Abstract
Overweight and/or obesity are known risk factors for many cancers and are associated with poor prognosis. Evidence for this relationship has primarily been obtained from epidemiological studies with in vitro studies characterizing potential pathways that help explain the pathological role of obesity in malignancies. Animal models provide the opportunity to more completely understand disease mechanisms and intervention strategies associated with obesity and tumorigenesis. The most widely used obese animal models result from either genetic defects or consumption of high-fat diets. Genetically obese animals used in cancer research include yellow obese mice, leptin and leptin receptor-deficient mice, and the Zucker rat. Goldthioglucose-induced obesity has occasionally been used as has been ovariectomized animals. A number of studies using rodents have explored the relationship and mechanisms of obesity and the development of mammary tumors. Additional studies have evaluated the effect of obesity in colon, skin, and prostate cancer models. These studies have provided insights into the role of body weight and tumorigenesis. However, more appropriate obesity models will be important in continuing to understand the factors associated with body weight’s impact on the development of cancer and to assist in providing pharmaceutical and nutritional interventions for cancer prevention and treatment.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Basen-Engquist K, Chang M. Obesity and cancer risk: recent review and evidence. Curr Oncol Rep. 2011;13:71–6.
Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91.
Pischon T, Nöthlilngs U, Boeing H. Obesity and cancer. Proc Nutr Soc. 2008;67:128–45.
Harvey AE, Lashinger LM, Hursting SD. The growing challenge of obesity and cancer: an inflammatory issue. Ann N Y Acad Sci. 2011;1229:45–52.
Lysaght J, van der Stok EP, Allott EH, et al. Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue. Cancer Lett. 2011;312:62–72.
Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–32.
Frederich RC, Hamann A, Anderson S, et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995;1:1311–4.
Wolff GL, Roberts DW, Mountjoy KG. Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome. Physiol Genomics. 1999;1:151–63.
Cleary MP, Maihle NJ. The role of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer. Proc Soc Exp Biol Med. 1997;216:28–43.
Grossmann ME, Ray A, Nkhata KJ, et al. Obesity and breast cancer: status of leptin and adiponectin in pathological processes. Cancer Metastasis Rev. 2010;29:641–53.
Rose DP, Vona-Davis L. Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas. 2010;66:33–8.
Heston WE, Vlahakis G. Influence of the Ay gene on mammary-gland tumors, hepatomas, and normal growth in mice. J Natl Cancer Inst. 1961;26:969–83.
Heston WE, Vlahakis G. C3H-Avy- a high hepatoma and mammary tumor strain of mice. J Natl Cancer Inst. 1968;40:1161–6.
Wolff GL, Medina D, Umholtz RL. Manifestation of hyperplastic alveolar modules and mammary tumors in “viable yellow” and non-yellow mice. J Natl Cancer Inst. 1979;63:781–5.
Wolff GL, Kodell RL, Cameron AM, et al. Accelerated appearance of chemically induced mammary carcinomas in obese yellow (Avy/A) (BALB/c Xvy) F1 hybrid mice. J Toxicol Environ Health. 1982;10:131–42.
Heston WE, Vlahakis G. Genetic obesity and neoplasia. J Natl Cancer Inst. 1962;29:197–209.
Cleary MP, Phillips FC, Getzin SC, et al. Genetically obese MMTV-TGF-α/Lep ob Lep ob mice do not develop of mammary tumors. Breast Cancer Res Treat. 2003;77:205–15.
Cleary MP, Juneja SC, Phillips FC, et al. Leptin receptor deficient MMTV-TGF-α/Lepr db Lepr db female mice do not develop oncogene-induced mammary tumors. Exp Biol Med. 2004;229:182–93.
Lee WM, Lu S, Medline A, et al. Susceptibility of lean and obese Zucker rats to tumorigenesis induced by N-methyl-N-nitrosurea. Cancer Lett. 2001;162:155–60.
Hakkak R, Holley AW, MacLeod SL, et al. Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female Zucker rats. Breast Cancer Res. 2005;7:R627–33.
Klurfeld DM, Lloyd LM, Welch CB, et al. Reduction of enhanced mammary carcinogenesis in LA/N-cp (corpulent) rats by energy restriction. Proc Soc Exp Biol Med. 1991;196:381–4.
