Abstract
ADAM9 is a metalloproteinase strongly expressed at the tumor-stroma border by both tumor and stromal cells. We previously showed that the host deletion of ADAM9 leads to enhanced growth of grafted B16F1 melanoma cells by a mechanism mediated by TIMP1 and the TNF-α/sTNFR1 pathway. This study aimed to dissect the structural modifications in the tumor microenvironment due to the stromal expression of ADAM9 during melanoma progression. We performed proteomic analysis of peritumoral areas of ADAM9 deleted mice and identified the altered expression of several matrix proteins. These include decorin, collagen type XIV, fibronectin, and collagen type I. Analysis of these matrices in the matrix producing cells of the dermis, fibroblasts, showed that ADAM9−/− and wild type fibroblasts synthesize and secreted almost comparable amounts of decorin. Conversely, collagen type I expression was moderately, but not significantly, decreased at the transcriptional level, and the protein increased in ADAM9−/− fibroblast mono- and co-cultures with melanoma media. We show here for the first time that ADAM9 can release a collagen fragment. Still, it is not able to degrade collagen type I. However, the deletion of ADAM9 in fibroblasts resulted in reduced MMP-13 and -14 expression that may account for the reduced processing of collagen type I. Altogether, the data show that the ablation of ADAM9 in the host leads to the altered expression of peritumoral extracellular matrix proteins that generate a more favorable environment for melanoma cell growth. These data underscore the suppressive role of stromal expression of ADAM9 in tumor growth and call for a better understanding of how protease activities function in a cellular context for improved targeting.
Highlights
The ability of tumor cells to grow and invade the surrounding tissue depends on their ability to remodel the extracellular matrix (ECM) directly or indirectly as a result of cellular communication with stromal cells [1]
By grafting of ADAM9 expressing B16F1 melanoma cells in animals carrying complete ablation of this protease, we could show that in vivo ablation of this protease in stromal fibroblasts leads to enhanced tumor growth as a result of altered cellular activities [15]
We sought to analyze whether alterations in extracellular matrix components might have contributed to modulating melanoma cell growth in vivo
Summary
The ability of tumor cells to grow and invade the surrounding tissue depends on their ability to remodel the extracellular matrix (ECM) directly or indirectly as a result of cellular communication with stromal cells [1]. Fibroblasts are the primary producers of matrices and produce a variety of proteases involved in remodeling of the ECM, modulating its functional characteristics. These proteases include serine-, cysteine-, aspartyl-, and metalloproteases [2]. ADAM9 is found to be highly expressed in peritumoral areas where activated fibroblasts are found [14,15] In these cells, altered expression of ADAM9 controls TIMP-1 expression and TNF-α/sTNFR1 pathway leads to modulation of melanoma cells proliferation and apoptosis [15]. Besides using in vitro cell culture systems and recombinant ADAM9, we addressed the role of fibroblast-derived ADAM9 in the regulation of ECM protein expression and the functional consequences for these on cell growth
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
