Role of Obesity in the Tumorigenesis of Gastric Cancer

Masoumeh Mohammadi

Abstract


Gastric cancer as a common cancer is a multi‑factorial disease that is dependent on parallel effects of environment and genetics. Endogenous and host factors, including gender and several genetic backgrounds are known risk factors also many environmental factors, including smoking, diet, infection and increasing body weight and body mass index (BMI) are associated with the gastric cancer. Epidemiological data have consistently demonstrated a positive relation between obesity and gastric cancer, whereas mechanistic studies have sought to uncover obesity related carcinogenic pathways. Biological mechanisms and the relationship between obesity and cancer are complex and not well understood. Different effective factors include obesity‑related hormones and adipokines, growth factors, modulation of energy balance and calorie restriction, inflammatory processes and multiple signaling pathways that affect cancer cell promotion and progression. In this review, we will discuss the recent advances in the understanding of the association of obesity changes in the gastric cancer.

Keywords


Adipokine; cytokine; gastric cancer; inflammation; obesity

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References


Camargo MC, Goto Y, Zabaleta J, Morgan DR, Correa P,

Rabkin CS. Sex hormones, hormonal interventions, and gastric

cancer risk: A meta-analysis. Cancer Epidemiol Biomarkers Prev

;21:20-38.

Parkin DM. International variation. Oncogene 2004;23:6329‑40.

Guilford P, Hopkins J, Harraway J, Mcleod M, Mcleod N,

Harawira P, et al. E‑cadherin germline mutations in familial

gastric cancer. Nature 1998;392:402‑5.

Malekzadeh R, Derakhshan MH, Malekzadeh Z. Gastric

cancer in Iran: Epidemiology and risk factors. Arch Iran Med

;12:576‑83.

Gunter MJ, Leitzmann MF. Obesity and colorectal cancer:

Epidemiology, mechanisms and candidate genes. J Nutr Biochem

;17:145‑56.

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

Epidemiological evidence and proposed mechanisms. Nat Rev

Cancer 2004;4:579‑91.

Yang P, Zhou Y, Chen B, Wan HW, Jia GQ, Bai HL, et al.

Overweight, obesity and gastric cancer risk: Results from a

meta‑analysis of cohort studies. Eur J Cancer 2009;45:2867‑73.

Available from: https://www.who.int/news‑room/fact‑sheets/

detail/obesity‑and‑overweight.

Lichtman MA. Obesity and the risk for a hematological

malignancy: Leukemia, lymphoma, or myeloma. Oncologist

;15:1083‑101.

Pi‑Sunyer X. The medical risks of obesity. Postgrad Med

;121:21‑33.

Harvey AE, Lashinger LM, Hursting SD. The growing challenge

of obesity and cancer: An inflammatory issue. Ann N Y Acad Sci

;1229:45‑52.

Nakajima TE, Yamada Y, Hamano T, Furuta K, Gotoda T,

Katai H, et al. Adipocytokine levels in gastric cancer

patients: Resistin and visfatin as biomarkers of gastric cancer.

J Gastroenterol 2009;44:685‑90.

Hursting SD, Berger NA. Energy balance, host‑related factors,

and cancer progression. J Clin Oncol 2010;28:4058‑65.

Hursting SD, Lashinger LM, Wheatley KW, Rogers CJ,

Colbert LH, Nunez NP, et al. Reducing the weight of cancer:

Mechanistic targets for breaking the obesity‑carcinogenesis link.

Best Pract Res Clin Endocrinol Metab 2008;22:659‑69.

Lakka HM, Salonen JT, Tuomilehto J, Kaplan GA, Lakka TA.

Obesity and weight gain are associated with increased incidence

of hyperinsulinemia in non‑diabetic men. Horm Metab Res

;34:492‑8.

Khan S, Shukla S, Sinha S, Meeran SM. Role of adipokines

and cytokines in obesity‑associated breast cancer: Therapeutic

targets. Cytokine Growth Factor Rev 2013;24:503‑13.

