Search for Early Biomarkers Predicting Hepatoma Invasion, Recurrence and Metastasis in the Unique Local and Systemic Cirrhosis Microenvironment (I)

More than 80% of hepatocellular carcinoma (HCC) develop in cirrhotic liver with a propensity to multifoci, unusually high tumor vascularity, unusually high recurrence, unusually high local invasion, and relatively resistance to cytotoxic chemo‐ and molecular target‐ therapies. These unique features very likely contribute to very dismal outcomes of patients with HCC. On the other hand, since cirrhosis is not only a disease of the liver but also has greatly impact on the general physiology of the body, the unique clinical manifestations of HCC might be attributable to the local and systemic effects of cirrhosis. However, little has been known why HCC prefers developing in cirrhotic liver and how cirrhotic liver fosters HCC development and progression. To elucidate the role of the cirrhotic local and systemic microenvironment in HCC development and progression is the long‐term goal of our studies. In this research project, we will focus on identifying the cirrhosis‐specific markers that are related to and are predict HCC recurrence and metastasis. We set the following specific aims to accomplish: 1. To systematic search for biomarkers related to tumor invasion, recurrence, and metastasis from the cirrhotic liver tissues and peripheral blood of patients with HCC. (1st yr) Considering that tissue interstital fluid serve as a bridge connecting the tissue cells and circulation and that potential blood markers are initially shed from the interstitial fluid into the circulation, we start our search for local and systemic cirrhosis markers for HCC progression in the tissue interstitial fluid extracted from surfically removed fresh tissues. Proteins and nucleic acids in the interstitial fluid will be determined by comparative proteomics and genomics. We will specifically focus on the factors specifically present in cirrhotic liver and tumors. 2. To validate the identified biomarkers in prediction of HCC invasion and metastasis. (1st‐2nd yr)The identified candidate markers will be verified in approximately 400 cases. Clinical validation for their efficacy in prediction of HCC recurrence, metastasis and survival will be performed in 3 cohorts of HCC patients collected from different regions in Taiwan (400, 1700, and 800 cases from Kee‐Lung, Lin‐Ko and Chia‐Yi, respectively). 3. To optimize the combination of identified biomarkers in the early prediction of HCC invasion and metastasis. (1st‐2nd yr)All these identified markers will be subjected to the coefficient and regression formula of the multivariate Cox model to identify the best combination for evaluation of tumor recurrence, invasion, metastasis, and survival. Receiver‐operating characteristic curve analyses will be carried out to estimate discriminatory power of the individular or paneled biomarkers. 4. To investigate the molecular mechanisms whereby the identified biomarkers orchestrate tumor behavior and clinical manifestations. (1st‐2nd yr) There should be underlying signaling pathways or mechanisms that steer tumor invasion, metastasis, angiogenesis or others for the identified metastasis related markers. The biological roles and the underlying molecular mechanisms will be further elucidated using cirrhotic mouse model and in vitro reconstruction assays. Mechanistic studies might not only shed light on the interaction between tumor cells and their microenvironment, but also provide novel therapeutic targets for further improvement of prevention and treatment of HCC.

Project ID:PC10309-0065
External Project ID:MOST103-2321-B182-016