Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting

Abstract

Fibronectin is a matrix glycoprotein which has not only been found to be over-expressed in several cancers, but has been shown to participate in several steps of tumorigenesis. The purpose of this review is to illustrate how aberrant fibronectin expression influences tumor growth, invasion, metastasis and therapy resistance. In particular, this review will focus on the interactions between cell receptor ligands and fibronectin and how this interaction influences downstream signaling events that aid tumor progression. This review will further discuss the possible implications of therapeutic drugs directed against fibronectin and/or cellular interactions with fibronectin and will additionally discuss novel approaches by which to limit intra- and extra-tumoral fibronectin expression and the cellular events which lead to aberrant fibronectin expression. It is anticipated that these studies will set a basis for future research that will not only aid understanding of fibronectin and its prognostic significance, but will further elucidate novel targets for therapeutics.

Keywords: Fibronectin; extracellular matrix; integrins; metastasis; therapy resistance.; tumorigenesis.

Figure 1

Fibronectin signaling in healthy and tumorigenic cells. In a healthy cell, fibronectin participates in the maintenance of homeostasis. Under pathological conditions, fibronectin is upregulated and associates with several integrin receptors, resulting in activation of various signaling cascades which ultimately promote tumorigenesis, metastasis and therapy resistance.

Figure 2

Integrin-fibronectin interaction in tumor therapy responses. (A) Tumor cell α₅β₁ or β₁ integrin interaction with fibronectin results in activation of cell signaling pathways which ultimately culminate in tumor cell resistance to chemotherapeutic agents. (B) Inhibition of α₅β₁ or β₁ integrin interaction with fibronectin restores tumor cell sensitivity to chemotherapeutic agents resulting in increased cytotoxicity.