TGF-β1-Induced Expression of the Poor Prognosis SERPINE1PAI-1 Gene Requires EGFR Signaling : A New Target for Anti-EGFR Therapy

Abstract EN

Increased transforming growth factor-β (TGF-β) 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-β 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-β1-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.