Molecular mechanisms of cancer development in obesity (original) (raw)

• Flegal, K. M., Carroll, M. D., Ogden, C. L. & Curtin, L. R. Prevalence and trends in obesity among US adults, 1999–2008 JAMA 303, 235–41 (2010).
  Article CAS PubMed Google Scholar
• Finucane, M. M. et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 377, 557–567 (2011).
  Article PubMed PubMed Central Google Scholar
• Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).
  Article PubMed Google Scholar
• Lichtman, M. A. Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist 15, 1083–1101 (2010).
  Article PubMed PubMed Central Google Scholar
• Li, D. et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 301, 2553–2562 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• MacInnis, R. J. & English, D. R. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control 17, 989–1003 (2006).
  Article PubMed Google Scholar
• Key, T. J. et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J. Natl Cancer Inst. 95, 1218–1226 (2003).
  Article CAS PubMed Google Scholar
• Lofdahl, H. E. et al. Increased population prevalence of reflux and obesity in the United Kingdom compared with Sweden: a potential explanation for the difference in incidence of esophageal adenocarcinoma. Eur. J. Gastroenterol. Hepatol. 23, 128–132 (2011).
  Article PubMed Google Scholar
• Jeffreys, M., Smith, G. D., Martin, R. M., Frankel, S. & Gunnell, D. Childhood body mass index and later cancer risk: a 50-year follow-up of the Boyd Orr study. Int. J. Cancer 112, 348–351 (2004).
  Article CAS PubMed Google Scholar
• Brown, K. A. & Simpson, E. R. Obesity and breast cancer: progress to understanding the relationship. Cancer Res. 70, 4–7 (2010).
  Article CAS PubMed Google Scholar
• Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
  Article CAS PubMed Google Scholar
• Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Fried, S. K., Bunkin, D. A. & Greenberg, A. S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J. Clin. Endocrinol. Metab. 83, 847–850 (1998).
  CAS PubMed Google Scholar
• Sawdey, M. S. & Loskutoff, D. J. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J. Clin. Invest. 88, 1346–1353 (1991).
  Article CAS PubMed PubMed Central Google Scholar
• Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ruan, H., Zarnowski, M. J., Cushman, S. W. & Lodish, H. F. Standard isolation of primary adipose cells from mouse epididymal fat pads induces inflammatory mediators and down-regulates adipocyte genes. J. Biol. Chem. 278, 47585–47593 (2003).
  Article CAS PubMed Google Scholar
• Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Carswell, E. A. et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666–3670 (1975).
  Article CAS PubMed PubMed Central Google Scholar
• Leibovich, S. J. et al. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329, 630–632 (1987).
  Article CAS PubMed Google Scholar
• Orosz, P. et al. Enhancement of experimental metastasis by tumor necrosis factor. J. Exp. Med. 177, 1391–1398 (1993).
  Article CAS Google Scholar
• Popivanova, B. K. et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560–570 (2008).
  CAS PubMed PubMed Central Google Scholar
• Moore, R. J. et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nature Med. 5, 828–831 (1999).
  Article CAS PubMed Google Scholar
• Knight, B. et al. Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J. Exp. Med. 192, 1809–1818 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Jain, S. S. & Bird, R. P. Elevated expression of tumor necrosis factor-alpha signaling molecules in colonic tumors of Zucker obese (fa/fa) rats. Int. J. Cancer 127, 2042–2050 (2010).
  Article CAS PubMed Google Scholar
• Kern, P. A., Ranganathan, S., Li, C., Wood, L. & Ranganathan, G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 280, E745–751 (2001).
  Article CAS PubMed Google Scholar
• Park, E. J. et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).
  Article CAS PubMed Google Scholar
• Bredel, M. et al. NFKBIA Deletion in Glioblastomas. N. Engl. J. Med. (2010).
• Calado, D. P. et al. Constitutive canonical NF-kappaB activation cooperates with disruption of BLIMP1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. Cancer Cell 18, 580–589 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, W. et al. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin. Cancer Res. 5, 119–127 (1999).
  CAS PubMed Google Scholar
• Pikarsky, E. et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).
