Abstract
Late stage ovarian cancer is characterized by disseminated intraperitoneal metastasis as secondary lesions anchor in the type I and III collagen-rich submesothelial matrix. Ovarian carcinoma cells preferentially adhere to interstitial collagen, and collagen-induced integrin clustering up-regulates the expression of the transmembrane collagenase membrane type 1 matrix metalloproteinase (MT1-MMP). Collagenolytic activity is important in intraperitoneal metastasis, potentiating invasion through the mesothelial cell layer and colonization of the submesothelial collagen-rich matrix. The objective of this study was to elucidate a potential mechanistic link between collagen adhesion and MT1-MMP expression. Our results indicate that culturing cells on three-dimensional collagen gels, but not thin layer collagen or synthetic three-dimensional hydrogels, results in rapid induction of the transcription factor EGR1. Integrin signaling through a SRC kinase-dependent pathway is necessary for EGR1 induction. Silencing of EGR1 expression using small interfering RNA abrogated collagen-induced MT1-MMP expression and inhibited cellular invasion of three-dimensional collagen gels. These data support a model for intraperitoneal metastasis wherein collagen adhesion and clustering of collagen binding integrins activates integrin-mediated signaling via SRC kinases to induce expression of EGR1, resulting in transcriptional activation of the MT1-MMP promoter and subsequent MT1-MMP-catalyzed collagen invasion. This model highlights the role of unique interactions between ovarian carcinoma cells and interstitial collagens in the ovarian tumor microenvironment in inducing gene expression changes that potentiate intraperitoneal metastatic progression.
Highlights
Multiple studies have shown that microenvironmental contacts with stromal cells or extracellular matrix elements may play a major role in tumor progression by inducing epigenetic changes in transformed cells [8, 9]
Analysis of membrane type 1 matrix metalloproteinase (MT1-MMP) Expression in Human Ovarian Carcinoma—The normal ovarian surface epithelium does not express MMPs and MT1-MMP is not detected in benign tumors; MT1-MMP has been detected in malignant ovarian tumors [22,23,24]
Reversible modulation of ovarian epithelial cells to a fibroblastic form occurs during post-ovulatory repair of the epithelium
Summary
Multiple studies have shown that microenvironmental contacts with stromal cells or extracellular matrix elements may play a major role in tumor progression by inducing epigenetic changes in transformed cells [8, 9]. Metastasizing ovarian cancer cells encounter a collagen-rich environment, as the submesothelial matrix is comprised primarily of interstitial collagens (types I and III) and ovarian tumors induce a fibro-proliferative response characterized by increased synthesis of collagen in the peritoneal cavity (10 –12). As invasion of three-dimensional collagen matrices by ovarian cancer cells is potentiated by MT1-MMP collagenolytic activity [14], these data support integrin-mediated collagen adhesion as an important microenvironmental regulator of ovarian cancer metastasis. Because of its role as an in vivo collagenase, the activity of MT1-MMP is stringently regulated via multiple mechanisms including transcriptional and post-translational control [15]. Our results support a model wherein 1 integrin signaling via a SRC kinase-dependent pathway can potentiate intra-peritoneal metastasis by rapid induction of the early growth response protein (EGR1), inducing transcriptional activation of the MT1-MMP promoter and subsequent MT1MMP-mediatated collagen invasion
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