BRAFV600Eand microenvironment in thyroid cancer: A functional link to drive cancer progression

Abstract

Papillary thyroid cancer (PTC) rates continue to increase in the United States and Europe, and, although most patients do well, some recur and die of their disease. Patients with PTC harboring the BRAFV600E mutation seem to display a more aggressive clinical behavior, but little is known about the role of this mutation in crucial processes in the tumor microenvironment, such as tumor adhesion, migration, invasion, and metastasis. The extracellular matrix (ECM) microenvironment is not merely a structural scaffold for the cellular elements of the epithelial and stromal microenvironment, but it also elicits a profound influence on cell behavior affecting viability, proliferation, adhesion, and motility. The effects of BRAFV600E on cell surface receptors (i.e., integrins) and ECM noncellular components [i.e., thrombospondin-1 (TSP-1) and fibronectin (FN)] seem to trigger different pathologic biological processes in a cell context-dependent manner. This review focuses on the recent progress in understanding the role of BRAFV600E in the regulation of some ECM noncellular components and trans-membrane receptors of the microenvironment in PTC in order to design novel targeted therapies directed at the BRAFV600E multifaceted signaling cascades. Some of these targeted therapeutics, such as ATP-competitive BRAF V600E inhibitors (i.e., orally bioavailable PLX4720 and PLX4032 compounds), are already under investigation. ©2011 AACR.