , Gopalakrishnan V , Xi Y , Zhao H , Amaria RN , Tawbi HA , Cogdill AP , Liu W , LeBleu VS , Kugeratski FG , Patel S , Davies MA , Hwu P , Lee JE , Gershenwald JE , Lucci A , Arora R , Woodman S , Keung EZ , Gaudreau PO , Reuben A , Spencer CN , Burton EM , Haydu LE , Lazar AJ , Zapassodi R , Hudgens CW , Ledesma DA , Ong S , Bailey M , Warren S , Rao D , Krijgsman O , Rozeman EA , Peeper D , Blank CU , Schumacher TN , Butterfield LH , Zelazowska MA , McBride KM , Kalluri R , Allison J , Petitprez F , Fridman WH , Sautes-Fridman C , Hacohen N , Rezvani K , Sharma P , Tetzlaff MT , Wang L , Wargo JA . B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020; 577(7791): 549–555

[148] Goralski KB , McCarthy TC , Hanniman EA , Zabel BA , Butcher EC , Parlee SD , Muruganandan S , Sinal CJ . Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem 2007; 282(38): 28175–28188

[149] Tan SK , Mahmud I , Fontanesi F , Puchowicz M , Neumann CKA , Griswold AJ , Patel R , Dispagna M , Ahmed HH , Gonzalgo ML , Brown JM , Garrett TJ , Welford SM . Obesity-dependent adipokine chemerin suppresses fatty acid oxidation to confer ferroptosis resistance. Cancer Discov 2021; 11(8): 2072–2093

[150] Gui Y , Pan Q , Chen X , Xu S , Luo X , Chen L . The association between obesity related adipokines and risk of breast cancer: a meta-analysis. Oncotarget 2017; 8(43): 75389–75399

[151] Steinhoff JS , Lass A , Schupp M . Biological functions of RBP4 and its relevance for human diseases. Front Physiol 2021; 12: 659977

[152] Zeng J , Sauter ER , Li B . FABP4: a new player in obesity-associated breast cancer. Trends Mol Med 2020; 26(5): 437–440

[153] Prentice KJ , Saksi J , Hotamisligil GS . Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses. J Lipid Res 2019; 60(4): 734–740

[154] Gholinejad Z , Kheiripour N , Nourbakhsh M , Ilbeigi D , Behroozfar K , Hesari Z , Golestani A , Shabani M , Einollahi N . Extracellular NAMPT/visfatin induces proliferation through ERK1/2 and AKT and inhibits apoptosis in breast cancer cells. Peptides 2017; 92: 9–15

[155] Hao J , Zhang Y , Yan X , Yan F , Sun Y , Zeng J , Waigel S , Yin Y , Fraig MM , Egilmez NK , Suttles J , Kong M , Liu S , Cleary MP , Sauter E , Li B . Circulating adipose fatty acid binding protein is a new link underlying obesity-associated breast/mammary tumor development. Cell Metab 2018; 28(5): 689–705.e5

[156] Yan F , Shen N , Pang JX , Zhang YW , Rao EY , Bode AM , Al-Kali A , Zhang DE , Litzow MR , Li B , Liu SJ . Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. Leukemia 2017; 31(6): 1434–1442

[157] Karunanithi S , Levi L , DeVecchio J , Karagkounis G , Reizes O , Lathia JD , Kalady MF , Noy N . RBP4-STRA6 pathway drives cancer stem cell maintenance and mediates high-fat diet-induced colon carcinogenesis. Stem Cell Reports 2017; 9(2): 438–450

[158] Noy N , Li L , Abola MV , Berger NA . Is retinol binding protein 4 a link between adiposity and cancer. Horm Mol Biol Clin Investig 2015; 23(2): 39–46

[159] Berry DC , Levi L , Noy N . Holo-retinol-binding protein and its receptor STRA6 drive oncogenic transformation. Cancer Res 2014; 74(21): 6341–6351

