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Journal of Oncology
Volume 2009 (2009), Article ID 963209, 12 pages
http://dx.doi.org/10.1155/2009/963209
Review Article

PAI-1 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma

1Center for Cell Biology & Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
2Department of Pathology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
3Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer, University of Liège, Avenue de l'Hôpital 3, 4000 Liège, Belgium

Received 26 August 2009; Accepted 24 November 2009

Academic Editor: Guus A. M. S. Van Dongen

Copyright © 2009 Jennifer Freytag et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF- synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF- /EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype. In one physiologically relevant model of human cutaneous SCC progression, TGF- 1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs), among the most prominent of which is MMP-10—an MMP known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC. One testable hypothesis proposes that TGF- 1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies.