EGFR Regulates the Development and Microarchitecture of Intratumoral Angiogenic Vasculature Capable of Sustaining Cancer Cell Intravasation

摘要: Many malignant characteristics of cancer cells are regulated through pathways induced by the tyrosine kinase activity epidermal growth factor receptor (EGFR). Herein, we show that besides directly affecting biology per se, EGFR also regulates primary tumor microenvironment. Specifically, our findings demonstrate both expression and signaling required for induction a distinct intratumoral vasculature capable sustaining cell intravasation, critical rate-limiting step in metastatic cascade. An intravasation-sustaining mode angiogenic vessels depends on high levels interplay between EGFR-regulated production interleukin 8 cells, interleukin-8–induced influx tumor-infiltrating neutrophils delivering their unique matrix metalloproteinase-9, neutrophil metalloproteinase-9–dependent release vascular permeability endothelial factor, VEGF. Our data indicate VEGF-mediated disruption layer integrity increase permeability, significantly facilitates active intravasation cells. Therefore, this study unraveled an important but overlooked function cancer, namely, its ability to create microenvironment within developing orchestrating several interrelated processes initial steps metastasis routes. suggest EGFR-targeted therapies might be more effective when implemented patients with early-staged tumors containing VEGF-dependent vasculature. Accordingly, early inhibition combined various anti-VEGF approaches could synergistically suppress inhibiting highly permeable EGFR-overexpressing aggressive