[160] Emerenziani S , Rescio MP , Guarino MP , Cicala M . Gastro-esophageal reflux disease and obesity, where is the link. World J Gastroenterol 2013; 19(39): 6536–6539

[161] Ayazi S , Hagen JA , Chan LS , DeMeester SR , Lin MW , Ayazi A , Leers JM , Oezcelik A , Banki F , Lipham JC , DeMeester TR , Crookes PF . Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms. J Gastrointest Surg 2009; 13(8): 1440–1447

[162] Schlottmann F , Molena D , Patti MG . Gastroesophageal reflux and Barrett’s esophagus: a pathway to esophageal adenocarcinoma. Updates Surg 2018; 70(3): 339–342

[163] Seo BR , Bhardwaj P , Choi S , Gonzalez J , Andresen Eguiluz RC , Wang K , Mohanan S , Morris PG , Du B , Zhou XK , Vahdat LT , Verma A , Elemento O , Hudis CA , Williams RM , Gourdon D , Dannenberg AJ , Fischbach C . Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med 2015; 7(301): 301ra130

[164] Druso JE , Fischbach C . Biophysical properties of extracellular matrix: linking obesity and cancer. Trends Cancer 2018; 4(4): 271–273

[165] Kim M , Lee C , Park J . Extracellular matrix remodeling facilitates obesity-associated cancer progression. Trends Cell Biol 2022; 32(10): 825–834

[166] Bobulescu IA , Lotan Y , Zhang J , Rosenthal TR , Rogers JT , Adams-Huet B , Sakhaee K , Moe OW . Triglycerides in the human kidney cortex: relationship with body size. PLoS One 2014; 9(8): e101285

[167] Bobulescu IA , Pop LM , Mani C , Turner K , Rivera C , Khatoon S , Kairamkonda S , Hannan R , Palle K . Renal lipid metabolism abnormalities in obesity and clear cell renal cell carcinoma. Metabolites 2021; 11(9): 608

[168] Li Z , Liu H , He J , Wang Z , Yin Z , You G , Wang Z , Davis RE , Lin P , Bergsagel PL , Manasanch EE , Wong STC , Esnaola NF , Chang JC , Orlowski RZ , Yi Q , Yang J . Acetyl-CoA synthetase 2: a critical linkage in obesity-induced tumorigenesis in myeloma. Cell Metab 2021; 33(1): 78–93.e7

[169] Ling R , Chen G , Tang X , Liu N , Zhou Y , Chen D . Acetyl-CoA synthetase 2(ACSS2): a review with a focus on metabolism and tumor development. Discov Oncol 2022; 13(1): 58

[170] Astrup A , Grunwald GK , Melanson EL , Saris WHM , Hill JO . The role of low-fat diets in body weight control: a meta-analysis of ad libitum dietary intervention studies. Int J Obes 2000; 24(12): 1545–1552

[171] Jiao L , Chen L , White DL , Tinker L , Chlebowski RT , Van Horn LV , Richardson P , Lane D , Sangi-Haghpeykar H , El-Serag HB . Low-fat dietary pattern and pancreatic cancer risk in the women’s health initiative dietary modification randomized controlled trial. J Natl Cancer Inst 2018; 110(1): 49–56

[172] Peng L , Xiang L , Xu Z , Gu H , Zhu Z , Tang Y , Jiang Y , He H , Wang Y , Zhao X . Association between low-fat diet and liver cancer risk in 98, 455 participants: Results from a prospective study. Front Nutr 2022; 9: 1013643

[173] Zhong GC , Li QJ , Yang PF , Wang YB , Hao FB , Wang K , Hu JJ , Wu JJ . Low-carbohydrate diets and the risk of pancreatic cancer: a large prospective cohort study. Carcinogenesis 2021; 42(5): 724–732

[174] Yu YC , Paragomi P , Wang R , Jin A , Schoen RE , Sheng LT , Pan A , Koh WP , Yuan JM , Luu HN . Composite dietary antioxidant index and the risk of colorectal cancer: findings from the Singapore Chinese Health Study. Int J Cancer 2022; 150(10): 1599–1608

