Granulin-epithelin precursor (GEP) as molecular target for treatment of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the major histological type of primary liver cancer, and is the third leading cancer killer worldwide. The disease is frequently diagnosed at an advanced stage and thus precludes curative surgical treatment. There is no effective therapeutic option for the majority of the HCC patients. A new therapeutic strategy is essential. We (Cancer Res 2002; Mol Biol Cell 2002) and others have reported the genome-wide expression profiles of HCC and their clinical implications. In the earlier study, we demonstrated that granulin-epithelin precursor (GEP, also called progranulin, acrogranin, or PC-derived growth factor), an autocrine growth factor, was overexpressed in more than 70% of HCC on the mRNA and protein levels. We also showed that GEP controlled HCC proliferation, invasion and tumorigenicity (Clin Cancer Res 2004). Here we show that GEP is a potential therapeutic target for HCC. We developed the anti-GEP monoclonal antibody (mAb), and demonstrated that it inhibited the growth of hepatoma cells, but revealed no significant effect on normal liver cells. In the nude mice model transplanted with human HCC, anti-GEP mAb decreased the serum GEP level and inhibited the growth of established tumors in a dose-dependent manner. The anti-GEP mAb reduced tumor cell proliferation via the p44/42 MAPK pathway, and reduced tumor angiogenesis to deprive of the nutrient supply with reduced microvessel density and tumor VEGF level. Overexpression of GEP has also been shown in breast, ovarian and prostate cancers, therefore anti-GEP therapy may also be applicable to a broad spectrum of human cancer types. From the expression profiling studies, we are able to identify a number of differentially expressed genes have diagnostic and prognostic significance, and reveal the potential to serve as molecular targets for cancer therapy. Genome-wide expression analysis definitely serves an important role in identification of new targets for cancer treatment.