Critical Function for ADAM9 in Mouse Prostate Cancer

Abstract

ADAM9 is a membrane-anchored metalloprotease that is markedly up-regulated in several human carcinomas. Here, we show that ADAM9 is similarly up-regulated in mouse models for prostate, breast, and intestinal carcinoma. To assess whether ADAM9 is critical for the pathogenesis of prostate carcinoma, one of the most common cancers in men, we evaluated how loss of ADAM9 affects tumorigenesis in W 10 mice, a mouse model for this disease. In the absence of ADAM9, most tumors in 50-week-old W 10 mice were well differentiated, whereas littermate controls expressing wild-type ADAM9 had predominantly poorly differentiated, and in some cases significantly larger, tumors. Moreover, gain-of-function experiments in which ADAM9 was overexpressed in mouse prostate epithelium resulted in significant abnormalities, including epithelial hyperplasia at 4 to 6 months of age, and prostatic intraepithelial neoplasia after 1 year. A potential underlying mechanism for the role of ADAM9 in prostate cancer emerged from cell-based assays: ADAM9 can cleave and release epidermal growth factor and FGFR2iiib from cells, both of which have pivotal functions in the pathogenesis of this disease. Taken together, these results suggest that ADAM9 contributes to the pathogenesis of prostate cancer and potentially also other carcinomas, raising the possibility that ADAM9 might be a good target for antitumor drugs. (Cancer Res 2005; 65(20): 9312-9)

ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progression

“…As a result of their ability to affect cell-cell interactions, ADAMs could conceivably contribute to tumorigenesis, especially if their function is dysregulated. We have previously shown that ADAM9 is upregulated in prostate tumor cells, and that it is critical for tumor progression in the W 10 mouse model for prostate cancer (Peduto et al, 2005). In the current study, we focused on the potential role of ADAM12 in prostate tumorigenesis.…”

Role of ADAMs in Cancer Formation and Progression

“…Peduto et al (32) reported that well-differentiated prostate cancers developed in ADAM-9 -deficient mice compared with poorly differentiated tumors in control mice expressing ADAM-9. These investigators also showed that overexpression of ADAM-9 in mouse prostate epithelial cells gave rise to epithelial hyperplasia and prostate intraepithelial neoplasia, a putative precursor lesion for prostate cancer (32). In studies on prostate cancer cell lines in culture, overexpression of ADAM-9 was found to be associated with the conversion of LNCaP cells to an androgen-independent and metastatic state (33).…”

Different ADAMs have distinct influences on Kit ligand processing: phorbol-ester-stimulated ectodomain shedding of Kitl1 by ADAM17 is reduced by ADAM19

“…ADAMs consist of an N-terminal signal sequence followed by a pro domain, metalloprotease domain, disintegrin domain, cysteine-rich domain, epidermal growth factor-like domain, transmembrane domain and cytoplasmic domain. ADAMs have been implicated in diverse functions, including fertilization (Primakoff and Myles, 2000), neurogenesis (Fambrough et al, 1996;Hattori et al, 2000), angiogenesis (Hartmann et al, 2002;Horiuchi et al, 2003), adipogenesis (Kawaguchi et al, 2003;Kawaguchi et al, 2002), heart development Jackson et al, 2003;Kurohara et al, 2004;Zhou et al, 2004), asthma (Van Eerdewegh et al, 2002) and cancer (Kveiborg et al, 2005;Peduto et al, 2005). A conserved zinc-binding catalytic site sequence motif (HEXXH) (Stocker et al, 1995) is found in approximately half of the known ADAMs.…”