  Article CAS PubMed Google Scholar
• Wunderlich, F. T. et al. Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc. Natl Acad. Sci. USA 105, 1297–1302 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mohamed-Ali, V. et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab. 82, 4196–4200 (1997).
  CAS PubMed Google Scholar
• Bromberg, J. F. et al. Stat3 as an oncogene. Cell 98, 295–303 (1999).
  Article CAS PubMed Google Scholar
• Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nature Genet. 14, 95–97 (1996).
  Article CAS PubMed Google Scholar
• Dano, K. et al. Plasminogen activation and cancer. Thromb. Haemost. 93, 676–681 (2005).
  Article CAS PubMed Google Scholar
• Ferrara, N. Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action. Mol. Biol. Cell 21, 687–690 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Foekens, J. A. et al. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J. Clin. Oncol. 12, 1648–1658 (1994).
  Article CAS PubMed Google Scholar
• Mutoh, M. et al. Plasminogen activator inhibitor-1 (Pai-1) blockers suppress intestinal polyp formation in Min. mice. Carcinogenesis 29, 824–829 (2008).
  Article CAS PubMed Google Scholar
• Bajou, K. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nature Med. 4, 923–928 (1998).
  Article CAS PubMed Google Scholar
• Bajou, K. et al. Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 14, 324–334 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
  Article CAS PubMed Google Scholar
• Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).
  Article CAS Google Scholar
• Snoussi, K. et al. Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer 6, 38 (2006).
  Article PubMed PubMed Central CAS Google Scholar
• Howard, J. M., Pidgeon, G. P. & Reynolds, J. V. Leptin and gastro-intestinal malignancies. Obes Rev. 11, 863–874 (2010).
  Article CAS PubMed Google Scholar
• Jarde, T., Perrier, S., Vasson, M. P. & Caldefie-Chezet, F. Molecular mechanisms of leptin and adiponectin in breast cancer. Eur. J. Cancer 47, 33–43 (2011).
  Article CAS PubMed Google Scholar
• Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Med. 1, 1155–1161 (1995).
  Article CAS PubMed Google Scholar
• Lagiou, P. et al. Leptin in relation to prostate cancer and benign prostatic hyperplasia. Int. J. Cancer 76, 25–28 (1998).
  Article CAS PubMed Google Scholar
• Stattin, P. et al. Leptin is associated with increased prostate cancer risk: a nested case-referent study. J. Clin. Endocrinol. Metab. 86, 1341–1345 (2001).
  CAS PubMed Google Scholar
• Mantzoros, C. S., Bolhke, K., Moschos, S. & Cramer, D. W. Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int. J. Cancer 80, 523–526 (1999).
  Article CAS PubMed Google Scholar
• Tamakoshi, K. et al. Leptin is associated with an increased female colorectal cancer risk: a nested case-control study in Japan. Oncology 68, 454–461 (2005).
  Article CAS PubMed Google Scholar
• Banks, A. S., Davis, S. M., Bates, S. H. & Myers, M. G., Jr. Activation of downstream signals by the long form of the leptin receptor. J. Biol. Chem. 275, 14563–14572 (2000).
  Article CAS PubMed Google Scholar
• Hardwick, J. C., Van Den Brink, G. R., Offerhaus, G. J., Van Deventer, S. J. & Peppelenbosch, M. P. Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121, 79–90 (2001).
  Article CAS PubMed Google Scholar
• Dieudonne, M. N. et al. Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochem. Biophys. Res. Commun. 293, 622–628 (2002).
  Article CAS PubMed Google Scholar
• Onuma, M., Bub, J. D., Rummel, T. L. & Iwamoto, Y. Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. J. Biol. Chem. 278, 42660–42667 (2003).
  Article CAS PubMed Google Scholar
• Choi, J. H., Park, S. H., Leung, P. C. & Choi, K. C. Expression of leptin receptors and potential effects of leptin on the cell growth and activation of mitogen-activated protein kinases in ovarian cancer cells. J. Clin. Endocrinol. Metab. 90, 207–210 (2005).
