The Extracellular Matrix in Epithelial Ovarian Cancer - A Piece of a Puzzle

Abstract

Epithelial ovarian cancer is the fifth leading cause of cancer-related deaths in women and the most lethal gynecological malignancy. Extracellular matrix (ECM) is an integral component of both the normal and tumor microenvironment. ECM composition varies between tissues and is crucial for maintaining normal function and homeostasis. Dysregulation and aberrant deposition or loss of ECM components is implicated in ovarian cancer progression. The mechanisms by which tumor cells induce ECM remodeling to promote a malignant phenotype are yet to be elucidated. A thorough understanding of the role of the ECM in ovarian cancer is needed for the development of effective biomarkers and new therapies.

Keywords: collagen; extracellular matrix; ovarian cancer; proteases; proteoglycan.

Figure 1

The ECM becomes dysregulated during ovarian tumorigenesis and contributes to tumor progression. The normal ovarian ECM consists of a highly ordered arrangement of collagen fibers, with hyaluronan interspersed throughout, regulating the distribution of the collagen in the ECM. Several proteoglycans, such as decorin and versican, are present to provide pressure and hydration to the tissue. In EOC, stromal fibroblasts are activated; collagen becomes progressively remodeled into short thick fibrils, randomly orientated into tracks at angles tending toward perpendicular rather than parallel to the epithelial boundary. In addition, versican, fibronectin, tenascin-C, and tenascin-X are upregulated with the loss of decorin. Reduced levels of HYALs lead to accumulation of hyaluronan; upregulation of LOXs leads to increased crosslinking of the ECM proteins resulting in increased stiffness of the ECM. MMPs are overexpressed in the EOC ECM, actively remodeling the ECM to promote tumor progression while TIMPs are unable to restrain these enzymes from dysregulating the ECM.