Potential Role for ADAM15 in Pathological Neovascularization in Mice

Abstract

ADAM15 (named for a disintegrin and metalloprotease 15, metargidin) is a membrane-anchored glycoprotein that has been implicated in cell-cell or cell-matrix interactions and in the proteolysis of molecules on the cell surface or extracellular matrix. To characterize the potential roles of ADAM15 during development and in adult mice, we analyzed its expression pattern by mRNA in situ hybridization and generated mice carrying a targeted deletion of ADAM15 (adam15 ؊/؊ mice). A high level of expression of ADAM15 was found in vascular cells, the endocardium, hypertrophic cells in developing bone, and specific areas of the hippocampus and cerebellum. However, despite the pronounced expression of ADAM15 in these tissues, no major developmental defects or pathological phenotypes were evident in adam15 ؊/؊ mice. The elevated levels of ADAM15 in endothelial cells prompted an evaluation of its role in neovascularization. In a mouse model for retinopathy of prematurity, adam15 ؊/؊ mice had a major reduction in neovascularization compared to wild-type controls. Furthermore, the size of tumors resulting from implanted B16F0 mouse melanoma cells was significantly smaller in adam15 ؊/؊ mice than in wild-type controls. Since ADAM15 does not appear to be required for developmental angiogenesis or for adult homeostasis, it may represent a novel target for the design of inhibitors of pathological neovascularization.Metalloprotease-disintegrins (ADAMs) are a family of membrane-anchored glycoproteins that are related to snake venom metalloproteases and integrin ligands, termed disintegrins. ADAMs have been implicated in fertilization, myogenesis, neurogenesis, and protein ectodomain shedding (for recent reviews, see references 5, 55, 62, and 63). ADAMs are also thought to have roles in cell-cell adhesion, for example, through interactions with integrins (9, 18, 49) or syndecans (32, 71). Over 30 ADAMs have been identified to date, and yet the function of less than a third of these proteins during development and in adulthood has been characterized. ADAM1 and -2 (fertilin ␣ and ␤) and ADAM3 have critical roles in fertilization (12, 13, 50, 64). ADAM9 and -12 are not required for development or adult survival (39, 76), although ADAM12 reportedly has a role in processing the heparin-binding epidermal growth factor (EGF)-like growth factor HB-EGF (3), in adipogenesis and myogenesis (34, 39), and in the pathology of muscular dystrophy (38). ADAM13 has been implicated in cranial neural crest migration in Xenopus laevis (2). The tumor necrosis factor alpha-converting enzyme (TACE/ADAM17) has a role in releasing the ectodomain of a number of physiologically relevant proteins, including tumor necrosis factor alpha (4, 47); ligands of the EGF receptor, such as HB-EGF (45, 70) and transforming growth factor ␣ (52); and the amyloid precursor protein (8). ADAM17/TACE is essential for survival of newborn mice, presumably because transforming growth factor ␣ and other ligands of the EGF receptor require functional TACE for their proper activation (...

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Transgenic B16F10 melanoma cells form less metastasis in mouse lungs after turning on RDD expression [105]. Angiogenesis is inhibited in ADAM-15-deficient mice in a model of retinopathy [106]. Mechanisms implicating ADAM-15 in the regulation of angiogenesis could be related to the presence of Arg-Gly-Asp (RGD) sequence in the disintegrin domain which binds integrins.…”

“…Indeed, ADAM-15 decreases integrin αvβ 3 /vitronectin-mediated ovarian cancer cell adhesion and motility in a RGD-dependent manner [107]. However, although tumours developed from melanoma cells implanted subcutaneously are smaller in ADAM-15 -/-mice, no difference in tumour vascularity has been observed between wild type and mutant mice [106]. The exact role of ADAM-15 during angiogenesis appears complex and requires further investigations.…”

Metalloproteinases and their inhibitors in tumor angiogenesis

“…However, although tumor growth was also inhibited in these mice, there was no difference in tumor vascularity in adam15 À/À mice versus their wild-type counterparts. 69 Studies using Mmp-knockout mice have been useful in demonstrating the increasingly recognized importance of host production of MMPs contributing to tumor growth and angiogenesis. One example of this comes from a study in which MMP-9-producing human ovarian cancer cells were injected into the peritoneal cavity of Mmp9 þ/þ or Mmp9 À/À nude mice.…”

Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC)

“…The putative interest of studying ADAMs and ADAMTS in lung carcinomas is reinforced by a recent report of Lemjabbar et al (2003), demonstrating that tobacco smoke-induced bronchial epithelial cell proliferation is mediated by the cleavage of amphiregulin, a ligand of EGF receptor, by ADAM-17. A disintegrin and metalloprotease-15 (ADAM-15) deficiency in mice is associated with impaired pathological angiogenesis and reduced tumour growth (Horiuchi et al, 2003). In addition, recently, an interplay between vascular endothelial growth factor (VEGF) and metalloproteases has been reported.…”