TGF- 1-Induced Expression of the Poor Prognosis SERPINE1-PAI-1 Gene Requires EGFR Signaling: A New Target for Anti-EGFR TherapyReport as inadecuate

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Journal of OncologyVolume 2009 2009, Article ID 342391, 6 pages

Review ArticleCenter for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA

Received 29 November 2008; Accepted 30 January 2009

Academic Editor: Daniel  Chua

Copyright © 2009 Rohan Samarakoon 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.


Increased transforming growth factor- TGF- expression and epidermal growth factor receptor EGFR amplification accompany the emergence of highly aggressive human carcinomas. Cooperative signaling between these two growth factor-receptor systems promotes cell migration and synthesis of stromal remodeling factors i.e., proteases, protease inhibitors that, in turn, regulate tumor invasion, neo-angiogenesis and inflammation. ranscript profiling of transformed human cells revealed that genes encoding wound healing, matrix remodeling and cell cycle proteins i.e., the “tissue repair” transcriptome are significantly up-regulated early after growth factor stimulation. The major inhibitor of plasmin generation, plasminogen activator inhibitor-1 PAI-1, is among the most highly induced transcripts during the phenotypic transition initiated by TGF- maximal expression requires EGFR signaling. PAI-1 induction occurs early in the progression of incipient epidermal squamous cell carcinoma SCC and is a significant indicator of poor prognosis in epithelial malignancies. Mouse modeling and molecular genetic analysis of complex systems indicates that PAI-1 regulates the temporal-spatial control of pericellular proteolysis, promotes epithelial plasticity, inhibits capillary regression and facilitates stromal invasion. Defining TGF- 1-initiated signaling events that cooperate with an activated EGFR to impact the protease-protease inhibitor balance in the tumor microenvironment is critical to the development of novel therapies for the clinical management of human cancers.

Author: Rohan Samarakoon, Craig E. Higgins, Stephen P. Higgins, and Paul J. Higgins



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