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

Abstract

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-α (PDGFRα) was identified from microarray using early developing mouse livers. Expression of PDGFRα 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-PDGFRα antibody (mAb 3G3, ImClone Systems, Inc.) was examined on human hepatoma cells. A high expression of PDGFRα was observed during early liver development. HCCs (17 of 21) revealed cytoplasmic PDGFRα and activated PDGFRα (phospho-Tyr754) by immunohistochemistry. Additional HCCs (14 of 22) showed elevated PDGFRα levels when compared with the adjacent normal livers by Western blots. Of these 14 patients, 3 showed increased PDGFRα gene expression, 3showed 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, ∼70% of HCC tissues had elevated PDGFRα levels due to diverse mechanisms. PDGFRα inhibition in hepatoma cells led to diminution of tumor cell survival and proliferation and thus might be of therapeutic significance. Copyright © 2007 American Association for Cancer Research.