[175] Parohan M , Sadeghi A , Khatibi SR , Nasiri M , Milajerdi A , Khodadost M , Sadeghi O . Dietary total antioxidant capacity and risk of cancer: a systematic review and meta-analysis on observational studies. Crit Rev Oncol Hematol 2019; 138: 70–86

[176] Roslan NH , Makpol S , Mohd Yusof YA . A review on dietary intervention in obesity associated colon cancer. Asian Pac J Cancer Prev 2019; 20(5): 1309–1319

[177] Schwingshackl L , Schwedhelm C , Galbete C , Hoffmann G . Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis. Nutrients 2017; 9(10): 1063

[178] Buckland G , Bach A , Serra-Majem L . Obesity and the Mediterranean diet: a systematic review of observational and intervention studies. Obes Rev 2008; 9(6): 582–593

[179] Bahrami A , Khalesi S , Makiabadi E , Alibeyk S , Hajigholam-Saryazdi M , Hejazi E . Adherence to the Mediterranean diet and the risk of lung cancer: a systematic review and dose-response meta-analysis of observational studies. Nutr Rev 2022; 80(5): 1118–1128

[180] Dominguez LJ , Veronese N , Di Bella G , Cusumano C , Parisi A , Tagliaferri F , Ciriminna S , Barbagallo M . Mediterranean diet in the management and prevention of obesity. Exp Gerontol 2023; 174: 112121

[181] Lotfi K , Saneei P , Hajhashemy Z , Esmaillzadeh A . Adherence to the Mediterranean diet, five-year weight change, and risk of overweight and obesity: a systematic review and dose-response meta-analysis of prospective cohort studies. Adv Nutr 2022; 13(1): 152–166

[182] Schwingshackl L , Hoffmann G . Adherence to Mediterranean diet and risk of cancer: A systematic review and meta-analysis of observational studies. Int J Cancer 2014; 135(8): 1884–1897

[183] Chen W , Liu X , Bao L , Yang P , Zhou H . Health effects of the time-restricted eating in adults with obesity: a systematic review and meta-analysis. Front Nutr 2023; 10: 1079250

[184] Lugo D , Pulido AL , Mihos CG , Issa O , Cusnir M , Horvath SA , Lin J , Santana O . The effects of physical activity on cancer prevention, treatment and prognosis: a review of the literature. Complement Ther Med 2019; 44: 9–13

[185] McTiernan A , Friedenreich CM , Katzmarzyk PT , Powell KE , Macko R , Buchner D , Pescatello LS , Bloodgood B , Tennant B , Vaux-Bjerke A , George SM , Troiano RP , Piercy KL; 2018 Physical Activity Guidelines Advisory Committee . Physical activity in cancer prevention and survival: a systematic review. Med Sci Sports Exerc 2019; 51(6): 1252–1261

[186] Rosa-Neto JC , Silveira LS . Endurance exercise mitigates immunometabolic adipose tissue disturbances in cancer and obesity. Int J Mol Sci 2020; 21(24): 9745

[187] McTiernan A , Tworoger SS , Ulrich CM , Yasui Y , Irwin ML , Rajan KB , Sorensen B , Rudolph RE , Bowen D , Stanczyk FZ , Potter JD , Schwartz RS . Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer Res 2004; 64(8): 2923–2928

[188] SydóN U , Iftikhar E , Csulak A , Meza B , Merkely AR , Bonikowske KAG , Carta N , Hussain Y , Assaf JG , Murphy F , Lopez-Jimenez RW , Squires KR , Bailey TG . Exercise test predicts both noncardiovascular and cardiovascular death in a primary prevention population. Mayo Clin Proc 2023; 98(9): 1297–1309

[189] Ozemek C , Arena R , Lavie CJ . Predicting the future in primary care patients through graded exercise testing. Mayo Clin Proc 2023; 98(9): 1270–1272