Brick DJ, Gerweck AV, Meenaghan E, Lawson EA, Misra M,

Fazeli P, et al. Determinants of IGF1 and GH across the weight

spectrum: From anorexia nervosa to obesity. Eur J Endocrinol

;163:185‑91.

Finkelstein JW, Kream J, Ludan A, Hellman L. Sulfation factor

(somatomedin): An explanation for continued growth in the

absence of immunoassayable growth hormone in patients with

hypothalamic tumors. J Clin Endocrinol Metab 1972;35:13‑7.

Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk:

The role of the insulin‑IGF axis. Trends Endocrinol Metab

;17:328‑36.

Leroith D, Roberts CT Jr. The insulin‑like growth factor system

and cancer. Cancer Lett 2003;195:127‑37.

Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL,

et al. Phosphorylated insulin‑like growth factor‑i/insulin receptor

is present in all breast cancer subtypes and is related to poor

survival. Cancer Res 2008;68:10238‑46.

Chan BT, Lee AV. Insulin receptor substrates (IRSs) and breast

tumorigenesis. J Mammary Gland Biol Neoplasia 2008;13:415‑22.

Shimoyama S. Diabetes mellitus carries a risk of gastric cancer:

A meta‑analysis. World J Gastroenterol 2013;19:6902‑910.

Raucci R, Rusolo F, Sharma A, Colonna G, Castello G,

Costantini S. Functional and structural features of adipokine

family. Cytokine 2013;61:1‑14.

Harvey AE, Lashinger LM, Hursting SD. The growing challenge

of obesity and cancer: An inflammatory issue. Ann N Y Acad Sci

;1229:45‑52.

Pérez‑Hernández AI, Catalán V, Gómez‑Ambrosi J,

Rodríguez A, Frühbeck G. Mechanisms linking excess adiposity

and carcinogenesis promotion. Front Endocrinol (Lausanne)

;5:65.

Arner E, Forrest AR, Ehrlund A, Mejhert N, Itoh M, Kawaji H,

et al. Ceruloplasmin is a novel adipokine which is overexpressed

in adipose tissue of obese subjects and in obesity‑associated

cancer cells. PLoS One 2014;9:e80274.

Urbanek M, Du Y, Silander K, Collins FS, Steppan CM, Strauss JF

rd, et al. Variation in resistin gene promoter not associated with

polycystic ovary syndrome. Diabetes 2003;52:214‑7.

Meier U, Gressner AM. Endocrine regulation of energy

metabolism: Review of pathobiochemical and clinical chemical

aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem

;50:1511‑25.

Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL.

Lipopolysaccharide increases resistin gene expression in vivo and

in vitro. FEBS Lett 2002;530:158‑62.

Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD,

Plumpton C, et al. Resistin is expressed in human macrophages

and directly regulated by PPAR gamma activators. Biochem

Biophys Res Commun 2003;300:472‑6.

Zheng LD, Tong QS, Weng MX, He J, Lv Q, Pu JR, et al.

Enhanced expression of resistin‑like molecule beta in human colon

cancer and its clinical significance. Dig Dis Sci 2009;54:274‑81.

Gorgian Mohammadi M, Hedayati M, Zarghami N,

Ghaemmaghami S, Mohaddes M. Adipocyte derived hormones

gene expression, resistin and visfatin, in AGS gastric cancer cell

line. Iran J Cancer Prev 2013;6:165‑9.

Mohammadi M, Hedayati M, Zarghami N, Ghaemmaghami S.

Resistin effects on telomerase gene expression in AGS gastric

cancer cell line. Acta Endocrinol (Buchar) 2016;12:145‑9.

Hsieh YY, Shen CH, Huang WS, Chin CC, Kuo YH,

Hsieh MC, et al. Resistin‑induced stromal cell‑derived factor‑1

expression through toll‑like receptor 4 and activation of

p38 MAPK/NFκB signaling pathway in gastric cancer cells.

J Biomed Sci 2014;21:59.

Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M,

Kishimoto K, et al. Visfatin: A protein secreted by visceral fat

that mimics the effects of insulin. Science 2005;307:426‑30.

Samal B, Sun Y, Stearns G, Xie C, Suggs S, Mcniece I.

