The pathogenesis of colitis-associated cancer is unclear. Filling this gap in our knowledge is an important challenge because without intervention, up to 18% of patients with chronic ulcerative colitis (UC) will develop colorectal cancer. Thus, our long-term goal is to develop chemopreventive strategies for CAC by defining the mechanisms by which inflammation promotes malignant transformation in patients with chronic ulcerative colitis. The objective of this particular application is to determine how autocrine IL8 contributes to the tumorigenicity of colitis-derived colon cancer initiating cells (CCICs). Similar to CCICs derived from sporadic colorectal cancer, CCICs from UC represent an excellent model for dissecting out mechanisms underlying the colitis-to-cancer transition using both in vitro and in vivo assays. The central hypothesis is that IL8 signaling is required fo the colitis-to-cancer transition. The rationale for the proposed research is that once we understand the contribution and mechanisms by which IL8 promotes tumor initiation, we will be able to develop ways to interfere in the progression from benign colitis to malignant cancer. Following up on our strong preliminary data, our hypothesis will be tested by pursuing three specific aims: 1) to define the effects of IL8 on the in vivo and in vitro formation of tumors derived from CCICs isolated from colitic colon, 2) to determine the influence of downstream mediators of IL8 signaling on the initiation of tumors induced by CCICs derived from colitic colon, and, 3) to delineate the contribution of gain-of-function p53 mutations to IL8-induced potentiation of tumorigenicity.
In Aim 1, we will examine how exogenous IL8 influences the behavior of colitis-derived CCICs in assays involving proliferation, invasion, tumorigenesis, angiogenesis and differentiation. We will inhibit both IL8 and its dominant receptor, CXCR1, and determine how interference affects these tumorigenic assays.
In Aim 2, we have evidence that Focal Adhesion Kinase (FAK) is a downstream mediator of IL8 function. We will inhibit FAK using RNAi and delineate alterations in the same tumorigenic assays.
Aim 3 involves the R273H p53 gain-of-function mutation which we found in each of our colitis-derived CCIC isolates. In other systems, this mutation has been associated with potentiation of IL8 mRNA and functions associated with IL8. The approach is innovative, because we have unique tools including the CCICs from colitis, and can use CCICs from sporadic colorectal cancer for comparison. The proposed research is significant as it will greatly expand our understanding of how IL8 contributes to colitis-associated cancer.

Public Health Relevance

The proposed research is relevant to public health because the discovery of how IL8 sustains and promotes the tumorigenicity of colon cancer initiating cells from the epithelium of ulcerative colitis patients will provide innovative therapeutic targets and strategies. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human illness and disability.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Daschner, Phillip J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Signs, Steven A; Fisher, Robert C; Tran, Uyen et al. (2018) Stromal miR-20a controls paracrine CXCL8 secretion in colitis and colon cancer. Oncotarget 9:13048-13059
Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730
Shawki, Sherief; Ashburn, Jean; Signs, Steven A et al. (2018) Colon Cancer: Inflammation-Associated Cancer. Surg Oncol Clin N Am 27:269-287
Fearon, Eric R; Huang, Emina H (2016) CDX2: Linking Cell and Patient Fates in Colon Cancer. Cell Stem Cell 18:168-9
Nagarsheth, Nisha; Peng, Dongjun; Kryczek, Ilona et al. (2016) PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer Res 76:275-82
Zhao, Junjie; Bulek, Katarzyna; Gulen, Muhammet F et al. (2015) Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice. Gastroenterology 149:1860-1871.e8
Carstens, Matthew R; Fisher, Robert C; Acharya, Abhinav P et al. (2015) Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells. Proc Natl Acad Sci U S A 112:8732-7
Kryczek, Ilona; Lin, Yanwei; Nagarsheth, Nisha et al. (2014) IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 40:772-784
Chen, Sugong; Huang, Emina H (2014) The colon cancer stem cell microenvironment holds keys to future cancer therapy. J Gastrointest Surg 18:1040-8
Shenoy, Anitha; Butterworth, Elizabeth; Huang, Emina H (2012) ALDH as a marker for enriching tumorigenic human colonic stem cells. Methods Mol Biol 916:373-85