The Role of NF-kappa B2 Pathway in Colon Cancer
Abstract
Scientific Objectives: Our study will focus on colon cancer and specific environmental and infectious agents that our military men and women are exposed to that can increase colon inflammation. Currently, it is clear that inflammation impacts cancer at two major levels. First, inflammation produces pro-growth factors, which can speed tumor growth, and second, inflammation can inhibit our body’s own immune cells, which are trying to eradicate tumor cells. NF-kappa B1 is well-studied complex of proteins that activates inflammation and promotes colon cancer. However, virtually nothing is known about the NF-kappa B2 pathway in the colon. The NF-kappa B2 pathway is very similar to NF-kappa B1; however, the complex is made up of two different proteins. For the first time, we demonstrate that NF-kappa B2 is activated in intestinal cells of colon tumors. Also, if we increase NF-kappa B2 activation, it will make the cells grow faster and more. In mice that have high activation of this pathway in colon cells, it leads to an increase in colon tumors. Whereas, genetic inhibition of this pathway dramatically reduces tumor growth. Since inhibition of this pathway does not have detrimental side effects in the intestine, this pathway could be a good target for colon cancer treatment. Our goals for this proposal are to: (1) Understand how the NF-kappa B2 pathway regulates colon cancer proliferation. (2) Understand if the NF-kappa B2 pathway alters the ability of our immune cells to eliminate tumors. (3) Use drugs that inhibit NF-kappa B2, which are being tested for blood-borne cancers in our colon cancer mouse models. Our lab is well positioned to make key findings in this area since we have developed mouse models and have several molecular tools to increase and decrease NF-kappa B2 activity in cells. Applicability: Understanding the role of NF-kappa B2 pathway in the colon has the potential to uncover new insights into colon cancer and could be a useful target in treatment of colon cancer. Moreover, the animal models generated may allow us to uncover the role of NF-kappa B2 in several cancer types. The time to the clinic will depend on the results from our study and is likely several years away. However, several factors may speed this transition. Pharmaceuticals companies are actively trying to find safe and effective NIK inhibitors to use in blood-borne cancer. Mutations in NF-kappa B2 pathways are evident in several blood-derived cancers such as multiple myeloma. Therefore, we could immediately assess these inhibitors using our mouse models. In addition, the NF-kappa B2 pathway in most normal tissues is expressed very low; therefore, targeting this pathway may lead to low or negligible side effects. Military Beneficiaries: A study published in the June 2009 edition of Cancer Epidemiology Biomarkers & Prevention found that colorectal cancer was one of the most common forms of cancer among active duty military personnel. Current treatments for colon cancer include surgical resection of the colon, radiation therapy, and chemotherapy. At early stages, these therapies are effective; however, over 40% of patients at time of diagnosis present with late-stage colon cancer where standard therapies are not effective. This proposal will assess the role of a novel pathway that is highly activated in colon cancer in hopes to provide a mechanistic insight and/or a therapeutic target to this deadly cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810443
Entities
People
- Yatrik M. Shah
Organizations
- United States Army
- University of Michigan