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Carcinogenesis Advance Access published online on February 12, 2009
Carcinogenesis, doi:10.1093/carcin/bgp041
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Novel mechanism for obesity-induced colon cancer progression

Janette M. Birmingham1, Julia V. Busik2, Fay M. Hansen-Smith3 and Jenifer I. Fenton1,*

1 Department of Food Science and Human Nutrition and College of Nursing, Michigan State University, East Lansing, MI, USA
2 Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
3 Department of Biological Sciences, Oakland University, Rochester, MI, USA

* Correspondence: Jenifer I. Fenton, PhD, MPH. Department of Food Science and Human Nutrition, College of Nursing, 208B G.M. Trout Building, Michigan State University, East Lansing, MI, USA. Phone: 517-355-8474 (ext 130). Fax: 517-353-8963. Email: imigjeni{at}msu.edu

Adipose tissue secretes factors linked to colon cancer risk including leptin. A hallmark of cancer is sustained angiogenesis. While leptin promotes angiogenesis in adipose tissue, it is unknown whether leptin can induce epithelial cells to produce factors that may drive angiogenesis, vascular development, and therefore cancer progression. The purpose of this study was to compare the effects of leptin-stimulated colon epithelial cells differing in Apc genotype (gate-keeper tumor suppressor gene for colon cancer) on angiogenesis. We employed novel colonic epithelial cell lines derived from the Immorto mouse (YAMC; young adult mouse colon), and the Immorto-Min mouse (IMCE; Immorto-Min colonic epithelial cell), which carries the Apc Min mutation, to study the effects of leptin-stimulated colon epithelial cells on angiogenesis. We utilized ex-vivo rat mesenteric capillary bioassay and human endothelial cell (HUVEC) models to study angiogenesis. IMCE cells stimulated with leptin produced significantly more vascular endothelial growth factor (VEGF) than YAMC (268±18 vs. 124±8 pg/ml; p<0.01) cells. Leptin treatment induced dose-dependent increases in VEGF only in IMCE cells. Conditioned media from leptin (50 ng/ml) treated IMCE cells induced significant capillary formation compared to control, which was blocked by the addition of a neutralizing antibody against VEGF. Conditioned media from leptin-treated IMCE cells also induced HUVEC cell proliferation, chemotaxis, upregulation of adhesion proteins, and cell-signaling activation resulting in NF{kappa}B nuclear translocation and DNA binding due to VEGF. This is the first study demonstrating that leptin can induce preneoplastic colon epithelial cells to orchestrate VEGF driven angiogenesis and vascular development, thus providing a specific mechanism and potential target for obesity-associated cancer.

Key Words: Leptin • IMCE • YAMC • angiogenesis • epithelial

Received September 4, 2008; revised January 14, 2009; accepted February 6, 2009.


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