Waxler SH, Tabar P, Melcher LP. Obesity and the time of appearance of spontaneous mammary carcinoma in C3H mice. Cancer Res. 1953;13:276–8.
Nkhata KJ, Ray A, Dogan S, et al. Mammary tumor development from T47-D human breast cancer cells in obese ovariectomized mice with and without estradiol supplements. Breast Cancer Res Treat. 2009;114:71–83.
Hu X, Juneja SC, Maihle NJ, et al. Leptin- a growth factor for normal and malignant breast cells and normal mammary gland development. J Natl Cancer Inst. 2002;94:1704–11.
Laud K, Gourdou I, Pessemesse L, et al. Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol. 2002;188:219–26.
Waxler SH, Leef MF. Augmentation of mammary tumors in castrated obese C3H mice. Cancer Res. 1966;26:860–2.
Pariza MW. Fat, calories, and mammary carcinogenesis: net energy effects. Am J Clin Nutr. 1987;45:261–3.
Welsch CW, House JL, Herr BL, et al. Enhancement of mammary carcinogenesis by high levels of dietary fat: a phenomenon dependent on ad libitum feeding. J Natl Cancer Inst. 1990;82:1615–20.
Cleary MP, Grande JP, Juneja SC, et al. Effect of dietary-induced obesity and mammary tumor development in MMTV-neu female mice. Nutr Cancer. 2004;50:174–80.
Cleary MP, Grande JP, Maihle NJ. Effect of a high fat diet on body weight and mammary tumor latency in MMTV-TGF-α mice. Int J Obes Relat Metab Disord. 2004;28:956–62.
Dogan S, Hu X, Zhang Y, et al. Effects of high fat diet and/or body weight on mammary tumor leptin and apoptosis signaling pathways in MMTV-TGF-α mice. Breast Cancer Res. 2007;9:R91.
Khalid S, Hwang D, Babichev Y, et al. Evidence for tumor promoting effect of high-fat diet independent of insulin resistance in HER2/Neu mammary carcinogenesis. Breast Cancer Res Treat. 2010;122:647–59.
Núnez NP, Perkins SN, Smith NCP, et al. Obesity accelerates mouse mammary tumor growth in the absence of ovarian hormones. Nutr Cancer. 2008;60:534–41.
Brodie A, Lu Q, Nakamura J. Aromatase in the normal breast and breast cancer. J Steroid Biochem Mol Biol. 1997;61:281–6.
Siiteri PK. Adipose tissue as a source of hormones. Am J Clin Nutr. 1987;45:277–82.
Subbaramaiah K, Howe LR, Bhardwaj P, et al. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila). 2011;4:329–46.
Sonnenschein EG, Glickman LT, Goldschmidt LT, et al. Body conformation, diet, and risk of breast cancer in pet dogs: a case-control study. Am J Epidemiol. 1991;133:694–703.
Alenza DP, Rutterman GR, Peña L, et al. Relation between habitual diet and canine mammary tumors in a case-control study. J Vet Intern Med. 1998;12:132–9.
Calle EE, Thun MJ. Obesity and cancer. Oncogene. 2004;23:6365–78.
Donohoe CL, Pidgeon GP, Lysaght J, et al. Obesity and gastrointestinal cancer. Br J Surg. 2010;97:628–42.
Freeman HJ. Risk of gastrointestinal malignancies and mechanisms of cancer development with obesity and its treatment. Best Pract Res Clin Gastroenterol. 2004;18:1167–75.
Hirose Y, Hata K, Kuno T, et al. Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-/db/db mice. Carcinogenesis. 2004;25:821–5.
Ealey KN, Lu S, Archer MC. Development of aberrant crypt foci in the colons of ob/ob and db/db mice: evidence that leptin is not a promoter. Mol Carcinog. 2008;47:667–77.
Bobe G, Barrett KG, Mentor-Marcel RA, et al. Dietary cooked navy beans and their fractions attenuate colon carcinogenesis in azoxymethane-induced ob/ob mice. Nutr Cancer. 2008;60:373–80.
Hayashi K, Suzuki R, Miyamoto S, et al. Citrus auraptene suppresses azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ/db/db mice. Nutr Cancer. 2007;58:75–84.
