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

Abstract

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

Intratumoral Cancer Cell Intravasation Can Occur Independent of Invasion into the Adjacent Stroma

“…Our previous studies have linked high intravasation capability of HT-hi/diss cells with their heightened expression of EGFR as compared to HT-lo/diss cells (Minder et al, 2015). Herein, the involvement of EGFR in intratumoral intravasation was mechanistically analyzed with a siRNA-mediated loss-of-function approach.…”

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…EGFR expression and activity are crucial for the induction of a distinct intratumoral vasculature that facilitates tumor metastasis (361,485). EGFR facilitates metastasis through VEGF-mediated disruption of endothelial layer integrity and increase of intratumoral vasculature permeability.…”

Hypoxia inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer

“…environment may have a profound role in breast tumor progression and metastases [4,[23][24][25], we hypothesized that there might be an association on a molecular level between PHD2 and EGFR. Therefore, we investigated how the expression of these two proteins is correlated in clinical samples of breast cancer patients and whether they may be directly linked.…”