Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Abstract

The assembly of pericellular matrix containing hyaluronan (HA) and versican has been shown to be a pre-requisite for proliferation and migration of mesenchymal cells. In this study, we investigated whether treatment with recombinant versican could induce the formation of a pericellular matrix by ovarian cancer cells (OVCAR-3, OVCAR-5, and SKOV-3) and promote their motility, invasion, and adhesion to peritoneal cells in vitro. We also determined whether versican-induced pericellular matrix formation and metastatic cancer cell behavior could be blocked by small HA oligosaccharides. Only combined treatment with recombinant versican and HA resulted in pericellular matrix formation by OVCAR-5 and SKOV-3 but not by OVCAR-3 cells, which lack the HA receptor, CD44. The motility of OVCAR-5 and SKOV-3 cells was significantly increased in scratch wound and chemotaxis assays following treatment with recombinant versican and HA. Versican and HA also promoted invasion of SKOV-3 and OVCAR-5 cells but had no effect on OVCAR-3 cells. We have demonstrated that exogenous HA significantly increased OVCAR-5 and SKOV-3 adhesion to peritoneal cells but adhesion was not further increased by versican treatment. Small HA oligomers (6-10 disaccharides) were able to significantly block formation of pericellular matrix by OVCAR-5 cells, as well as the increased motility and invasion induced by recombinant versican. HA oligomers also significantly blocked OVCAR-5 adhesion to peritoneal cells both in the presence and absence of exogenous HA. The dependence of CD44 for the versican and HA mediated effects were demonstrated by the inhibition of pericellular matrix formation as well as motility and invasion of OVCAR-5 cells following treatment with CD44 neutralizing antibody in the presence of versican and HA. We conclude that the acquisition of a HA/versican pericellular matrix by ovarian cancer cells increases their metastatic potential. HA oligomers can block this mechanism and are promising inhibitors of ovarian cancer dissemination.

WOMEN IN CANCER PROFILE: My pathway to understanding the role of the tumour microenvironment in cancer progression

“…Recent studies focussing on the tumour microenvironment have identified that the ECM molecule HA, plays an important role in both ovarian cancer invasion and the development of chemotherapy resistance (Ween et al 2011a, Ricciardelli et al 2013. Our studies have confirmed that HA plays an important role in promoting attachment of cancer cells to peritoneal cells via interactions with the HA receptor, CD44 (Ween et al 2011a).…”

“…Our studies have confirmed that HA plays an important role in promoting attachment of cancer cells to peritoneal cells via interactions with the HA receptor, CD44 (Ween et al 2011a). We have also shown that HA can induce resistance to the chemotherapeutic drug carboplatin and increase the expression of ABC transporters that function as drug efflux pumps in ovarian cancer cell lines (Ricciardelli et al 2013).…”

“…Functional studies went on to demonstrate that versican purified from prostatic fibroblast culture medium could inhibit prostate cancer cell attachment to ECM components (Sakko et al 2003). Studies with a Ph.D. student Miranda Ween showed that cancer cells could assemble versican and hyaluronan (HA) into a pericellular sheath to aid motility and invasion of prostate and ovarian cancer cells , Ween et al 2011a. These landmark studies showed that cancer cells could recruit stromal components to remodel their pericellular environment to promote their motility and invasion.…”

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

“…Apart from integrins, other ECM adhesion molecules that contribute to cancer migration and invasion involve interactions between hyaluronan (HA) and versican, which can be blocked by small HA oligosaccharides (70). More importantly, there have been several documented studies showing the pivotal role of HA in the adhesion of cancer cells to the peritoneum, which is one of the early events of EOC progression (71).…”

Probing chromatin landscape reveals roles of endocardial TBX20 in septation

“…Inhibition of VCAN expression or function in glioma cells, ovarian cancer cells, or lung cancer cells has been shown to inhibit cell invasion (64)(65)(66). Targeting of VCAN thus provides a potential strategy for suppressing tumor invasion (65,67,68). Our identification of a transcriptional enhancer that is active in fibroblasts may prove useful in understanding Vcan regulation in the context of tumorigenesis and could provide a therapeutic target.…”