Obesity, Adipocytokines, and Breast Cancer

Adipose tissue is an active endocrine organ, secreting fatty acids and peptide hormones or cytokines, collectively called adipocytokines. These biologically active factors act locally or peripherally to influence multiple processes, including glucose and fatty acid metabolism, insulin sensitivity, adipocyte differentiation, inflammation, and the immune response. Accumulating evidence suggests that obesity, a condition characterized by an increase in adipocyte size and number, altered adipocytokine secretion, and increased angiogenesis, is one of the risk factors for certain types of cancer, including post-menopausal breast cancer and endometrial cancer.¹ While the cause of these obesity-related cancers has been primarily ascribed to excess estrogen production by adipose tissue, they have also been speculated to be due, in part, to changes in the levels of adipocytokines secreted by adipocytes, infiltrating macrophages, or associated stromal cells.² Changes in adipocytokine levels can affect cell proliferation, apoptosis, invasive growth, and angiogenesis. Although numerous adipocyto­kines have been identified, the effects of only a few in promoting or inhibiting mammary tumor growth have been extensively studied to date. These include leptin, hepatocyte growth factor (HGF), and adiponectin.

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Obesity is characterized by an increase in adipocyte size and number, changes in the levels of adipocytokine secretion, and recruitment of macrophages that release pro-inflammatory cytokines. Altered circulating levels of adipocytokines, released by adipocytes themselves, associated macrophages, or stromal cells can have deleterious effects on cellular proliferation, apoptosis, invasive growth, or angiogenesis. This suggests that adipocytokines may be involved in the growth and/or metastasis of obesity-related cancers. [Figure adapted from Tilg, H. et al. (2006) Nat. Rev. Immunol. 6:772]

Obese individuals typically have elevated levels of circulating leptin, a hormone associated with appetite suppression and energy expenditure. Identifying a causal link between elevated leptin levels and obesity-related post-menopausal breast cancers has been complicated by conflicting results, but multiple studies now suggest that leptin has proliferative and pro-angiogenic effects that may promote mammary tumorigenesis. Leptin has been shown to increase the proliferation of human breast cancer cell lines expressing the leptin receptor (Ob-R), including MCF-7, ZR75-1, and the estrogen-receptor negative, HTB-26 cells.^{3, 4} Cleary et al. took these observations one step further by establishing a direct link between leptin signaling and breast cancer development in vivo. Their results demonstrated that obese mice deficient in either leptin or the leptin receptor, and over-expressing TGF-alpha, have a reduced occurrence of oncogene-induced mammary tumors, compared to lean control mice.^{5, 6} Significantly, it was found that obese mice lacking leptin, or the leptin receptor also display defects in mammary gland morphogenesis, implicating leptin in normal mammary tissue development.⁷ A subsequent study demonstrated that increasing concentrations of a leptin receptor antagonist could also slow tumor development in mice.⁸ This study showed that leptin signaling promotes the expression of vascular endothelial growth factor (VEGF) and VEGF R2, indicating that leptin may stimulate tumor-related angiogenesis.⁸ In addition to acting through its own receptor, leptin has been shown to induce ligand-independent activation of estrogen receptor a in MCF-7 breast cancer cells.⁹ It also promotes aromatase activity in these cells which is a key enzyme required for estrogen biosynthesis.¹⁰ Taken together, these studies suggest that leptin signaling through its own receptor, or through activation of estrogen receptor signaling pathways, promotes cell proliferation and angiogenesis. Obesity-related leptin hypersecretion may contribute to the excess estrogen production, unregulated cell growth, and increased angiogenesis associated with mammary tumorigenesis.