  Article CAS PubMed Google Scholar
• Amemori, S. et al. Adipocytes and preadipocytes promote the proliferation of colon cancer cells in vitro. Am. J. Physiol. Gastrointest Liver Physiol. 292, G923–929 (2007).
  Article CAS PubMed Google Scholar
• Catalano, S. et al. Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J. Biol. Chem. 279, 19908–19915 (2004).
  Article CAS PubMed Google Scholar
• Teraoka, N. et al. High susceptibility to azoxymethane-induced colorectal carcinogenesis in obese KK-A(y) mice. Int. J. Cancer 129, 528–535 (2011).
  Article CAS PubMed Google Scholar
• Aparicio, T. et al. Leptin reduces the development of the initial precancerous lesions induced by azoxymethane in the rat colonic mucosa. Gastroenterology 126, 499–510 (2004).
  Article CAS PubMed Google Scholar
• Park, J., Kusminski, C. M., Chua, S. C. & Scherer, P. E. Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo. Am. J. Pathol. 177, 3133–3144 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).
  Article CAS PubMed Google Scholar
• Hu, E., Liang, P. & Spiegelman, B. M. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 271, 10697–10703 (1996).
  Article CAS PubMed Google Scholar
• Barb, D., Williams, C. J., Neuwirth, A. K. & Mantzoros, C. S. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am. J. Clin. Nutr. 86, s858–s866 (2007).
  Article PubMed Google Scholar
• Tworoger, S. S. et al. Plasma adiponectin concentrations and risk of incident breast cancer. J. Clin. Endocrinol. Metab. 92, 1510–1516 (2007).
  Article CAS PubMed Google Scholar
• Dal Maso, L. et al. Circulating adiponectin and endometrial cancer risk. J. Clin. Endocrinol. Metab. 89, 1160–1163 (2004).
  Article CAS Google Scholar
• Cust, A. E. et al. Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women. J. Clin. Endocrinol. Metab. 92, 255–263 (2007).
  Article CAS PubMed Google Scholar
• Soliman, P. T., Cui, X., Zhang, Q., Hankinson, S. E. & Lu, K. H. Circulating adiponectin levels and risk of endometrial cancer: the prospective Nurses' Health Study. Am. J. Obstet. Gynecol. 204, 167 e1–e5 (2011).
  Article CAS Google Scholar
• Kaklamani, V. G. et al. Variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes and colorectal cancer risk. JAMA 300, 1523–1531 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Bub, J. D., Miyazaki, T. & Iwamoto, Y. Adiponectin as a growth inhibitor in prostate cancer cells. Biochem. Biophys. Res. Commun. 340, 1158–1166 (2006).
  Article CAS PubMed Google Scholar
• Kim, A. Y. et al. Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol. Endocrinol. 24, 1441–1452 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lam, J. B. et al. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities. PLoS One 4, e4968 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Fogarty, S. & Hardie, D. G. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim. Biophys. Acta 1804, 581–591 (2010).
  Article CAS PubMed Google Scholar
• Sharma, D. et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology 52, 1713–1722 (2010).
  Article CAS PubMed Google Scholar
• Sun, Y. & Lodish, H. F. Adiponectin deficiency promotes tumor growth in mice by reducing macrophage infiltration. PLoS One 5, e11987 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Holland, W. L. et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nature Med. 17, 55–63 (2011).
  Article CAS PubMed Google Scholar
• Ogretmen, B. & Hannun, Y. A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Rev. Cancer 4, 604–616 (2004).
  Article CAS Google Scholar
• Grossmann, M. E. et al. Role of the adiponectin leptin ratio in prostate cancer. Oncol. Res. 18, 269–277 (2009).
  Article CAS PubMed Google Scholar
• Rabe, K., Lehrke, M., Parhofer, K. G. & Broedl, U. C. Adipokines and insulin resistance. Mol. Med. 14, 741–751 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sood, A. Obesity, adipokines, and lung disease. J. Appl. Physiol. 108, 744–753 (2010).
