Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation

Abstract

SUMMARY The tumor vascular microenvironment supports tumorigenesis by supplying not only oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feed-forward mechanism in which endothelial cells (EC), in response to tumor-derived mediators, release angiocrines driving aberrant vascularization and glioblastoma multiforme (GBM) progression through a hypoxia-independent induction of hypoxia-inducible factor (HIF)-1α. Phosphorylation of profilin-1 (Pfn-1) at Tyr129 in EC induces binding to tumor suppressor protein von Hippel-Lindau (VHL), prevents VHL-mediated degradation of prolyl-hydroxylated HIF-1α, culminating in HIF-1α accumulation even in normoxia. Elevated HIF-1α induces expression of multiple angiogenic factors, leading to vascular abnormality and tumor progression. In a genetic model of GBM, mice with an EC-specific defect in Pfn-1 phosphorylation exhibit reduced tumor angiogenesis, normalized vasculature, and improved survival. Moreover, EC-specific Pfn-1 phosphorylation is associated with tumor aggressiveness in human glioma. These findings suggest that targeting Pfn-1 phosphorylation may offer a selective strategy for therapeutic intervention of malignant solid tumors.

A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses

“…Endothelial IL-6 production promotes chemoresistance EC paracrine signaling has been implicated in the creation of tissue niches that promote stem cell homeostasis (Ding et al 2012), tissue regeneration , and cancer cell growth and aggressiveness Cao et al 2014;Fan et al 2014;Tavora et al 2014); however, which secreted factors promote cancer chemoresistance in vivo is not well understood. We bred endothelial-specific IL-6 knockout mice that express tamoxifen-inducible Cre under the control of the endothelial-specific VE-Cadherin (CDH5) promoter (Wang et al 2010) and also carry floxed alleles of IL-6 (Quintana et al 2013), allowing its excision by Cre [Cdh5(PAC)-CreERT2; IL6 f/f ] (Fig.…”

Subcellular Localization and Ser-137 Phosphorylation Regulate Tumor-suppressive Activity of Profilin-1

“…2-4). Recently, Pfn1 has been found to destabilize hypoxia-inducible factor-1␣ (HIF-1␣) and consequently inhibit angiogenesis, indicating the multifaceted nature of its antitumor functions (14,33). However, until now it has remained puzzling how Pfn1 can simultaneously support and inhibit proliferation within the same cellular context.…”

Extra-CNS metastasis from glioblastoma: a rare clinical entity

“…For example, glioma cells secrete factors into the tumor microenvironment that drive Profilin-1 phosphorylation in neighboring endothelial cells. Profilin-1 phosphorylation results in aberrant activation of HIF-1a, which prompts EC proliferation and secretion of angiocrine factors that then activate glioma cell proliferation and migration, and decreases pericyte coverage of adjacent blood vessels [16]. Data from mouse models of GBM describe a more complex role for pericytes in GBM progression: whereas the proliferation of 'naked' blood vessels appear to be typical of the glioma core, pericyte migration into the surrounding brain may have a role in facilitating glioma cell invasion [17].…”