Adipose tissue is a major source of HGF, another adipocytokine that, like leptin, is elevated in obesity and promotes both cell proliferation and angiogenesis. Expression of a constitutively active form of the HGF receptor, also known as c-Met, in transgenic mice induces mammary tumor formation, indicating that loss of HGF:c-Met regulation may be involved in breast cancer pathogenesis.¹¹ In addition, HGF signaling was demonstrated to regulate the loss of tumor mass adhesion, and breakdown of the extracellular matrix, suggesting that HGF plays a central role in tumor cell metastasis.¹² Significantly, HGF has been shown to increase the migration and invasiveness of MDA-MB-231 human breast cancer cells in vitro.¹³ HGF also stimulates VEGF-dependent or independent tumor angiogenesis,¹⁴ indicating that it may help sustain tumor growth through its ability to induce the formation of new blood vessels. Several other adipocytokines promote angiogenesis as well, including heparin-binding epidermal growth factor-like growth factor (HB-EGF), tumor necrosis factor alpha (TNF-alpha), and IL-6 (see Table), imply­ing that increases in the levels of these adipocytokines may also be associated with obesity-related cancers.

Adiponectin levels, unlike leptin and HGF levels, are reduced in obesity and in breast cancer patients. In fact, the concentration of circulating adiponectin is inversely associated with the risk for developing post-menopausal breast cancer.¹⁵ Recent studies have demon­strated that adiponectin inhibits the growth of breast cancer cell lines (MDA-MB-231 and MCF-7 cells) expressing the two adiponectin receptors, AdipoR1 and AdipoR2.^{16, 17} Brakenhielm, et al. have also shown that adiponectin acts as a negative regulator of angiogenesis in vivo by inducing endothelial cell apoptosis.¹⁸ Significantly, the same study demonstrated that adiponectin could directly inhibit tumor growth and reduce neovascularization in vivo.¹⁸ Therefore, the reduction in the levels of adiponectin associated with obesity may promote cancer growth by way of a decrease in anti-angiogenic and anti-proliferative activities.

Characteristics of obesity, such as changes in adipocyte size and number and the recruitment of pro-inflammatory mediators lead to changes in adipocytokine secretion which can increase the risk of developing certain forms of cancer. Since these physiologically active molecules seem to play important roles in cell proliferation and angiogenesis, determining the mechanisms by which adipocytokines act locally and peripherally is critical to understanding how they may be involved in promoting or inhibiting tumor growth and metastasis.

References

1. Calle, E. et al. (2004) Nat. Rev. Cancer 4:579.
2. Vona-Davis, L. et al. (2007) Endocr. Relat. Cancer 14:189.
3. Dieudonne, M-N. et al. (2002) Biochem. Biophys. Res. Commun. 293:622.
4. Frankenberry, K. et al. (2006) Int. J. Oncol. 28:985.
5. Cleary, M.P. et al. (2003) Breast Cancer Res. Treat. 77:205.
6. Cleary, M.P. et al. (2004) Exp. Biol. Med. 229:182.
7. Hu, X. et al. (2002) J. Natl. Cancer Inst. 94:1704.
8. Gonzalez, R. et al. (2006) J. Biol. Chem. 281:26320.
9. Catalano, S. et al. (2004) J. Biol. Chem. 279:19908.
10. Catalano, S. et al. (2003) J. Biol. Chem. 278:28668.
11. Liang, T.J. et al. (1996) J. Clin. Invest. 97:2872.
12. Hiscox, S. and W.G. Jiang. (1999) Biochem. Biophys. Res. Commun. 261:406.
13. Martin, T.A. et al. (2003) Carcinogenesis 24:1317.
14. Lesko, E. and M. Majka. (2008) Front. Biosci. 13:1271.
15. Mantzoros, C. et al. (2004) J. Clin. Endocrinol. Metab. 89:1102.
16. Kang, J.H. et al. (2005) Arch. Pharm. Res. 28:1263.
17. Dieudonne, M-N. et al. (2006) Biochem. Biophys. Res. Commun. 345:271.
18. Brakenhielm, E. et al. (2004) Proc. Natl. Acad. Sci. USA 101:2476.

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