ADAM8 affects glioblastoma progression by regulating osteopontin-mediated angiogenesis

Abstract

Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer with a median survival of only 15 months. To complement standard treatments including surgery, radiation and chemotherapy, it is essential to understand the contribution of the GBM tumor microenvironment. Brain macrophages and microglia particularly contribute to tumor angiogenesis, a major hallmark of GBM. ADAM8, a metalloprotease-disintegrin strongly expressed in tumor cells and associated immune cells of GBMs, is related to angiogenesis and correlates with poor clinical prognosis. However, the specific contribution of ADAM8 to GBM tumorigenesis remains elusive. Knockdown of ADAM8 in U87 glioma cells led to significantly decreased angiogenesis and tumor volumes of these cells after stereotactic injection into striate body of mice. We found that the angiogenic potential of ADAM8 in GBM cells and in primary macrophages is mediated by the regulation of osteopontin (OPN), an important inducer of tumor angiogenesis. By in vitro cell signaling analyses, we demonstrate that ADAM8 regulates OPN via JAK/STAT3 pathway in U87 cells and in primary macrophages. As ADAM8 is a dispensable protease for physiological homeostasis, we conclude that ADAM8 could be a tractable target to modulate angiogenesis in GBM with minor side-effects.

Mechanistic Target of Rapamycin Complex 2 Regulation of the Primary Human Trophoblast Cell Transcriptome

“…It plays an essential role in embryo development in the mouse ( Weintraub et al, 2004 ). Furthermore, osteopontin promotes invasion ( Ke et al, 2020 ) and angiogenesis in the trophoblast and other cells ( Li et al, 2021 ). Phosphatidylinositol 3-kinase (PI3K) is a heterodimer containing a regulatory subunit (p85) and a catalytic subunit (p110).…”

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

“…The angiogenic potential of ADAM8 in GBM cells and in primary macrophages is mediated by the regulation of osteopontin. ADAM8 could be a tractable target to modulate angiogenesis in GBM [ 74 ]. Zhu et al found that surgical debulking with anti-CD47 blocking immunotherapy causes a decrease in angiogenic proteins besides enhanced inflammatory response and prolonged survival in animals [ 75 ].…”

Three Potential Tumor Markers Promote Metastasis and Recurrence of Colorectal Cancer by Regulating the Inflammatory Response: ADAM8, LYN, and S100A9

“…Previous studies have shown that ADAM8 has significant roles in immunomodulation and inflammatory diseases [10][11][12]. ADAM8 is also associated with a variety of tumors, including glioblastoma and breast carcinoma, and is thus a promising potential therapeutic target [13,14]. In pancreatic ductal adenocarcinoma cells, functional inhibition of ADAM8 by BK-1361 was shown to lead to reduced invasiveness and less ERK1/2 and matrix metalloproteinase activation [15].…”