Vosseler Silvia, Lederle Wiltrud, Airola Kristiina, Obermueller Eva, Fusenig Norbert E, Mueller Margareta M
Department of Tumor- and Microenvironment Unit (A101), German Cancer Research Center, Heidelberg, Germany.
Int J Cancer. 2009 Nov 15;125(10):2296-306. doi: 10.1002/ijc.24589.
Matrix metalloproteinases (MMPs) are critically involved in tumor invasion and metastasis. However, failure of broad spectrum MMP inhibitors in clinical trials emphasizes the need for detailed analyses of the specific role of different MMPs in tumor malignancy. Using HaCaT-keratinocyte clones representing distinct stages in skin squamous cell carcinoma (SCC) progression, we demonstrate the expression of specific tumor and stroma-derived MMPs with the onset and maintenance of tumor invasion. Although MMP-9-positive leukocytes are present in benign and malignant tumor transplants at the onset of stromal activation and angiogenesis, mRNA expression of stroma-derived MMP-9 as well as MMP-2, -13 and -14 is exclusively found in enhanced malignant tumor transplants. Their expression initiates with the onset of invasion, whereas being absent in early noninvasive stages of malignant transplants. In addition, a high expression of tumor-derived MMP-1, -2 and -14 contributes to malignant and invasive tumor growth. However, stroma-derived MMP-3 is exclusively restricted to very late-stage invasive and malignant transplants. The functional contribution of these proteases to invasive growth is supported by the gelatinolytic activity in the tumor transplants that again initiates with the onset of invasive growth suggesting a crucial role of MMP-2, -9, -13 and -14 for the establishment of a reactive stroma that promotes tumor invasion. These data demonstrate a complex cooperation of distinct tumor and stroma-derived MMPs in the establishment of malignant tumors and provide the basis for a more specific use of highly selective MMP inhibitors during distinct stages of tumor progression.
基质金属蛋白酶（MMPs）在肿瘤侵袭和转移过程中起着关键作用。然而，广谱MMP抑制剂在临床试验中的失败凸显了详细分析不同MMPs在肿瘤恶性发展中具体作用的必要性。利用代表皮肤鳞状细胞癌（SCC）进展不同阶段的HaCaT角质形成细胞克隆，我们证明了特定肿瘤和基质来源的MMPs的表达与肿瘤侵袭的起始和维持相关。尽管在基质激活和血管生成开始时，良性和恶性肿瘤移植中存在MMP-9阳性白细胞，但基质来源的MMP-9以及MMP-2、-13和-14的mRNA表达仅在增强的恶性肿瘤移植中发现。它们的表达始于侵袭开始时，而在恶性移植的早期非侵袭阶段不存在。此外，肿瘤来源的MMP-1、-2和-14的高表达有助于恶性和侵袭性肿瘤生长。然而，基质来源的MMP-3仅局限于非常晚期的侵袭性和恶性移植。这些蛋白酶对侵袭性生长的功能贡献得到肿瘤移植中明胶酶活性的支持，这种活性同样始于侵袭性生长开始时，表明MMP-2、-9、-13和-14对于建立促进肿瘤侵袭的反应性基质起着关键作用。这些数据证明了不同肿瘤和基质来源的MMPs在恶性肿瘤形成过程中的复杂协作，并为在肿瘤进展的不同阶段更特异性地使用高度选择性MMP抑制剂提供了依据。
