Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 125, Issue 10, Pages 2296-2306Publisher
WILEY
DOI: 10.1002/ijc.24589
Keywords
matrix metalloproteinase; tumor progression; angiogenesis; tumor-stroma interaction
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Funding
- European Union
- Deutsche Forschungsgemeinschaft [SPP1190, Mu1830/3-1]
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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 bile-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 or 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. (C) 2009 UICC
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