[190] Aminian A , Wilson R , Al-Kurd A , Tu C , Milinovich A , Kroh M , Rosenthal RJ , Brethauer SA , Schauer PR , Kattan MW , Brown JC , Berger NA , Abraham J , Nissen SE . Association of bariatric surgery with cancer risk and mortality in adults with obesity. JAMA 2022; 327(24): 2423–2433

[191] Colquitt JL , Pickett K , Loveman E , Frampton GK . Surgery for weight loss in adults. Cochrane Database Syst Rev 2014; 2014(8): CD003641

[192] Wiggins T , Antonowicz SS , Markar SR . Cancer risk following bariatric surgery—systematic review and meta-analysis of national population-based cohort studies. Obes Surg 2019; 29(3): 1031–1039

[193] Pararas N , Pikouli A , Dellaportas D , Nastos C , Charalampopoulos A , Muqresh MA , Bagias G , Pikoulis E , Papaconstantinou D . The protective effect of bariatric surgery on the development of colorectal cancer: a systematic review and meta-analysis. Int J Environ Res Public Health 2023; 20(5): 3981

[194] Lazzati A , Poghosyan T , Touati M , Collet D , Gronnier C . Risk of esophageal and gastric cancer after bariatric surgery. JAMA Surg 2023; 158(3): 264–271

[195] Upala S , Anawin S . Bariatric surgery and risk of postoperative endometrial cancer: a systematic review and meta-analysis. Surg Obes Relat Dis 2015; 11(4): 949–955

[196] Ishihara BP , Farah D , Fonseca MCM , Nazario A . The risk of developing breast, ovarian, and endometrial cancer in obese women submitted to bariatric surgery: a meta-analysis. Surg Obes Relat Dis 2020; 16(10): 1596–1602

[197] Chierici A , Amoretti P , Drai C , De Fatico S , Barriere J , Schiavo L , Iannelli A . Does bariatric surgery reduce the risk of colorectal cancer in individuals with morbid obesity? A systematic review and meta-analysis. Nutrients 2023; 15(2): 467

[198] Wilson RB , Lathigara D , Kaushal D . Systematic review and meta-analysis of the impact of bariatric surgery on future cancer risk. Int J Mol Sci 2023; 24(7): 6192

[199] Playdon MC , Hardikar S , Karra P , Hoobler R , Ibele AR , Cook KL , Kumar A , Ippolito JE , Brown JC . Metabolic and bariatric surgery and obesity pharmacotherapy for cancer prevention: current status and future possibilities. J Natl Cancer Inst Monogr 2023; 2023(61): 68–76

[200] Alhassan S , Kim S , Bersamin A , King AC , Gardner CD . Dietary adherence and weight loss success among overweight women: results from the A TO Z weight loss study. Int J Obes 2008; 32(6): 985–991

[201] Rubino DM , Greenway FL , Khalid U , O’Neil PM , Rosenstock J , Sørrig R , Wadden TA , Wizert A , Garvey WT , Arauz-Pacheco C , Cannon K , Downey HJ , Fitz-Patrick D , Geohas J , Gerety G , Gilbert J , Hollander P , Klein E , Laufer K , O’Donnell P , Rosenblit P , Toth P . Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA 2022; 327(2): 138–150

[202] Magro DO , Geloneze B , Delfini R , Pareja BC , Callejas F , Pareja JC . Long-term weight regain after gastric bypass: a 5-year prospective study. Obes Surg 2008; 18(6): 648–651

[203] Anderson JW , Konz EC , Frederich RC , Wood CL . Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr 2001; 74(5): 579–584

[204] Shirakami Y , Kochi T , Kubota M , Sakai H , Ibuka T , Yoshimi K , Kuramoto T , Tanaka T , Shimizu M , Seishima M . Inhibitory effects of pentoxifylline on inflammation-related tumorigenesis in rat colon. Oncotarget 2018; 9(74): 33972–33981

