<i>ADAM8</i> 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. <i>ADAM8</i>, 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 <i>ADAM8</i> to GBM tumorigenesis remains elusive. Knockdown of <i>ADAM8</i> 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 <i>ADAM8</i> in GBM cells and in primary macrophages is mediated by the regulation of osteopontin (OPN), an important inducer of tumor angiogenesis. By <i>in vitro</i> cell signaling analyses, we demonstrate that <i>ADAM8</i> regulates OPN via JAK/STAT3 pathway in U87 cells and in primary macrophages. As <i>ADAM8</i> is a dispensable protease for physiological homeostasis, we conclude that <i>ADAM8</i> could be a tractable target to modulate angiogenesis in GBM with minor side-effects.