Miyamoto S, Yasui Y, Ohigashi H, et al. Dietary flavonoids suppress azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice. Chem Biol Interact. 2010;183:276–83.
Yasuda Y, Shimizu M, Shirakami Y, et al. Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci. 2010;101:1701–7.
Raju J, Bird RP. Energy restriction reduces the number of advanced aberrant crypt foci and attenuates the expression of colonic transforming growth factor β and cyclooxygenase isoforms in Zucker obese (fa/fa) rats. Cancer Res. 2003;63:6595–601.
Weber RV, Stein DE, Kim J, et al. Obesity potentiates experimental colon cancer. Int J Obes. 1997;20:S85.
Cowey SL, Quast M, Belalcazar LM, et al. Abdominal obesity, insulin resistance, and colon carcinogenesis are increased in mutant mice lacking gastrin gene expression. Cancer. 2005;103:2643–53.
Teraoka N, Mutoh M, Takasu S, et al. High susceptibility to azoxymethane-induced colorectal carcinogenesis in obese KK-Ay mice. Int J Cancer. 2011;129:528–35.
Fodde R, Edelmann W, Yang K, et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA. 1994;91:8969–73.
Gravaghi C, Bo J, LaPerle KMD, et al. Obesity enhances gastrointestinal tumorigenesis in APC-mutant mice. Int J Obes. 2008;32:1716–9.
Ding S, McEntee MF, Whelan J, et al. Adiposity-related protection of intestinal tumorigenesis: interaction with dietary calcium. Nutr Cancer. 2007;58:153–61.
Algire C, Amrein L, Zakikhani M, et al. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:351–60.
Yakar S, Nunez NP, Pennisi P, et al. Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology. 2006;147:5826–34.
Wu Y, Brodt P, Sun H, et al. Insulin-like growth factor-I regulates the liver microenvironment in obese mice and promotes liver metastasis. Cancer Res. 2010;70:57–67.
Drew JE, Farquharson AJ, Padidar S, et al. Insulin, leptin, and adiponectin receptors in colon: regulation relative to differing body adiposity independent of diet and in response to dimethylhydrazine. Am J Physiol. 2007;293:G682–91.
Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–38.
Qian Y, Fan J-G. Obesity, fatty liver and liver cancer. Hepatobiliary Pancreat Dis Int. 2005;4:173–7.
Waxler SH. Obesity and cancer susceptibility in mice. Am J Clin Nutr. 1960;8:760–6.
Yang S, Lin HZ, Hwang J, et al. Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition? Cancer Res. 2001;61:5016–23.
Soga M, Hashimoto M, Kishimoto Y, et al. Insulin resistance, steatohepatitis, and hepatocellular carcinoma in a new congeneic strain of fatty liver Shionogi (FLS) mice with the Lep ob gene. Exp Anim. 2010;59:407–19.
Hill-Baskin AE, Markiewski MM, Buchner DA, et al. Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum Mol Genet. 2009;18:2975–88.
Wunderlich FT, Luedde T, Stinger S, et al. 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;105:1297–302.
Park EJ, Lee JH, Yu G-Y, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.
Lemke LB, Rogers AB, Nambiar PR, et al. Obesity and non-insulin-dependent diabetes mellitus in Swiss-Webster mice associated with late-onset hepatocellular carcinoma. J Endocrinol. 2008;199:21–32.
Stauffer JK, Scarzello AJ, Anderson JB, et al. Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors. Cancer Res. 2011;71:2718–27.
Iatropoulos MJ, Duan JD, Jeffrey AM, et al. Hepatocellular proliferation and hepatocarcinogen bioactivation in mice with diet-induced fatty liver and obesity. Exp Toxicol Pathol. 2013;65:451–6.
Shimizu M, Sakai H, Shirakami Y, et al. Preventive effects of (−)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Prev Res (Phila). 2011;4:396–403.
Amling CL. Relationship between obesity and prostate cancer. Curr Opin Urol. 2005;15:167–71.
Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2011;4:486–501.
De Nunzio C, Freedland SJ, Miano L, et al. The uncertain relationship between obesity and prostate cancer: an Italian biopsy cohort analysis. Eur J Surg Oncol. 2011;37:1025–9.
Fowke JH, Motley SS, Concepcion RS, et al. Obesity, body composition, and prostate cancer. BMC Cancer. 2012;12:23.