[205] Fukuta K , Shirakami Y , Maruta A , Obara K , Iritani S , Nakamura N , Kochi T , Kubota M , Sakai H , Tanaka T , Shimizu M . Preventive effects of pentoxifylline on the development of colonic premalignant lesions in obese and diabetic mice. Int J Mol Sci 2017; 18(2): 413

[206] Samlaska CP , Winfield EA . Pentoxifylline. J Am Acad Dermatol 1994; 30(4): 603–621

[207] Kubota M , Shimizu M , Sakai H , Yasuda Y , Ohno T , Kochi T , Tsurumi H , Tanaka T , Moriwaki H . Renin-angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Biochem Biophys Res Commun 2011; 410(1): 108–113

[208] Løfling L , Stoer NC , Nafisi S , Ursin G , Hofvind S , Botteri E . Low-dose aspirin and risk of breast cancer: a Norwegian population-based cohort study of one million women. Eur J Epidemiol 2023; 38(4): 413–426

[209] Cui Y , Deming-Halverson SL , Shrubsole MJ , Beeghly-Fadiel A , Cai H , Fair AM , Shu XO , Zheng W . Use of nonsteroidal anti-inflammatory drugs and reduced breast cancer risk among overweight women. Breast Cancer Res Treat 2014; 146(2): 439–446

[210] Shimizu M , Tanaka T , Moriwaki H . Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis. Semin Immunopathol 2013; 35(2): 191–202

[211] Shimizu M , Sakai H , Shirakami Y , Iwasa J , Yasuda Y , Kubota M , Takai K , Tsurumi H , Tanaka T , Moriwaki H . Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BLKS/J-+Lepr^db/+Lepr^db mice. Cancer Prev Res (Phila) 2011; 4(1): 128–136

[212] Derbyshire AE , Allen JL , Gittins M , Lakhiani B , Bolton J , Shaw J , Pemberton PW , Needham M , MacKintosh ML , Edmondson RJ , Kitchener HC , Crosbie EJ . PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) trial: a feasibility study. Cancer Prev Res (Phila) 2021; 14(2): 263–274

[213] Kato J , Shirakami Y , Ohnishi M , Mizutani T , Kubota M , Sakai H , Ibuka T , Tanaka T , Shimizu M . Suppressive effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin on colorectal tumorigenesis in diabetic and obese mice. Oncol Rep 2019; 42(6): 2797–2805

[214] Obara K , Shirakami Y , Maruta A , Ideta T , Miyazaki T , Kochi T , Sakai H , Tanaka T , Seishima M , Shimizu M . Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Oncotarget 2017; 8(35): 58353–58363

[215] Poole RM , Prossler JE . Tofogliflozin: first global approval. Drugs 2014; 74(8): 939–944

[216] Archer E , Lavie CJ . Obesity subtyping: the etiology, prevention, and management of acquired versus inherited obese phenotypes. Nutrients 2022; 14(11): 2286

[217] Pfalzer AC , Nesbeth PD , Parnell LD , Iyer LK , Liu Z , Kane AV , Chen CY , Tai AK , Bowman TA , Obin MS , Mason JB , Greenberg AS , Choi SW , Selhub J , Paul L , Crott JW . Diet- and genetically-induced obesity differentially affect the fecal microbiome and metabolome in Apc1638N mice. PLoS One 2015; 10(8): e0135758

[218] Amin HA , Kaewsri P , Yiorkas AM , Cooke H , Blakemore AI , Drenos F . Mendelian randomisation analyses of UK Biobank and published data suggest that increased adiposity lowers risk of breast and prostate cancer. Sci Rep 2022; 12(1): 909

[219] Martincorena I , Campbell PJ . Somatic mutation in cancer and normal cells. Science 2015; 349(6255): 1483–1489

[220] Drapela S , Ilter D , Gomes AP . Metabolic reprogramming: a bridge between aging and tumorigenesis. Mol Oncol 2022; 16(18): 3295–3318

[221] Biragyn A , Ferrucci L . Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging. Lancet Oncol 2018; 19(6): e295–e304

