Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Abstract

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein enriched on the cell surface of cancer cells, including melanoma, glioblastoma, and triple-negative breast cancer. There is growing evidence identifying GPNMB as a tumor-promoter; however, despite its biological and clinical significance, the molecular mechanisms engaged by GPNMB to promote tumorigenesis are not well understood. GPNMB promotes aggressive behaviors such as tumor cell proliferation, migration, and invasion. The extracellular domain of GPNMB shed from the cell surface interacts with integrins to facilitate in the recruitment of immune-suppressive and pro-angiogenic cells to the tumor microenvironment, thereby enhancing tumor migration and invasion. GPNMB also modulates receptor tyrosine kinases and integrin signaling in a cell autonomous fashion, leading to downstream kinase signaling that in turn triggers the expression and secretion of tumorigenic factors such as matrix metalloproteinases (MMPs) and cytokines. Therefore, GPNMB exerts its pro-tumorigenic role both intracellularly and in a paracrine fashion through shedding its extracellular domain. This review highlights the importance of GPNMB in cancer progression and discusses molecular mediators of GPNMB-induced tumor growth and invasion.

Glycoprotein nmb Is Exposed on the Surface of Dormant Breast Cancer Cells and Induces Stem Cell–like Properties

“…CDX-011 (glembatumumab vedotin) is an antibody-drug conjugate that contains CR011, a human mAb against GPNMB, and conjugates with a cytotoxic agent (MMAE). CDX-011 has been developed for the treatment of GPNMB-expressing cancers, and clinical studies of CDX-011 against patients with breast cancer and melanoma were conducted (12,13,50). We have shown that the cell surface-GPNMB high cells have higher stem cell-like properties than do the cell surface-GPNMB low cells (Fig.…”

Role of the kringle‐like domain in glycoprotein NMB for its tumorigenic potential

“…Glycoprotein NMB is a type IA transmembrane protein that is highly expressed in many types of cancers, including melanoma, glioblastoma, and breast cancer. It is considered a poor prognostic factor in those cancers and it might be an attractive therapeutic target …”

“…Glembatumumab vedotin, or CDX‐011, an Ab against GPNMB conjugated with an anticancer drug, has been developed to treat GPNMB‐expressing cancers and is in clinical trials for breast cancer and melanoma patients . This suggests the potential of GPNMB as a therapeutic target.…”

“…Glembatumumab vedotin, or CDX-011, an Ab against GPNMB conjugated with an anticancer drug, has been developed to treat GPNMB-expressing cancers and is in clinical trials for breast cancer and melanoma patients. 5,[40][41][42][43] This suggests the potential of GPNMB as a therapeutic target. From the findings of this study, we propose that specifically targeting the KLD in the ECD of GPNMB is a possible therapeutic target.…”

“…It is considered a poor prognostic factor in those cancers and it might be an attractive therapeutic target. [1][2][3][4][5] We have previously reported that enhanced expression of GPNMB induces EMT and increases sphere formation in vitro and tumor growth in vivo, whereas knockdown of GPNMB attenuated the tumorigenic ability of breast cancer cells. 6 We also showed that cell surface expression of GPNMB is induced in limited numbers of breast cancer cells in sphere-culture conditions in vitro and in growing tumors in vivo and induces stem-like properties, such as high expression of stemness genes, low expression of proliferation genes, and high sphere and tumor formation.…”