Modeling Human Hepatocellular Carcinoma in Humanized Mice
Abstract
Relevance to Peer Reviewed Cancer Research Program Topic Area: The work in this proposal is specifically targeted to Liver Cancer and is focused on creating an improved model of human liver cancer that will greatly impact our understanding of liver cancer formation and help identify targets for treatment (areas of Military Relevance). Scientific Objective and Rationale; Relevance to the Military Population and Veterans: Liver cancer is one of the most common and most deadly cancers worldwide. The great majority of primary liver cancers are so-called hepatocellular carcinomas (HCC), the type of liver cancer that is the focus of this proposal. The incidence of HCC is rising every year, and about 700,000 patients are diagnosed with this type of cancer annually. HCC has a particularly poor prognosis as it remains very difficult to treat with current therapies, and consequently about 600,000 people die of HCC annually worldwide. In the Veteran population, both HCC incidence and HCC mortality rose 3-fold from 2001-2013 and rose 10-fold in the decade prior (while the 5-year survival rate has remained below 12 percent). Research completed by the Department of Veterans Affairs system has noted that HCC disproportionately impacts military Veterans rather than the general U.S. population. Moreover, recent advances in liver disease treatment will not improve this trend but will lead to a higher impact of HCC to military Veterans as compared to the general U.S. population. African-American and Hispanic active duty members (which comprise 32% of the U.S. military) are at a higher and disproportionate risk for HCC development as compared to the general population. The liver chimeric mouse model can incorporate human hepatocytes from a variety of ethnic backgrounds representative of the diversity of our military and Veteran populations and will enable the study of the impact that specific mutations and treatments play in HCC formation and treatment. Applicability of the Proposed Research: It is poorly understood how HCC develops. There are a number of environmental factors that can promote development of HCCs. These include infections with certain viruses that infect the liver, specifically hepatitis B, C, and delta viruses, excessive alcohol consumption, exposure to toxins and metabolic disorders. However, these external stimuli cannot explain on their own why some individuals do and other do not develop HCCs. Over the years, evidence has emerged that the genetic makeup of a patient can drastically influence disease outcome. Specific alterations in the host genome have been identified that correlate with the incidence and severity of HCC. While several of such genetic markers are now known, it remains almost completely unclear how these mutations would initiate and/or promote cancer development. A major challenge in gaining better insights into these processes has been the scarcity of adequate experimental systems. Commonly used cell culture systems are frequently based on already cancerous cells, and isolated primary liver cells cannot be maintained sufficiently long outside of the human body to monitor the impact of these mutations on cancer development. Previous studies have relied on conventional mouse models. However, it has become increasingly clear that mice do not closely mimic human disease processes. Thus, we propose here to capitalize on a novel, so-called humanized mouse model that we have pioneered. Such humanized mice grow a (partially) human liver and have proven to be an enabling tool to study a variety of human diseases including infectious and metabolic disorders. Specifically, we will combine our humanized mouse technology with advanced genome engineering techniques to introduce the specific genome alterations that have been associated with HCCs. By doing this, we can monitor over several months whether and how individual or combinations of these mutations give rise to HCCs. Our work will de
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810237
Entities
People
- Alexander Ploss
Organizations
- Princeton University
- United States Army