Role of versican, hyaluronan and CD44 in ovarian cancer metastasis

Abstract

There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can extensively modify the structure and composition of the matrix. In ovarian cancer alterations in the extracellular environment are critical for tumor initiation and progression and intra-peritoneal dissemination. ECM molecules including versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis. This review focuses on versican, HA, and CD44 and their potential as therapeutic targets for ovarian cancer.

Keywords: CD44; adhesion; extracellular matrix; hyaluronan; metastasis; versican.

Figure 1.

Co-localization of versican, HA and CD44 in ovarian tissues. Normal ovary (a, d, g), benign serous cystadenoma (b, e, h) and serous ovarian carcinoma (c, f, i). Formalin fixed paraffin sections (5 μm) were immunostained with versican (Vc, 1/500, a, b, c) provided by Assoc Prof Richard Le Baron (Division of Life Science, University of Texas at San Antonio, San Antonio, TX) previously described [76] following digestion with chondroitinase ABC. HA was detected using biotinylated HABP (d, e, f) as described previously [77]. CD44 immunohistochemistry (g, h, i) was achieved using mouse anti-CD44 (1/800 Clone 156-3C11, Neomarkers, Fremont, USA), with citrate buffer microwave retrieval. bar = 100 μm. All images are at the same magnification. Strong stromal (St) staining for versican, HA and CD44 is present in serous ovarian carcinoma tissue. In comparison, lower versican, HA and CD44 stromal staining is present in the stroma of normal ovary and benign serous cystadenoma tumor tissues. No versican or HA staining was detected in the ovarian surface epithelium (OSE), benign epithelial cells (Ep) or serous ovarian carcinoma cells (Ca).

Figure 2.

Pericellular matrix formation in motile ovarian cancer SKOV-3 cells. The confluent SKOV-3 monolayer was wounded and treated with versican containing media (0.5 U/mL) for 4 h. The white asterisks indicate motile SKOV-3 cells with a polar pericellular matrix observed over a 70 min time period, using a red blood cell exclusion assay. The black asterisks indicate non-motile SKOV-3 cells lacking a pericellular matrix. The white arrows indicate the direction of cell movement. Red blood cells diameter = 7 m. From Ween et al. [26].

Figure 3.

Proposed model of HA, CD44 and versican interactions between ovarian cancer and peritoneal cells. The formation of a stabilized HA/versican pericellular matrix surrounding ovarian cancer cells increases motility and protects the ovarian cancer cells against the mechanical forces in the peritoneal cavity and enable ovarian cancer cells to strongly adhere to CD44 expressed on peritoneal cells. This allows subsequent ovarian cancer invasion and peritoneal dissemination. From Ween et al. [26].