Skip Navigation


Carcinogenesis Advance Access originally published online on February 12, 2009
Carcinogenesis 2009 30(4):690-697; doi:10.1093/carcin/bgp041
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
30/4/690    most recent
bgp041v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Birmingham, J. M.
Right arrow Articles by Fenton, J. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Birmingham, J. M.
Right arrow Articles by Fenton, J. I.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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. Birmingham, Julia V. Busik1, Fay M. Hansen-Smith2 and Jenifer I. Fenton*

Department of Food Science and Human Nutrition, College of Nursing, Michigan State University, East Lansing, MI 48824, USA
1 Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA
2 Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA

* To whom correspondence should be addressed. Department of Food Science and Human Nutrition, College of Nursing, 208B G.M. Trout Building, Michigan State University, East Lansing, MI, USA. Tel: +1 517 355 8474 ext. 130; Fax: +1 517 353 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 adenomatous polyposis coli (Apc) genotype (gatekeeper tumor suppressor gene for colon cancer) on angiogenesis. We employed novel colonic epithelial cell lines derived from the Immorto mouse [young adult mouse colon (YAMC)] and the Immorto-Min mouse [Immorto-Min colonic epithelial cell (IMCE)], 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 umbilical vein endothelial cell (HUVEC) models to study angiogenesis. IMCE cells stimulated with leptin produced significantly more vascular endothelial growth factor (VEGF) than YAMC (268 ± 18 versus 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 with 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 nuclear factor 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.

Abbreviations: APC, adenomatous polyposis coli; ELISA, enzyme-linked immunosorbent assay; HUVEC, human umbilical vein endothelial cell; ICAM, inter-cellular adhesion molecule; IMCE, immorto-min colonic epithelial cell; MIP3, macrophage inflammatory protein 3; NF{kappa}B, nuclear factor kappa B; PDTC, pyrrolidine dithiocarbamate; SAPK, stress-activated protein kinase; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; YAMC, young adult mouse colon

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


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.