[222] Drijvers JM , Sharpe AH , Haigis MC . The effects of age and systemic metabolism on anti-tumor T cell responses. eLife 2020; 9: e62420

[223] Pawelec G . Does patient age influence anti-cancer immunity. Semin Immunopathol 2019; 41(1): 125–131

[224] Takeuchi T , Kameyama K , Miyauchi E , Nakanishi Y , Kanaya T , Fujii T , Kato T , Sasaki T , Tachibana N , Negishi H , Matsui M , Ohno H . Fatty acid overproduction by gut commensal microbiota exacerbates obesity. Cell Metab 2023; 35(2): 361–375.e9

[225] Brake B , Braghetta P , Banting G , Bressan G , Luzio JP , Stanley KK . A new recombinant DNA strategy for the molecular cloning of rare membrane proteins. Biochem J 1990; 267(3): 631–637

[226] Wei M , Huang F , Zhao L , Zhang Y , Yang W , Wang S , Li M , Han X , Ge K , Qu C , Rajani C , Xie G , Zheng X , Zhao A , Bian Z , Jia W . A dysregulated bile acid-gut microbiota axis contributes to obesity susceptibility. EBioMedicine 2020; 55: 102766

[227] Khoruts A , Sadowsky MJ . Understanding the mechanisms of faecal microbiota transplantation. Nat Rev Gastroenterol Hepatol 2016; 13(9): 508–516

[228] Lee KA , Thomas AM , Bolte LA , Bjork JR , de Ruijter LK , Armanini F , Asnicar F , Blanco-Miguez A , Board R , Calbet-Llopart N , Derosa L , Dhomen N , Brooks K , Harland M , Harries M , Leeming ER , Lorigan P , Manghi P , Marais R , Newton-Bishop J , Nezi L , Pinto F , Potrony M , Puig S , Serra-Bellver P , Shaw HM , Tamburini S , Valpione S , Vijay A , Waldron L , Zitvogel L , Zolfo M , de Vries EGE , Nathan P , Fehrmann RSN , Bataille V , Hospers GAP , Spector TD , Weersma RK , Segata N . Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat Med 2022; 28(3): 535–544

[229] Chaput N , Lepage P , Coutzac C , Soularue E , Le Roux K , Monot C , Boselli L , Routier E , Cassard L , Collins M , Vaysse T , Marthey L , Eggermont A , Asvatourian V , Lanoy E , Mateus C , Robert C , Carbonnel F . Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017; 28(6): 1368–1379

[230] Peng Z , Cheng S , Kou Y , Wang Z , Jin R , Hu H , Zhang X , Gong JF , Li J , Lu M , Wang X , Zhou J , Lu Z , Zhang Q , Tzeng DTW , Bi D , Tan Y , Shen L . The gut microbiome is associated with clinical response to anti-PD-1/PD-L1 immunotherapy in gastrointestinal cancer. Cancer Immunol Res 2020; 8(10): 1251–1261

[231] Routy B , Le Chatelier E , Derosa L , Duong CPM , Alou MT , Daillere R , Fluckiger A , Messaoudene M , Rauber C , Roberti MP , Fidelle M , Flament C , Poirier-Colame V , Opolon P , Klein C , Iribarren K , Mondragon L , Jacquelot N , Qu B , Ferrere G , Clemenson C , Mezquita L , Masip JR , Naltet C , Brosseau S , Kaderbhai C , Richard C , Rizvi H , Levenez F , Galleron N , Quinquis B , Pons N , Ryffel B , Minard-Colin V , Gonin P , Soria JC , Deutsch E , Loriot Y , Ghiringhelli F , Zalcman G , Goldwasser F , Escudier B , Hellmann MD , Eggermont A , Raoult D , Albiges L , Kroemer G , Zitvogel L . Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371): 91–97

[232] Zhao J , Xu H , Su Y , Pan J , Xie S , Xu J , Qin L . Emerging regulatory mechanisms of N⁶-methyladenosine modification in cancer metastasis. Phenomics 2023; 3(1): 83–100

