ADAM10 Releases a Soluble Form of the GPNMB/Osteoactivin Extracellular Domain with Angiogenic Properties

Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
PLoS ONE (Impact Factor: 3.23). 08/2010; 5(8):e12093. DOI: 10.1371/journal.pone.0012093
Source: PubMed


Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; however, little is known about the functions of GPNMB/OA within the primary tumor microenvironment.
We have employed mouse and human breast cancer cells to investigate the effects of GPNMB/OA on tumor growth and angiogenesis. GPNMB/OA-expressing tumors display elevated endothelial recruitment and reduced apoptosis when compared to vector control-derived tumors. Primary human breast cancers characterized by high vascular density also display elevated levels of GPNMB/OA when compared to those with low vascular density. Using immunoblot and ELISA assays, we demonstrate the GPNMB/OA ectodomain is shed from the surface of breast cancer cells. Transient siRNA-mediated knockdown studies of known sheddases identified ADAM10 as the protease responsible for GPNMB/OA processing. Finally, we demonstrate that the shed extracellular domain (ECD) of GPNMB/OA can promote endothelial migration in vitro.
GPNMB/OA expression promotes tumor growth, which is associated with enhanced endothelial recruitment. We identify ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells, which induces endothelial cell migration. Thus, ectodomain shedding may serve as a novel mechanism by which GPNMB/OA promotes angiogenesis in breast cancer.

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    • "OA increases in tissue matrices during fracture re- pair[13]and influences adhesion and migration of select cell types (including fibroblasts) that are involved in tissue repair[17], and regulates muscle regeneration in desmin-deficient cardiomyocytes[18]. In a process called ectodomain shedding, the extracellular fragments of OA are cleaved on the plasma membrane and released to the ECM where they act as cytokines or growth factors192021in addition to increasing MMP production[14]. While it is clear that OA increases under several types of repair and regeneration conditions, its expression in association with overuse injuries has yet to be examined. "
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    ABSTRACT: BACKGROUND: Expression of the growth factor osteoactivin (OA) increases during tissue degeneration and regeneration, fracture repair and after denervation-induced disuse atrophy, concomitant with increased matrix metalloproteinases (MMPs). However, OA's expression with repetitive overuse injuries is unknown. The aim of this study was to evaluate: 1) OA expression in an operant rat model of repetitive overuse; 2) expression of MMPs; 3) inflammatory cytokines indicative of injury or inflammation; and 4) the inducible form of heat shock protein 70 (HSPA1A/HSP72) as the latter is known to increase during metabolic stress and to be involved in cellular repair. Young adult female rats performed a high repetition negligible force (HRNF) food retrieval task for up to 6 weeks and were compared to control rats. METHODS: Flexor digitorum muscles and tendons were collected from 22 young adult female rats performing a HRNF reaching task for 3 to 6 weeks, and 12 food restricted control (FRC) rats. OA mRNA levels were assessed by quantitative polymerase chain reaction (qPCR). OA, MMP-1, -2, -3, and -13 and HSP72 protein expression was assayed using Western blotting. Immunohistochemistry and image analysis was used to evaluate OA and HSP72 expression. ELISA was performed for HSP72 and inflammatory cytokines. RESULTS: Flexor digitorum muscles and tendons from 6-week HRNF rats showed increased OA mRNA and protein expression compared to FRC rats. MMP-1, -2 and -3 progressively increased in muscles whereas MMP-1 and -3 increased in tendons with HRNF task performance. HSP72 increased in 6-week HRNF muscles and tendons, compared to controls, and co-localized with OA in the myofiber sarcolemma. IL-1alpha and beta increased transiently in tendons or muscles in HRNF week 3 before resolving in week 6. CONCLUSION: The simultaneous increases of OA with factors involved in tissue repair (MMPs and HSP72) supports a role of OA in tissue regeneration after repetitive overuse.
    Full-text · Article · Jan 2016 · BMC Musculoskeletal Disorders
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    • "Furthermore, GPNMB/OA overexpression has been linked to several aggressive cancers, including uveal and cutaneous melanoma [14] [15], hepatocellular carcinoma [16], glioma [17] [18] and breast cancer (BC) [19] [20]. Indeed, the GPNMB/ OA ectopic overexpression enhances the cell invasive phenotype both in vitro and in vivo [16] [17] [19] [21]. In line with this, the role of GPNMB/OA in the human PCa, in particular in the advanced PCa, characterized by metastatic dissemination to liver, lung, brain and bone and currently incurable, has been recently investigated with conflicting results [22] [23]. "
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    ABSTRACT: Non-metastatic glycoprotein melanoma protein B (GPNMB), also known as osteoactivin (OA) is expressed in a wide array of tumors and represents an emerging target for drug development. In this study, we investigated the role of GPNMB/OA in the progression of human metastatic DU145 and PC3 prostate cancer cells. GPNMB/OA contribution in PCa malignant phenotype has been analysed by small interfering RNA-induced GPNMB/OA silencing. We found that following GPNMB/OA silencing the migration capability of both DU145 and PC3 cells, evaluated by using in vitro invasivity assay, as well as the metalloproteinases MMP-2 and MMP-9 activity were equally strongly inhibited. By contrast knocking down GPNMB/OA weakly attenuated cell proliferation rate of DU145, an effect that paralleled with an increase number of apoptotic cells. However, PC3 cell growth seems to be not affected by GPNMB/OA. Together, these data reveal that GPNMB/OA acts as a critical molecular mediator promoting the acquisition of the more aggressive, pro-metastatic phenotype distinctive of human DU145 and PC3 cell lines.
    Full-text · Article · Apr 2014 · Experimental Cell Research
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    • "GPNBM-OA stimulates recruitment of tumors-associated macrophages, which produce VEGF. ADAM-10 and ADAM 17 proteases release the extracellular domain of GPNMB-OA, which stimulates migration of endothelial cells, acting as a chemoattractant [23]. Progranulin stimulates proliferation of endothelial cells [26]. "
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    ABSTRACT: Triple negative breast cancer is a heterogeneous group of tumors, lacking the expression of estrogen, progesterone and HER-2 receptors. As frequency, it accounts about 15-20% of all breast cancers. Although in the last years there was a "boom" in publishing over this issue, multiple molecular classifications being elaborated, "the triple negative breast cancer odyssey " is still far away from ending, as the complicated molecular pathways of pathogenesis and drug resistance mechanisms remain yet insufficiently explored. The aim of this review is presentation of molecular signatures that could predict outcome and drug resistance in triple negative breast cancer.
    Full-text · Article · Sep 2013 · Breast (Edinburgh, Scotland)
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