Steven Lidofsky, MD, Associate Professor, Medicine & Pharmacology
The hepatitis B X protein in migration and invasion
Hepatocellular carcinoma is a major cause of cancer death worldwide, and its incidence in the U.S. is rising precipitously. Chronic infection with the hepatitis B virus is a well-established risk factor for the development of hepatocellular carcinoma; however, the mechanisms responsible for hepatitis B-mediated carcinogenesis remain unknown. There is mounting evidence that a viral protein, hepatitis Bx (HBx) contributes to the development of hepatic carcinogenesis. HBx appears to have pluripotent functions. In addition to activation of transcription factors, HBx has been shown to stimulate cell migration and invasion, all of which play key roles in cancer biology. Moreover, HBx potentiates cell migration in response to extracellular motogenic stimuli. How this occurs is largely undefined.
Recent observations suggest that HBx increases cell migration and invasion via pathways mediated by Src family tyrosine kinases and the Ca2+-dependent transcription factor NFAT. HBx also increases the amplitude of cell Ca2+ transients elicited by Ca2+-mobilizing hormones. It has also been shown that HBx activates the tyrosine kinase Pyk2, an upstream regulator of Src family kinases, in a Ca2+-dependent manner. These observations raise the possibility that HBx potentiates cellular responses to motogenic stimuli through intracellular Ca2+ mobilization.
Two motogenic stimuli that elicit intracellular Ca2+ mobilization are extracellular matrix components such as hyaluronan, and peptides, such as hepatocyte growth factor (HGF); each has been linked to tumor aggressiveness in hepatocellular carcinoma. Whether HBx potentiates tumor cell migration and invasion in response to such stimuli via Ca2+-dependent mediators defined in other systems has not been examined. To address these issues, Lidofsky will test the following hypothesis: HBx-mediated increases in cell Ca2+ promote cell migration and invasion via activation of Pyk2 and NFAT, and increases in cell Ca2+ combined with the activation of Pyk2 and NFAT potentiate migration and invasion in response to hyaluronan and to HGF.
Chris Holmes, MD, PhD, Assistant Professor, Medicine
Platelet Modulation by Angiogenesis Inhibitors
The induction of angiogenesis is a key mechanism by which neoplastic cells promote continued growth and metastasis. Bevacizumab and thalidomide are new and effective anti-neoplastic agents whose mechanism of action depends, at least in part, on angiogenesis inhibition. A recent surprise was the clinical finding that up to 25% of myeloma patients treated with thalidomide in combination with traditional chemotherapeutic agents developed venous thrombosis. As compelling clinically is a two-fold increased risk of arterial thrombosis (myocardial infarction and cerebrovascular events) seen in patients treated with bevacizumab.
The observation of increased venous and arterial thrombosis in patients treated with the angiogenesis inhibitors thalidomide and bevacizumab suggests an impact on hemostasis and thrombosis pathways by these drugs. Given that 1) platelet activation plays a major role in arterial thrombosis and 2) the primary relevant coagulation surface for venous thrombosis is the activated platelet membrane, the platelet likely serves as a heretofore unrecognized target of angiogenesis inhibitors. Holmes’s translational research project will be the first to evaluate the potentially important interaction between angiogenesis inhibitors and platelet function. Research efforts in the laboratory will focus on the in vitro effect of these drugs on selected parameters of platelet function including platelet activation and procoagulant potential. The in vivo impact on platelet function will be assessed in a translational clinical study of patients initiating treatment with these drugs.