  Article CAS PubMed Google Scholar
• Sun, K., Kusminski, C. M. & Scherer, P. E. Adipose tissue remodeling and obesity. J. Clin. Invest. 121, 2094–2101 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Y., Bellows, C. F. & Kolonin, M. G. Adipose tissue-derived progenitor cells and cancer. World J. Stem Cells 2, 103–113 (2010).
  Article PubMed PubMed Central Google Scholar
• Zhang, Y. et al. White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models. Cancer Res. 69, 5259–5266 (2009).
  Article CAS PubMed Google Scholar
• Pasqualini, R. & Ruoslahti, E. Organ. targeting in vivo using phage display peptide libraries. Nature 380, 364–366 (1996).
  Article CAS PubMed Google Scholar
• Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Cinti, S., Cigolini, M., Bosello, O. & Bjorntorp, P. A morphological study of the adipocyte precursor. J. Submicrosc Cytol. 16, 243–251 (1984).
  CAS PubMed Google Scholar
• McLean, K. et al. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J. Clin. Invest. 121, 3206–3219 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).
  Article CAS PubMed Google Scholar
• Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kosteli, A. et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J. Clin. Invest. 120, 3466–3479 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Ehses, J. A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007).
  Article CAS PubMed Google Scholar
• Varma, V. et al. Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action. Am. J. Physiol. Endocrinol. Metab. 296, E1300–1310 (2009).
  Article CAS Google Scholar
• Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Rev. Cancer 4, 71–78 (2004).
  Article CAS Google Scholar
• Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nature Rev. Cancer 8, 618–631 (2008).
  Article CAS Google Scholar
• Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ueno, T. et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin. Cancer Res. 6, 3282–3289 (2000).
  CAS PubMed Google Scholar
• Campbell, M. J. et al. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res. Treat 128, 703–711 (2011).
  Article PubMed Google Scholar
• Morris, P. G. et al. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev. Res. (Phila) 4, 1021–1029 (2011).
  Article CAS Google Scholar
• Samuel, V. T., Petersen, K. F. & Shulman, G. I. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375, 2267–2277 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Michels, K. B. et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care 26, 1752–1758 (2003).
  Article PubMed Google Scholar
• Ma, J. et al. A prospective study of plasma C-peptide and colorectal cancer risk in men. J. Natl Cancer Inst. 96, 546–553 (2004).
  Article CAS PubMed Google Scholar
• Vigneri, P., Frasca, F., Sciacca, L., Pandini, G. & Vigneri, R. Diabetes and cancer. Endocr. Relat Cancer 16, 1103–1123 (2009).
  Article CAS PubMed Google Scholar
• Michaud, D. S. et al. Prediagnostic plasma C-peptide and pancreatic cancer risk in men and women. Cancer Epidemiol. Biomarkers Prev. 16, 2101–2109 (2007).
  Article CAS PubMed Google Scholar
• Ma, J. et al. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 9, 1039–1047 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Barone, B. B. et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300, 2754–2764 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Brown, M. S. & Goldstein, J. L. Selective versus total insulin resistance: a pathogenic paradox. Cell. Metab. 7, 95–96 (2008).
  Article CAS PubMed Google Scholar
• Osborne, C. K., Bolan, G., Monaco, M. E. & Lippman, M. E. Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. Proc. Natl Acad. Sci. USA 73, 4536–4540 (1976).
  Article CAS PubMed PubMed Central Google Scholar
• Nagle, J. A., Ma, Z., Byrne, M. A., White, M. F. & Shaw, L. M. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol. Cell Biol. 24, 9726–9735 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nature Rev. Cancer 8, 915–928 (2008).
  Article CAS Google Scholar
• Boni-Schnetzler, M., Schmid, C., Meier, P. J. & Froesch, E. R. Insulin regulates insulin-like growth factor I mRNA in rat hepatocytes. Am. J. Physiol. 260, E846–851 (1991).
  CAS PubMed Google Scholar
• Zhang, L. et al. Gene expression profiles in normal and cancer cells. Science 276, 1268–1272 (1997).
  Article CAS PubMed Google Scholar
• Frystyk, J., Skjaerbaek, C., Vestbo, E., Fisker, S. & Orskov, H. Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes Metab. Res. Rev. 15, 314–322 (1999).