Llaverias G, Danillo C, Wang Y, et al. A Western-type diet accelerates tumor progression in an autochtonous mouse model of prostate cancer. Am J Pathol. 2010;177:3180–91.
Bonorden MJL, Grossmann ME, Ewing SA, et al. Growth and progression of TRAMP prostate tumors in relation to diet and obesity. Prostate Cancer. 2012;2012:543970.
Blando J, Moore T, Hursting S, et al. Dietary energy balance modulates prostate cancer progression in Hi-Myc mice. Cancer Prev Res (Phila). 2011;4:2002–14.
Ribeiro AM, Andrade S, Pihno F, et al. Prostate cancer cell proliferation and angiogenesis in different obese mice models. Int J Exp Pathol. 2010;91:374–86.
Lamarre NS, Ruggieri MR, Braverman AS, et al. Effect of obese and lean Zucker rat sera on human and rat prostate cancer cells: implications in obesity-related prostate tumor biology. Urology. 2007;69:191–5.
Dinkova-Kostova AT, Fahey JW, Jenkins SN, et al. Rapid body weight gain incrases the risk of UV radiation-induced skin carcinogenesis in SKH-1 hairless mice. Nutr Res. 2008;28:539–43.
Sharma SD, Katiyar SK. Leptin deficiency-induced obesity exacerbates ultraviolet B radiation induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin. Toxicol Appl Pharmacol. 2010;244:328–35.
Yun JP, Behan JW, Heisterkamp N, et al. Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models. Cancer Prev Res (Phila). 2010;3:1259–64.
Yu W, Cline M, Maxwell LG, et al. Dietary vitamin D exposure prevents obesity-induced increase in endometrial cancer in Pten +/− mice. Cancer Prev Res (Phila). 2010;3:1246–58.
Shors AR, Solomon C, McTiernan A, et al. Melanoma risk in relation to height, weight, and exercise (United States). Cancer Causes Control. 2001;12:599–606.
Gallus S, Naldi L, Martin L, et al. Anthropometric measures and risk of cutaneous malignant melanoma: a case-control study from Italy. Melanoma Res. 2006;16:83–7.
Naldi L, Altieri A, Imberti G, et al. Cutaneous malignant melanoma in women. Phenotypic characteristics, sun exposure, and hormonal factors: a case-control study from Italy. Ann Epidemiol. 2005;15:545–50.
Dennis LK, Lowe JB, Lynch CF, et al. Cutaneous melanoma and obesity in the agricultural health study. Ann Epidemiol. 2008;18:214–21.
Pandley V, Vijaykumar MV, Ajay AK, et al. Diet-induced obesity increases melanoma progression: involvement of Cav-1 and FASN. Int J Cancer. 2012;130:497–508.
Brandon EL, Gu J-W, Cantwell L, et al. Obesity promotes melanoma tumor growth: role of leptin. Cancer Biol Ther. 2009;8:1871–9.
Kushiro K, Núnez NP. Ob/ob serum promotes mesenchymal cell phenotype in B16BL6 melanoma cells. Clin Exp Metastasis. 2011;28:877–86.
Mori A, Sakurai H, Choo M-K, et al. Severe pulmonary metastasis in obese and diabetic mice. Int J Cancer. 2006;119:2760–7.
Zyromski NJ, Mathur A, Pitt HA, et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery. 2009;146:258–63.
White PB, True EM, Ziegler KM, et al. Insulin, leptin, and tumoral adipocytes promote murine pancreatic cancer growth. J Gastrointest Surg. 2010;14:1888–94.
Zhang Q, Shen Q, Celestino J, et al. Enhanced estrogen-induced proliferation in obese rat endometrium. Am J Obstet Gynecol. 2009;200:186.e1–8.
Acknowledgments
This work was supported by NIH-NCI grant CA157012 and the Hormel Foundation.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Ray, A., Cleary, M.P. (2013). Animal Models to Study the Interplay Between Cancer and Obesity. In: Kolonin, M. (eds) Adipose Tissue and Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7660-3_6
Download citation
DOI: https://doi.org/10.1007/978-1-4614-7660-3_6
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-7659-7
Online ISBN: 978-1-4614-7660-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)