Cloning and characterization of the cDNA encoding a novel

human pre‑B‑cell colony‑enhancing factor. Mol Cell Biol

;14:1431‑7.

Imai S. Nicotinamide phosphoribosyltransferase (Nampt): A link

between NAD biology, metabolism, and diseases. Curr Pharm

Des 2009;15:20‑8.

Brown JE, Onyango DJ, Ramanjaneya M, Conner AC, Patel ST,

Dunmore SJ, et al. Visfatin regulates insulin secretion, insulin

receptor signalling and mRNA expression of diabetes‑related

genes in mouse pancreatic beta‑cells. J Mol Endocrinol

;44:171‑8.

Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A,

et al. Nampt/PBEF/Visfatin regulates insulin secretion in beta

cells as a systemic NAD biosynthetic enzyme. Cell Metab

;6:363‑75.

Kim JG, Kim EO, Jeong BR, Min YJ, Park JW, Kim ES, et al.

Visfatin stimulates proliferation of MCF‑7 human breast cancer

cells. Mol Cells 2010;30:341‑5.

Patel ST, Mistry T, Brown JE, Digby JE, Adya R, Desai KM,

et al. A novel role for the adipokine visfatin/pre‑B cell

colony‑enhancing factor 1 in prostate carcinogenesis. Peptides

;31:51‑7.

Bi TQ, Che XM. Nampt/PBEF/visfatin and cancer. Cancer Biol

Ther 2010;10:119‑25.

Adya R, Tan BK, Punn A, Chen J, Randeva HS. Visfatin

induces human endothelial VEGF and MMP‑2/9 production via

MAPK and PI3K/Akt signalling pathways: Novel insights into

visfatin‑induced angiogenesis. Cardiovasc Res 2008;78:356‑65.

Adya R, Tan BK, Punn A, Chen J, Randeva HS. Visfatin

induces human endothelial VEGF and MMP‑2/9 production via

MAPK and PI3K/Akt signalling pathways: Novel insights into

visfatin‑induced angiogenesis. Cardiovasc Res 2008;78:356‑65.

Kim JY, Bae YH, Bae MK, Kim SR, Park HJ, Wee HJ, et al.

Visfatin through STAT3 activation enhances IL‑6 expression

that promotes endothelial angiogenesis. Biochim Biophys Acta

;1793:1759‑67.

Mohammadi M, Zarghami N, Hedayati M, Ghaemmaghami S,

Yamchi RM, Mohaddes M. Visfatin effects on telomerase gene

expression in AGS gastric cancer cell line. Indian J Cancer

;52:32‑5.

Green ED, Maffei M, Braden VV, Proenca R, Desilva U,

Zhang Y, et al. The human obese (OB) gene: RNA expression

pattern and mapping on the physical, cytogenetic, and genetic

maps of chromosome 7. Genome Res 1995;5:5‑12.

Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP,

Bortoluzzi MN, et al. The stomach is a source of leptin. Nature

;394:790‑3.

Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: A review of

its peripheral actions and interactions. Int J Obes Relat Metab

Disord 2002;26:1407‑33.

Considine RV, Sinha MK, Heiman ML, Kriauciunas A,

Stephens TW, Nyce MR, et al. Serum immunoreactive‑leptin

concentrations in normal‑weight and obese humans. N Engl J

Med 1996;334:292‑5.

Ishikawa M, Kitayama J, Nagawa H. Expression pattern of leptin

and leptin receptor (OB‑R) in human gastric cancer. World J

Gastroenterol 2006;12:5517‑22.

Zhao L, Shen ZX, Luo HS, Shen L. Possible involvement of

leptin and leptin receptor in developing gastric adenocarcinoma.

World J Gastroenterol 2005;11:7666‑70.

Schneider R, Bornstein SR, Chrousos GP, Boxberger S,

Ehninger G, Breidert M. Leptin mediates a proliferative response

in human gastric mucosa cells with functional receptor. Horm

Metab Res 2001;33:1‑6.

Shida D, Kitayama J, Mori K, Watanabe T, Nagawa H.

