Abstract
The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in acquisition of an invasive phenotype. TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs) in human SCC. Among the most prominent is MMP-10 which is 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 up-regulated under these conditions and is an early event in progression of incipient epidermal SCC. A model is proposed in which TGF-β1+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 mechanisms that maintain this elegant balance is critical to developing potential therapeutics for the treatment of human cutaneous malignancies.
Highlights
The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR) amplification
The development and progression of epithelial skin tumors is causally linked to ultraviolet (UV) radiation exposure, with UV-B “signature” base changes (C→T or CC→TT) frequently mapping to codons 177 and 278 (squamous cell carcinoma (SCC)) in the tumor suppressor p53 gene [3, 4]
Recent findings suggest that the emergence of highly aggressive subtypes of SCC and the development of metastatic variants are causally linked to overexpression of transforming growth factor-β1 (TGF-β1) [2, 8,9,10]
Summary
The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR) amplification. A model is proposed in which TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Transition of a normal keratinocyte to an initiated pre- or early malignant phenotype for example often involves p53 inactivation, ras gene mutation and amplified ras expression. These changes frequently accompany growth of lesional subsets in both actinic keratosis and SCC [5,6,7]. Despite high levels of TGF-β in the immediate tumor microenvironment, at least some malignant epithelial cells become refractory to the normal program of proliferative arrest initiated by TGF-β which is likely a consequence of Actinic keratosis
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