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Distinct progression‐associated expression of tumor and stromal MMPs in HaCaT skin SCCs correlates with onset of invasion
Author(s) -
Vosseler Silvia,
Lederle Wiltrud,
Airola Kristiina,
Obermueller Eva,
Fusenig Norbert E.,
Mueller Margareta M.
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24589
Subject(s) - stroma , matrix metalloproteinase , stromal cell , tumor progression , biology , metastasis , cancer research , angiogenesis , pathology , tumor microenvironment , proteases , cancer , medicine , immunology , immunohistochemistry , tumor cells , enzyme , biochemistry , genetics
Abstract 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. © 2009 UICC