Transactivation of epidermal growth factor receptor is involved

in leptin‑induced activation of janus‑activated kinase 2 and

extracellular signal‑regulated kinase 1/2 in human gastric cancer

cells. Cancer Res 2005;65:9159‑63.

Pai R, Lin C, Tran T, Tarnawski A. Leptin activates STAT and

ERK2 pathways and induces gastric cancer cell proliferation.

Biochem Biophys Res Commun 2005;331:984‑92.

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.

Hong SJ, Kwon KW, Kim SG, Ko BM, Ryu CB, Kim YS,

et al. Variation in expression of gastric leptin according to

differentiation and growth pattern in gastric adenocarcinoma.

Cytokine 2006;33:66‑71.

Sobhani I, Bado A, Vissuzaine C, Buyse M, Kermorgant S,

Laigneau JP, et al. Leptin secretion and leptin receptor in the

human stomach. Gut 2000;47:178‑83.

Bolukbas FF, Kilic H, Bolukbas C, Gumus M, Horoz M,

Turhal NS, et al. Serum leptin concentration and advanced

gastrointestinal cancers: A case controlled study. BMC Cancer

;4:29.

Park HK, Ahima RS. Leptin signaling. F1000Prime Rep

;6:73.

Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA,

Mantzoros CS. Leptin at the intersection of neuroendocrinology

and metabolism: Current evidence and therapeutic perspectives.

Cell Metab 2013;18:29‑42.

Moon HS, Dalamaga M, Kim SY, Polyzos SA, Hamnvik OP,

Magkos F, et al. Leptin’s role in lipodystrophic and

nonlipodystrophic insulin‑resistant and diabetic individuals.

Endocr Rev 2013;34:377‑412.

Motoshima H, Wu X, Sinha MK, Hardy VE, Rosato EL,

Barbot DJ, et al. Differential regulation of adiponectin secretion

from cultured human omental and subcutaneous adipocytes:

Effects of insulin and rosiglitazone. J Clin Endocrinol Metab

;87:5662‑7.

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

Holt PR. Mechanisms of obesity‑induced gastrointestinal

neoplasia. Gastroenterology 2014;146:357‑73.

Ouchi N, Walsh K. Adiponectin as an anti‑inflammatory factor.

Clin Chim Acta 2007;380:24‑30.

Barb D, Williams CJ, Neuwirth AK, Mantzoros CS. Adiponectin

in relation to malignancies: A review of existing basic research

and clinical evidence. Am J Clin Nutr 2007;86:858S‑66S.

Wei T, Ye P, Peng X, Wu LL, Yu GY. Circulating adiponectin

levels in various malignancies: An updated meta‑analysis of 107

studies. Oncotarget 2016;7:48671‑91.

Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K.

Obesity, adiponectin and vascular inflammatory disease. Curr

Opin Lipidol 2003;14:561‑6.

Coussens LM, Werb Z. Inflammation and cancer. Nature

;420:860‑7.

Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer

;9:361‑71.

Araújo EP, De Souza CT, Ueno M, Cintra DE, Bertolo MB,

Carvalheira JB, et al. Infliximab restores glucose homeostasis

in an animal model of diet‑induced obesity and diabetes.

Endocrinology 2007;148:5991‑7.

Hotamisligil GS, Peraldi P, Budavari A, Ellis R. IRS‑1‑mediated

inhibition of insulin receptor tyrosine kinase activity in

TNF‑alpha‑and obesity‑induced insulin resistance. Science

;271:665.

Ghosh S, Karin M. Missing pieces in the NF‑κB puzzle. Cell

;109:S81‑96.

Lee YH, Giraud J, Davis RJ, White MF. c‑Jun N‑terminal

kinase (JNK) mediates feedback inhibition of the insulin

signaling cascade. J Biol Chem 2003;278:2896‑902.

Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE,

White MF. Phosphorylation of Ser307 in insulin receptor

substrate‑1 blocks interactions with the insulin receptor and

inhibits insulin action. J Biol Chem 2002;277:1531‑7.

Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ,

et al. Serine phosphorylation of insulin receptor substrate 1 by

inhibitor κB kinase complex. J Biol Chem 2002;277:48115‑21.

