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

ABSTRACT 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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Available from: April Ann Nicole Rose, Sep 29, 2015
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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.
    Breast (Edinburgh, Scotland) 09/2013; 22(6). DOI:10.1016/j.breast.2013.08.007 · 2.38 Impact Factor
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    • "GPNMB, initially termed glycoprotein non-metastatic gene B (NMB), was first cloned and described in 1995 as a protein highly expressed in a melanoma cell line with low metastatic potential.38 However, since this initial publication, elevated GPNMB expression is observed in numerous cancers and is often associated with the metastatic phenotype.27–34 GPNMB is also known as hematopoietic growth factor inducible, neurokinin-1 type (HGFIN),39 and is located on the small arm of chromosome 7 (7p15). "
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    ABSTRACT: Molecularly targeted therapies are rapidly growing with respect to their clinical development and impact on cancer treatment due to their highly selective anti-tumor action. However, many aggressive cancers such as triple-negative breast cancer (TNBC) currently lack well-defined therapeutic targets against which such agents can be developed. The identification of tumor-associated antigens and the generation of antibody drug-conjugates represent an emerging area of intense interest and growth in the field of cancer therapeutics. Glycoprotein non-metastatic b (GPNMB) has recently been identified as a gene that is over-expressed in numerous cancers, including TNBC, and often correlates with the metastatic phenotype. In breast cancer, GPNMB expression in the tumor epithelium is associated with a reduction in disease-free and overall survival. Based on these findings, glembatumumab vedotin (CDX-011), an antibody-drug conjugate that selectively targets GPNMB, is currently being investigated in clinical trials for patients with metastatic breast cancer and unresectable melanoma. This review discusses the physiological and potential pathological roles of GPNMB in normal and cancer tissues, respectively, and details the clinical advances and challenges in targeting GPNMB-expressing malignancies.
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    • "ADAMs are also important for the shedding of proteolytic enzymes from the plasma membrane [20, 70, 71]. ADAM10 itself is released from the cell surface through cleavage by ADAM9 and ADAM15, indicating that ADAM10 has dual functions in the cell [72]. "
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