Wilkins-Port Cynthia E, Higgins Craig E, Freytag Jennifer, Higgins Stephen P, Carlson J Andrew, Higgins Paul J
Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
J Biomed Biotechnol. 2007;2007(2):85208. doi: 10.1155/2007/85208. Epub 2007 Mar 20.
The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-beta synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-beta/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-beta1+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-beta1+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.
人类皮肤鳞状细胞癌（SCC）高侵袭性亚型的出现通常反映出自分泌/旁分泌转化生长因子-β（TGF-β）合成增加以及表皮生长因子受体（EGFR）扩增。协同的TGF-β/EGFR信号传导促进细胞迁移，并诱导蛋白酶和蛋白酶抑制剂的表达，这些蛋白酶和蛋白酶抑制剂调节基质重塑，从而导致侵袭性表型的获得。TGF-β1+表皮生长因子（EGF）刺激可增加人类SCC中几种基质金属蛋白酶（MMP）的产生。其中最突出的是MMP-10，已知其在原位SCC中升高。基质纤溶酶原的激活似乎在触发下游MMP活性中起关键作用。矛盾的是，纤溶酶生成的主要生理抑制剂纤溶酶原激活物抑制剂-1（PAI-1）在这些条件下也会上调，并且是早期表皮SCC进展中的一个早期事件。提出了一个模型，其中TGF-β1+EGF依赖性MMP-10升高指导局部基质重塑事件，促进上皮细胞可塑性和组织侵袭。PAI-1表达增加有助于在时间和空间上调节纤溶酶启动的细胞周围蛋白水解，进一步促进上皮侵袭潜力。确定维持这种精妙平衡的复杂信号传导机制对于开发治疗人类皮肤恶性肿瘤的潜在疗法至关重要。