Zhao C, Lu X, Bu X, Zhang N, Wang W. Involvement of tumor

necrosis factor‑alpha in the upregulation of CXCR4 expression

in gastric cancer induced by helicobacter pylori. BMC Cancer

;10:419.

Oshima H, Ishikawa T, Yoshida GJ, Naoi K, Maeda Y,

Naka K, et al. TNF‑[alpha]/TNFR1 signaling promotes gastric

tumorigenesis through induction of Noxo1 and Gna14 in tumor

cells. Oncogene 2014;33:3820‑9.

Ghigliotti G, Barisione C, Garibaldi S, Fabbi P, Brunelli C,

Spallarossa P, et al. Adipose tissue immune response: Novel

triggers and consequences for chronic inflammatory conditions.

Inflammation 2014;37:1337‑53.

Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C,

Pratley RE. Circulating interleukin‑6 in relation to adiposity,

insulin action, and insulin secretion. Obes Res 2001;9:414‑7.

Lukaszewicz‑Zajac M, Mroczko B, Szmitkowski M. [The role

of interleukin‑6 and C‑reactive protein in gastric cancer]. Pol

Merkur Lekarski 2010;29:382‑6.

Ashizawa T, Okada R, Suzuki Y, Takagi M, Yamazaki T, Sumi T,

et al. Clinical significance of interleukin‑6 (IL‑6) in the spread

of gastric cancer: Role of IL‑6 as a prognostic factor. Gastric

Cancer 2005;8:124‑31.

Rojano‑Rodríguez ME, Valenzuela‑Salazar C, Cárdenas‑Lailson LE,

Romero Loera LS, Torres‑Olalde M, Moreno‑Portillo M.

C‑Reactive protein level in morbidly obese patients before and

after bariatric surgery. Revista de Gastroenterología de México

(English Edition) 2014;79:90‑5.

Shimura T, Kitagawa M, Yamada T, Ebi M, Mizoshita T,

Tanida S, et al. C‑reactive protein is a potential prognostic factor

for metastatic gastric cancer. Anticancer Res 2012;32:491‑6.

Chen Z, Sun Y, Wang J, Shen X, Chen L, Zhuang Z. Prognostic

and predictive value of serum C‑reactive protein levels in

patients with metastatic or locally recurrent gastric cancer. Int J

Biol Markers 2016;31:e294‑9.

Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG,

Coronado‑Heinsohn E, Osborne CK, et al. Enhancement of

insulin‑like growth factor signaling in human breast cancer:

Estrogen regulation of insulin receptor substrate‑1 expression

in vitro and in vivo. Mol Endocrinol 1999;13:787‑96.

Clegg DJ, Brown LM, Woods SC, Benoit SC. Gonadal hormones

determine sensitivity to central leptin and insulin. Diabetes

;55:978‑87.

Edelstein ZR, Farrow DC, Bronner MP, Rosen SN,

Vaughan TL. Central adiposity and risk of Barrett’s esophagus.

Gastroenterology 2007;133:403‑11.

Lu Y, Lu F, Zeng S, Sun S, Lu L, Liu L. Genetics and gastric

cancer susceptibility. Int J Clin Exp Med 2015;8:8377‑83.

Motoshima H, Wu X, Sinha MK, Hardy VE, Rosato EL,

Barbot DJ, et al. Differential regulation of adiponectin secretion

from cultured human omental and subcutaneous adipocytes:

Effects of insulin and rosiglitazone. J Clin Endocrinol Metab

;87:5662‑7.

Hemminki K, Li X, Sundquist J, Sundquist K. Obesity

and familial obesity and risk of cancer. Eur J Cancer Prev

;20:438‑43.

Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP,

Tung YC, et al. Role for the obesity‑related FTO gene in the

cellular sensing of amino acids. Proc Natl Acad Sci U S A

;110:2557‑62.

Vongsuvanh R, George J, Qiao L, Van Der Poorten D. Visceral

adiposity in gastrointestinal and hepatic carcinogenesis. Cancer

Lett 2013;330:1‑10.