Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation
Copyright policy )Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation
The tumour vascular microenvironment supports tumorigenesis not only by supplying oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feedforward mechanism in which endothelial cells (ECs), in response to tumour-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 Tyr 129 in ECs induces binding to the tumour suppressor protein von Hippel-Lindau (VHL), and 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 tumour progression. In a genetic model of GBM, mice with an EC-specific defect in Pfn-1 phosphorylation exhibit reduced tumour angiogenesis, normalized vasculature and improved survival. Moreover, EC-specific Pfn-1 phosphorylation is associated with tumour aggressiveness in human glioma. These findings suggest that targeting Pfn-1 phosphorylation may offer a selective strategy for therapeutic intervention of malignant solid tumours.
- Cleveland Clinic United States
- CLEVELAND CLINIC LERNER COM-CWRU
- Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania United States
- Cleveland Clinic Lerner Research Institute United States
- Department of Radiation Oncology Perelman School of Medicine University of Pennsylvania United States
Male, Mice, Transgenic, Article, Capillary Permeability, Mice, Cell Line, Tumor, Animals, Humans, Cell Proliferation, Neovascularization, Pathologic, Brain Neoplasms, Endothelial Cells, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Inbred C57BL, Autocrine Communication, Disease Models, Animal, Mutation, Disease Progression, Female, Neoplasm Grading, Glioblastoma
Male, Mice, Transgenic, Article, Capillary Permeability, Mice, Cell Line, Tumor, Animals, Humans, Cell Proliferation, Neovascularization, Pathologic, Brain Neoplasms, Endothelial Cells, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Inbred C57BL, Autocrine Communication, Disease Models, Animal, Mutation, Disease Progression, Female, Neoplasm Grading, Glioblastoma
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