TGFβ and matrix-regulated epithelial to mesenchymal transition

Abstract

Background: The progression of cancer through stages that guide a benign hyperplastic epithelial tissue towards a fully malignant and metastatic carcinoma, is driven by genetic and microenvironmental factors that remodel the tissue architecture. The concept of epithelial-mesenchymal transition (EMT) has evolved to emphasize the importance of plastic changes in tissue architecture, and the cross-communication of tumor cells with various cells in the stroma and with specific molecules in the extracellular matrix (ECM).

Scope of the review: Among the multitude of ECM-embedded cytokines and the regulatory potential of ECM molecules, this article focuses on the cytokine transforming growth factor β (TGFβ) and the glycosaminoglycan hyaluronan, and their roles in cancer biology and EMT. For brevity, we concentrate our effort on breast cancer.

Major conclusions: Both normal and abnormal TGFβ signaling can be detected in carcinoma and stromal cells, and TGFβ-induced EMT requires the expression of hyaluronan synthase 2 (HAS2). Correspondingly, hyaluronan is a major constituent of tumor ECM and aberrant levels of both hyaluronan and TGFβ are thought to promote a wounding reaction to the local tissue homeostasis. The link between EMT and metastasis also involves the mesenchymal-epithelial transition (MET). ECM components, signaling networks, regulatory non-coding RNAs and epigenetic mechanisms form the network of regulation during EMT-MET.

General significance: Understanding the mechanism that controls epithelial plasticity in the mammary gland promises the development of valuable biomarkers for the prognosis of breast cancer progression and even provides new ideas for a more integrative therapeutic approach against disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Keywords: Epithelial–mesenchymal transition; Hyaluronan; Proteoglycan; Signal transduction; Transforming growth factor β; Tumor invasiveness.