Scientific Abstract
Proposal No. IBD-0239R2
Principal Investigator: Emina Huang, M.D.
Applicant Organization: University of Florida (Gainesville, U.S.A.)
Project Title: Colitis derived tumorigenic stem cells and the inflammatory bowel
Period of Award: February 1, 2009 – June 30, 2010
The relationship between colitis and colon cancer has been recognized for decades. This association is an example of inflammation-associated cancer, an association which currently includes 15% of the world’s malignancies. In those patients with long-standing colitis, the incidence of colorectal cancer is increased up to five-fold over that of sporadic colon cancer. The recent discovery of colon cancer stem cells suggests that a rare population of cells within a tumor has the capacity to regenerate the entire tumor. The regenerative capacity of some of these cells is supported and may be stimulated by surrounding cells in the microenvironment. The long-term goal of these studies is to determine how cellular elements of the colitic microenvironment contribute to malignant transformation.
The objective of this application is to determine the contribution of IL8, a cytokine secreted by fibroblasts in colitis and colon cancer. The central hypothesis of this proposal is that IL8 produced by the fibroblasts in the colitic niche facilitates tumorigenicity of the epithelial tumor-initiating cells. The rationale for the proposed research is that tumorigenesis is possible from colitic tissues, as exemplified by successful xenografting. In vitro data reveals that fibroblasts from both colitis and colon cancer are capable of stimulating epithelial proliferation. Unlike their normal colon counterparts, fibroblasts from these microenvironments secrete IL8. Furthermore, xenografts from colitic tissues and from colon cancer tissues express the receptor for IL8. Thus, the proposed research is relevant to the BMRP’s mission since the contributions will increase the understanding of colitic regeneration and malignant transformation.
Guided by the preliminary data, the hypothesis will be tested with two specific aims: 1.) To examine the IL8-specific crosstalk between putative tumorigenic epithelial cells and fibroblasts in vitro, and 2.) To determine the contribution of IL8 on in vivo xenograft tumorigenicity of colon epithelial stem cells. In the first aim, the presence of IL8 and IL8 receptors on epithelial cell lines and primary tumorigenic isolates will be tested. These cells will be placed in culture with fibroblasts from colitic and malignant environments, and proliferation will be measured. A small molecule inhibitor of the IL8 receptor, repertaxin, will then be evaluated for inhibition of this proliferation. The second aim will test these cellular combinations in vivo. Similarly, the capacity for repertaxin to decrease tumorigenicity will be tested. The proposed studies are innovative since colon cancer and colitis-derived epithelial stem cells are a new concept. Moreover, analysis of the stem cell-microenvironment paracrine relationship is novel. Additionally, the use of repertaxin to antagonize this relationship would provide evidence that such a relationship might contribute to proliferation both in vitro and in vivo. The proposed research is significant as it will advance and expand understanding of both regeneration and tumorigenicity.