Carr Lab.

Biology of HCC Phenotypes

OVERVIEW

Hepatocellular carcinoma (HCC) appears to consist of several poorly-defined phenotypes, with several distinct poor prognostic factors, such as high alpha-fetoprotein (AFP) and presence of portal vein thrombosis (PVT). Recently, systemic inflammation has been identified as a major independent poor prognosis factor, based on the Glasgow score that utilizes serum C-reactive protein (CRP) and albumin levels. This implicated the tumor microenvironment (inflammation) in prognosis and thus as an influence on the biology of the tumor itself.

RESEARCH INTERESTS

Our over-all aims are to: A, identify distinct clinical HCC profiles/phenotypes; to B, study the effects of inflammatory mediator influence on HCC growth and invasion in vitro; and C, to continue our previous studies on multikinase drug resistance in HCC cells and to learn how to enhance the effects of these agents on HCC growth inhibition.

RESEARCH HIGHLIGHTS

We have collaborated with a group of 15 Turkish institutions that treat HCC, to assemble a 1700 HCC patient database for phenotype analysis. We have published one paper (in Oncology) with 3 more in press, to show that Turkish HCC, which is predominantly HBV based- and thus similar to Chinese but not Western HCC in this respect- is broadly similar to western HCC, with regard to presence of PVT, importance of AFP and our identification of the characteristics of that 50% of patients that do not have elevated AFP levels. Interestingly, HCC in different regions of Turkey may have marked variations, such as the high incidence of HDV infection in HCC patients in the Diyabakir region.

We have worked on the significance of albumin and C-reactive protein (CRP) on HCC biology. We reasoned that to have such important clinical prognostic significance (high CRP and low albumin predict poor outcomes). These 2 proteins must have effects. Directly or indirectly on HCC biology. In 2017 we published 2 papers to show that low albumin levels were associated with more aggressive tumor parameters of larger tumors and more portal vein invasion, that could explain the poor prognosis 8by contrast, higher serum albumin levels were associated with smaller tumors). We followed this up, by showing that pure albumin in tissue culture could slow HCC cell line growth a limit invasiveness. This sets the scene for future experiments to test these ideas in animals. We have recently shown that high CRP levels are associated with larger and more aggressive tumors in Turkish HCC patients (in press) and we are beginning to study the actions of pure CRP on and in (CRP is synthesized by cells of liver origin) HCC cells in culture.

In collaboration with the labs of Profs Nese Atabey and Esra Erdal, we are working in the development of Regorafenib-resistant and double Regorafenib/Sorafenib resistant HCC cell lines, to examine both the peculiarities of their cell signaling compared to the parental cells and also to identify possible mechanisms of limiting their resistance to drug growth-inhibitory actions. Furthermore, since both Sorafenib and Regorafenib are FDA-approved for treating HCC patients, they are quite toxic (multiple side-effects) and thus we are examining ways to enhance the effects on HCC cells of both drugs when used at low concentrations.