[233] Riquelme E , Zhang Y , Zhang L , Montiel M , Zoltan M , Dong W , Quesada P , Sahin I , Chandra V , San Lucas A , Scheet P , Xu H , Hanash SM , Feng L , Burks JK , Do KA , Peterson CB , Nejman D , Tzeng CD , Kim MP , Sears CL , Ajami N , Petrosino J , Wood LD , Maitra A , Straussman R , Katz M , White JR , Jenq R , Wargo J , McAllister F . Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 2019; 178(4): 795–806.e12

[234] Troy EB , Kasper DL . Beneficial effects of Bacteroides fragilis polysaccharides on the immune system. Front Biosci 2010; 15(1): 25–34

[235] Hidalgo-Cantabrana C , Delgado S , Ruiz L , Ruas-Madiedo P , Sanchez B , Margolles A . Bifidobacteria and their health-promoting effects. Microbiol Spectr 2017; 5: 1–1

[236] Lu Y , Yuan X , Wang M , He Z , Li H , Wang J , Li Q . Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J Hematol Oncol 2022; 15(1): 47

[237] Deng H , Li Z , Tan Y , Guo Z , Liu Y , Wang Y , Yuan Y , Yang R , Bi Y , Bai Y , Zhi F . A novel strain of Bacteroides fragilis enhances phagocytosis and polarises M1 macrophages. Sci Rep 2016; 6(1): 29401

[238] Mocanu V , Zhang Z , Deehan EC , Kao DH , Hotte N , Karmali S , Birch DW , Samarasinghe KK , Walter J , Madsen KL . Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial. Nat Med 2021; 27(7): 1272–1279

[239] Wei MY , Shi S , Liang C , Meng QC , Hua J , Zhang YY , Liu J , Zhang B , Xu J , Yu XJ . The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer 2019; 18(1): 97

[240] No authors listed . Lung microbiota promote lung cancer. Cancer Discov 2019; 9(4): 458

[241] Jin C , Lagoudas GK , Zhao C , Bullman S , Bhutkar A , Hu B , Ameh S , Sandel D , Liang XS , Mazzilli S , Whary MT , Meyerson M , Germain R , Blainey PC , Fox JG , Jacks T . Commensal microbiota promote lung cancer development via γδT cells. Cell 2019; 176(5): 998–1013.e16

[242] Schmandt RE , Iglesias DA , Co NN , Lu KH . Understanding obesity and endometrial cancer risk: opportunities for prevention. Am J Obstet Gynecol 2011; 205(6): 518–525

[243] Onstad MA , Schmandt RE , Lu KH . Addressing the role of obesity in endometrial cancer risk, prevention, and treatment. J Clin Oncol 2016; 34(35): 4225–4230

[244] Istfan NW , Anderson WA , Hess DT , Yu L , Carmine B , Apovian CM . The mitigating effect of phentermine and topiramate on weight regain after Roux-en-Y gastric bypass surgery. Obesity (Silver Spring) 2020; 28(6): 1023–1030

[245] Hsu YJ , Chiu CC , Lee MC , Huang WC . Combination of treadmill aerobic exercise with Bifidobacterium longum OLP-01 supplementation for treatment of high-fat diet-induced obese murine model. Obes Facts 2021; 14(3): 306–319

Acknowledgements

This work was supported by Macao Science and Technology Development Fund (FDCT) grants 0073/2021/A2, and 0009/2022/AKP to K. M.; Research Institute of Tsinghua, Pearl River Delta, ITPRD GBA Innovation Center.

Compliance with ethics guidelines

Xiaoye Shi, Aimin Jiang, Zhengang Qiu, Anqi Lin, Zaoqu Liu, Lingxuan Zhu, Weiming Mou, Quan Cheng, Jian Zhang, Kai Miao, and Peng Luo declare that they have no conflict of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2024 Higher Education Press