Colitis associated cancer (CAC) is the most deadly and devastating complication of inflammatory bowel disease (IBD). With no effective preventive or treatment strategy for CAC it is important to understand how IBD induces CAC. Cytokines are small protein mediators of inflammation that are instrumental for IBD development, and may also exhibit tumor-promoting properties. This project is focused on the role of Interleukin 23 (IL-23) in regulation of chronic inflammation and CAC tumorigenesis. During the last 8 years I worked on different aspects of cytokine biology and the role of cytokines in inflammation, autoimmunity and cancer. For a long time our lab has used a azoxymethane+DSS induced CAC mouse model to mimic CAC development in humans. Using this model, our lab has shown a mechanistic connection between the transcription factor NF-B and tumorigenesis. Having long-term interest in how cytokines promote cancer, I have searched for pro-inflammatory cytokines, whose expression is controlled by NF-B, which mediate effects of inflammation on CAC. Such cytokines are better targets for therapy in comparison with global inhibition of NF-B itself. My preliminary data suggests an important role for IL-23 in CAC. I hypothesize that IL-23 increases tumor multiplicity and growth by activating several pathways, which maintain chronic inflammation and pro-survival pathways in epithelial and malignant cells, and eventually enhance tumor formation and growth. To study the role of IL-23 in CAC I will use various gene modified mice and a mouse model of CAC. I will pursue 5 separate Aims (2 Aims during Mentored phase and 3 Aims during Independent phase of the award):
Aim1. Evaluate the role of IL-23 in CAC development, growth and progression Aim2. Explore molecular mechanisms of IL-23 action in CAC Aim3. Examine the contribution of different IL-23 responsive cell types in CAC tumorigenesis Aim4. Examine the contribution of different IL-23 dependent pathways (IL-17 and IL-22) in CAC tumorigenesis Aim 5. Determine the role of IL-23 at different stages of CAC tumorigenesis and the consequences of its genetic or pharmacological blockade The long-term objective of this study is to dissect a cytokine network required for CAC tumorigenesis and to establish IL-23 as master regulator of intestinal inflammation and CAC tumord evelopment. If proven that IL-23 is instrumental for both IBD and cancer development, this cytokine would represent an attractive target for specific therapy or prevention of CAC and IBD.

Public Health Relevance

The most serious complication of inflammatory bowel disease (IBD) is the development of colitis associated colon cancer (CAC), which happens in up to 20% of IBD patients and results in over 50% mortality. The regulation of inflammation involves many small proteins known as cytokines and my preliminary data suggests that the cytokine called IL-23 warrants detailed investigation, as its absence or inactivation in mice renders them resistant to CAC. I will study the role of IL-23 in CAC and determine the molecular mechanism of its action, with the aim of providing evidence that its inhibition can be used to prevent or treat CAC in IBD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
5K99DK088589-02
Application #
8261925
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hamilton, Frank A
Project Start
2011-05-03
Project End
2012-09-09
Budget Start
2012-05-01
Budget End
2012-09-09
Support Year
2
Fiscal Year
2012
Total Cost
$40,459
Indirect Cost
$2,997
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Valeri, Nicola; Braconi, Chiara; Gasparini, Pierluigi et al. (2014) MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer. Cancer Cell 25:469-83
Grivennikov, Sergei I (2013) Inflammation and colorectal cancer: colitis-associated neoplasia. Semin Immunopathol 35:229-44
Kuraishy, Ali; Karin, Michael; Grivennikov, Sergei I (2011) Tumor promotion via injury- and death-induced inflammation. Immunity 35:467-77