Could Growth Factor-Mediated Extracellular Matrix Deposition and Degradation Offer the Ground for Directed Pharmacological Targeting in Fibrosarcoma?

D.      Nikitovic; A.      Berdiaki; A.      Banos; A.      Tsatsakis; N.   K.   Karamanos; G.   N.   Tzanakakis

Abstract

The specific organization of the tumor extracellular matrix (ECM) is an intrinsic and basic step in the convoluted pathways of tumorigenesis. Fibrosarcoma is a rare, lethal, malignant tumor originating from fibroblasts, characterized by the formation of an abundant ECM. Fibroblastoid cells undergoing malignant transformation specifically alter composition and organization of their ECM to facilitate growth, survival and invasion. Fibrosarcoma cells were shown to have a high content and turnover of ECM components including hyaluronan, proteoglycans, collagens, fibronectin and laminin. Cell signaling by endogenous growth factors, such as TGFβ, EGF, FGF2, VEGF and IFG-I, is directly correlated to ECM remodeling, stroma formation and fibrosarcoma progression. In this regard, growth factors affect the expression of matrix macromolecules, such as secreted and cell-associated proteoglycans, hyaluronan and its receptors CD44 and RHAMM, as well as the expression and activity of matrix- degrading metalloproteinases, which are of critical importance in tissue remodeling and fibrosarcoma progression. Therefore, therapeutic approaches considering growth factors and their receptors as well as downstream signaling in human cancers may well be pharmacological targets being currently explored. In this article, we focus on growth factor signaling regulating fibrosarcoma cell ECM organization at the level of deposition and degradation of ECM macromolecules, the relation of ECM remodeling with fibrosarcoma cell malignant behaviour as well as the putative strategies for its therapeutic intervention.

Keywords: Fibrosarcoma, extracellular matrix, growth factors, therapeutic targets, tumor cell signalling.

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