  Article CAS PubMed Google Scholar
• Nunez, N. P. et al. Obesity accelerates mouse mammary tumor growth in the absence of ovarian hormones. Nutr. Cancer 60, 534–541 (2008).
  Article CAS PubMed Google Scholar
• Frystyk, J., Brick, D. J., Gerweck, A. V., Utz, A. L. & Miller, K. K. Bioactive insulin-like growth factor-I in obesity. J. Clin. Endocrinol. Metab. 94, 3093–3097 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Heald, A. H. et al. Close relation of fasting insulin-like growth factor binding protein-1 (IGFBP-1) with glucose tolerance and cardiovascular risk in two populations. Diabetologia 44, 333–339 (2001).
  Article CAS PubMed Google Scholar
• Buckbinder, L. et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377, 646–649 (1995).
  Article CAS PubMed Google Scholar
• Kaaks, R. et al. Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J. Natl Cancer Inst. 92, 1592–1600 (2000).
  Article CAS PubMed Google Scholar
• Wolpin, B. M. et al. Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J. Clin. Oncol. 27, 176–185 (2009).
  Article PubMed PubMed Central Google Scholar
• Hsieh, D., Hsieh, A., Stea, B. & Ellsworth, R. IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochem. Biophys. Res. Commun. 397, 367–372 (2010).
  Article CAS PubMed Google Scholar
• Papa, V. et al. Elevated insulin receptor content in human breast cancer. J. Clin. Invest. 86, 1503–1510 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• McCampbell, A. S., Broaddus, R. R., Loose, D. S. & Davies, P. J. Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin. Cancer Res. 12, 6373–6378 (2006).
  Article CAS PubMed Google Scholar
• Jiang, Y. et al. A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin. Exp. Metastasis 21, 755–764 (2004).
  Article CAS PubMed Google Scholar
• Weber, M. M. et al. Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 95, 2086–2095 (2002).
  Article CAS PubMed Google Scholar
• Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550–562 (2009).
  Article CAS Google Scholar
• Schubbert, S., Shannon, K. & Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nature Rev. Cancer 7, 295–308 (2007).
  Article CAS Google Scholar
• Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011).
  Article CAS Google Scholar
• Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Bol., D. K., Kiguchi, K., Gimenez-Conti, I., Rupp, T. & DiGiovanni, J. Overexpression of insulin-like growth factor-1 induces hyperplasia, dermal abnormalities, and spontaneous tumor formation in transgenic mice. Oncogene 14, 1725–1734 (1997).
  Article CAS PubMed Google Scholar
• DiGiovanni, J. et al. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc. Natl Acad. Sci. USA 97, 3455–3460 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Lopez, T. & Hanahan, D. Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1, 339–353 (2002).
  Article CAS PubMed Google Scholar
• Carboni, J. M. et al. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res. 65, 3781–3787 (2005).
  Article CAS PubMed Google Scholar
• Moorehead, R. A., Sanchez, O. H., Baldwin, R. M. & Khokha, R. Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma. Oncogene 22, 853–857 (2003).
  Article CAS PubMed Google Scholar
• Pravtcheva, D. D. & Wise, T. L. Metastasizing mammary carcinomas in H19 enhancers-Igf2 transgenic mice. J. Exp. Zool. 281, 43–57 (1998).
  Article CAS PubMed Google Scholar
• Jones, R. A. et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 26, 1636–1644 (2007).
  Article CAS PubMed Google Scholar
• Chan, J. M. et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279, 563–566 (1998).
  Article CAS PubMed Google Scholar
• Wu, Y. et al. Insulin-like growth factor-I regulates the liver microenvironment in obese mice and promotes liver metastasis. Cancer Res. 70, 57–67 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, P. L. et al. Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival. J. Clin. Oncol. 28, 3958–3964 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kuhajda, F. P. et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl Acad. Sci. USA 91, 6379–6383 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Alli, P. M., Pinn, M. L., Jaffee, E. M., McFadden, J. M. & Kuhajda, F. P. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N. transgenic mice. Oncogene 24, 39–46 (2005).
  Article CAS PubMed Google Scholar
• Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070–2075 (2004).
  Article CAS PubMed Google Scholar
• Chakravarthy, M. V. et al. Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell 138, 476–488 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Peters, J. M., Cattley, R. C. & Gonzalez, F. J. Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14, 643. Carcinogenesis 18, 2029–2033 (1997).
  Article CAS PubMed Google Scholar
• Reddy, J. K., Azarnoff, D. L. & Hignite, C. E. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature 283, 397–398 (1980).
  Article CAS PubMed Google Scholar
• Gupta, R. A. et al. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth. Nature Med. 10, 245–247 (2004).
  Article CAS PubMed Google Scholar
• Hollingshead, H. E. et al. Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands do not potentiate growth of human cancer cell lines. Carcinogenesis 28, 2641–2649 (2007).
  Article CAS PubMed Google Scholar
• Nomura, D. K. et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49–61 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Robertson, R. P., Harmon, J., Tran, P. O. & Poitout, V. Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53 Suppl 1, S119–124 (2004).
  Article PubMed Google Scholar
• Elsner, M., Gehrmann, W. & Lenzen, S. Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells. Diabetes 60, 200–208 (2011).
  Article CAS PubMed Google Scholar
• Moitra, J. et al. Life without white fat: a transgenic mouse. Genes Dev. 12, 3168–3181 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Nunez, N. P. et al. Accelerated tumor formation in a fatless mouse with type 2 diabetes and inflammation. Cancer Res. 66, 5469–5476 (2006).
  Article CAS PubMed Google Scholar
• Fierz, Y., Novosyadlyy, R., Vijayakumar, A., Yakar, S. & LeRoith, D. Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59, 686–693 (2010).
  Article CAS PubMed Google Scholar
• Novosyadlyy, R. et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 70, 741–751 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Adams, T. D. et al. Long-term mortality after gastric bypass surgery. N. Engl. J. Med. 357, 753–761 (2007).
  Article CAS PubMed Google Scholar
• Adams, T. D. et al. Cancer incidence and mortality after gastric bypass surgery. Obesity (Silver Spring) 17, 796–802 (2009).
  Article Google Scholar
• Ostlund, M. P., Lu, Y. & Lagergren, J. Risk of obesity-related cancer after obesity surgery in a population-based cohort study. Ann. Surg. 252, 972–976 (2010).
  Article PubMed Google Scholar
• Currie, C. J., Poole, C. D. & Gale, E. A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777 (2009).
  Article CAS PubMed Google Scholar
• Jonasson, J. M. et al. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 52, 1745–1754 (2009).
  Article CAS PubMed Google Scholar
• Bowker, S. L., Majumdar, S. R., Veugelers, P. & Johnson, J. A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29, 254–258 (2006).
  Article PubMed Google Scholar
• Erickson, K. et al. Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J. Clin. Oncol. 29, 54–60 (2011).
  Article PubMed Google Scholar
• Colhoun, H. M. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52, 1755–1765 (2009).
  Article PubMed PubMed Central Google Scholar
• Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N. & Struhl, K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69, 7507–7511 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Girnun, G. D. et al. Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin. Clin. Cancer Res. 14, 6478–6486 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mueller, E. et al. Terminal differentiation of human breast cancer through PPAR gamma. Mol. Cell 1, 465–470 (1998).
  Article CAS PubMed Google Scholar
• Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Kalender, A. et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell. Metab. 11, 390–401 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Girnun, G. D. et al. Synergy between PPARgamma ligands and platinum-based drugs in cancer. Cancer Cell 11, 395–406 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Govindarajan, R. et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J. Clin. Oncol. 25, 1476–1481 (2007).
  Article CAS PubMed Google Scholar
• Kim, S. et al. Aspirin may be more effective in preventing colorectal adenomas in patients with higher BMI (United States). Cancer Causes Control 17, 1299–1304 (2006).
  Article PubMed Google Scholar
• Roberts, D. L., Dive, C. & Renehan, A. G. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 61, 301–316 (2010).
  Article CAS PubMed Google Scholar