BRAF(V600E) and 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 BRAF(V600E) 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 BRAF(V600E) 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 BRAF(V600E) 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 BRAF(V600E) 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.

Figure 1. The BRAF^V600E oncoprotein activates phospho-ERK1/2 signaling pathway and regulates the expression of extracellular matrix non-cellular components

The BRAF^V600E oncoprotein elicits dramatically an increased kinase activity and activates phospho-ERK1/2. This oncoprotein is constitutively active and does not require RAS signaling. The BRAF^V600E -activated phospho-ERK1/2 pathway is able to transform normal thyroid cells (NT) to thyroid cancer cells (TC). It up-regulates some extracellular matrix (ECM) non-cellular components (i.e. Thrombospondin-1 (TSP-1), Fibronectin) and cellular trans-membrane receptors (e.g. integrins), which together may increase the levels of phospho-ERK1/2 through a positive feedback driven by TSP-1. These pathological processes trigger ECM remodeling and determines tumor cell invasion into the lymphatic (LV) and/or blood vessels (BV) through basement membrane causing thyroid cancer progression.