Prosurvival function of the granulin‐epithelin precursor is important in tumor progression and chemoresponse

Abstract

The granulin-epithelin precursor (GEP/PCDGF), a 68-88 kDa secreted glycoprotein, has been shown to be an important growth and survival factor for ovarian cancer cells. Furthermore, GEP expression is a predictor of patient survival in metastatic ovarian cancer cells. Up to this point, however, the molecular mechanisms and clinical relevance of a GEP-mediated prosurvival phenotype remain poorly characterized. We hypothesize that the prosurvival function of GEP is important in ovarian cancer tumor progression and chemoresponse. To explore this hypothesis, we examined the effects of GEP overexpression on migration, invasion and cisplatin (CDDP) chemosensitivity in the ovarian cancer cell line A2780. Full length GEP transfectants demonstrated an increased capacity to migrate and invade their substratum when compared to empty vector controls. In addition, GEP overexpression was associated with CDDP chemoresistance. Finally, GEP overexpression increased tumor formation and protected cells from tumor regression in response to CDDP treatment in vivo. Taken together, these data support a role for GEP in tumor progression and development of drug resistance. ' 2007 Wiley-Liss, Inc.

Progranulin A-mediated MET Signaling Is Essential for Liver Morphogenesis in Zebrafish

“…Numerous genes have been identified that are required for outgrowth, and it has been demonstrated that a loss of the expression of these genes decreases hepatic proliferation and leads to apoptosis (37)(38)(39)(40). PGRN has been reported to be a growth factor that stimulates cell proliferation (41,42) and decreases apoptosis (43)(44)(45). The present work is the first to show that PGRN is involved in embryonic liver growth regulation.…”

The granulin gene family: from cancer to dementia

“…PGRN supports tumor growth by increased proliferation, (8,15) decreased apoptosis, (9,29,(86)(87)(88) and greater invasiveness through the ECM. (9,19) Each of these actions requires the activity of the ERK and PI3K signal transduction pathways, although the extent to which either pathway contributes is variable.…”

The Glycoprotein Growth Factor Progranulin Promotes Carcinogenesis and has Potential Value in Anti-cancer Therapy

“…The over-production of PGRN in the estrogen-dependent breast cancer cell line MCF7, for example, results in increased tumorigenicity, estrogen-independence and resistance to the estrogen receptor blocking drug Tamoxifen [63,67]. Similarly, PGRN over-production confers greater tumorigenicity upon liver [46], ovarian [68] and endometrial cancer cells [36] when grown as xenografts in mice. SW13 cells, which derive from an adrenal carcinoma, are highly sensitive to the proliferative effects of PGRN [3,65].…”

“…Ovarian cancer cells that constitutively over-produce PGRN were resistant to the platinum containing drug cisplatin [68] (which is used to treat ovarian cancer [97]). However, ovarian cancer stromal cells that were sampled after chemotherapy with platinum drugs tended to show reduced staining for PGRN compared to comparable tissues inspected before treatment [31] suggesting a level of complexity in the drug-PGRN relationship.…”