Role of Osteopontin in Hepatocellular Carcinoma
Abstract
Hepatocellular carcinoma is the main type of liver cancer. It affects more than 25,000 new patients every year in the US, being the third cause of cancer-related deaths worldwide and whose incidence has triplicated since the 1980s. US Veterans are particularly vulnerable to develop hepatocellular carcinoma due to a strong prevalence of the main risk factors including Hepatitis B and C infection, alcoholism, obesity, and non-alcoholic steatohepatitis. In 2013, Department of Veterans Affairs (VA) hospitals treated around 8,000 Veterans with hepatocellular carcinoma. Current treatment options for hepatocellular carcinoma are still quite limited. While liver transplant has proven effective in some cases, only patients diagnosed early are good candidates and organ availability is always a limiting factor. Also, the precise mechanisms leading to the onset and progression of hepatocellular carcinoma are far from well-known. Therefore, it is vital to deepen our understanding on the events leading to the onset and progression of hepatocellular carcinoma in order to better monitor patients with liver disease before they develop cancer. A single injection of diethylnitrosamine, a drug that induces DNA mutations, has been widely used as a preclinical mouse model to understand the mechanisms driving the onset and progression of hepatocellular carcinoma. Mice develop hepatocellular carcinoma within a few months as cells undergo unrestrained divisions, a phenomenon amplified by inactivation of the tumor suppressor gene p53. While the role of the cell membrane receptor CD44 in blocking p53 has been previously described, the ligands and the events leading to CD44 activation are unknown. We have identified that osteopontin could activate CD44 to drive the onset and progression of hepatocellular carcinoma. When p53 is blocked, cells reprogram and become cancer stem cells, and this leads to cancer progression. Unfortunately, these cells are highly resistant to chemotherapy and are responsible for cancer re-emergence after treatment. Cancer stem cells show high expression of CD44, which plays a major role in maintaining and inducing their proliferation. We believe that osteopontin could also stimulate the proliferation of these cancer stem cells by activating the CD44 receptor. With the research plan we propose, we will demonstrate our hypothesis that osteopontin could enhance the transformation of liver cells to cancer stem cells and promote their maintenance and proliferation; hence, contributing to the onset and progression of hepatocellular carcinoma. This will help our understanding of how hepatocellular carcinoma develops and progresses and in the future it could lead to new treatment options to potentially increase the lifespan of US Veterans and of the general population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810243
Entities
People
- Natalia Nieto
Organizations
- United States Army
- University of Illinois at Chicago