Platelet-derived growth factor receptor-α:: a novel therapeutic target in human hepatocellular cancer

Hepatocellular cancer (HCC) is a disease of poor prognosis. Identifying novel molecular aberrations might present opportunities to identify new therapeutic targets. Due to the similarities between the processes of development and cancer, we used early developing livers to identify genes that might play a primary role in HCC. Platelet-derived growth factor receptor-alpha (PDGFR alpha) was identified from microarray using early developing mouse livers. Expression of PDGFR alpha and its upstream effectors, PDGF-AA and PDGF-CC, were examined in HCC tissues (n = 43) by Western blot, real-time PCR, and immunohistochemistry. Finally, effect of anti-PDGFR alpha antibody (mAb 3G3, ImClone Systems, Inc.) was examined on human hepatoma cells. A high expression of PDGFR alpha was observed during early liver development. HCCs (17 of 2 1) revealed cytoplasmic PDGFR alpha and activated PDGFR alpha (phospho-Tyr(754)) by immumohistochemistry. Additional HCCs (14 of 22) showed elevated PDGFR alpha, levels when compared with the adjacent normal livers by Western blots. Of these 14 patients, 3 showed increased PDGFR alpha gene expression, 3 showed elevated PDGF-AA, and 4 had higher PDGF-CC levels in the tumors compared with adjacent livers. Multiple hepatoma cell lines, when treated with mAb 3G3, showed significant decreases in cell proliferation and survival (P < 0.05). In conclusion, similar to 70% of HCC tissues had elevated PDGFR alpha levels due to diverse mechanisms. PDGFR alpha inhibition in hepatoma cells led to diminution of tumor cell survival and proliferation and thus might be of therapeutic significance.