Mechanisms of ovarian cancer metastasis

Summary

Our current work is determining the detailed mechanisms underlying the spread of cancerous ovarian granulosa cells in order to develop new therapeutic strategies to block tumour metastasis.

Description

Cancer of the ovary is the most common fatal gynaecological malignancy. Most ovarian cancers are detected in an advanced stage, when treatment options are limited and ineffective. Most deaths by cancer are a result of metastasis, or the spread of cancer by malignant cells moving away from the primary tumour site to distant parts of the body.

Understanding how these cells migrate to and invade new sites is essential for early detection, prevention, and treatment of metastasis.

One family of multifunctional growth factors, the Transforming Growth Factor-beta (TGF-β) family, has been shown to be involved in several aspects of tumour progression. A particular focus of our group is a protein called betaglycan which facilitates the actions of several of these growth factors.

Our approach uses human ovarian cancer cell lines and human clinical tumour samples. We have shown that betaglycan is lost from the surface of malignant ovarian cells and that this loss results in cancer cells which exhibit increased motility and invasion. Re-introduction of betaglycan to cancer cells prevents their spread and may have therapeutic benefits.

In order to fully understand the role of betaglycan during cancer progression and metastasis, we are currently studying the downstream signaling pathways and molecular targets of betaglycan.

We use a broad range of cellular and molecular biology techniques, including cell culture and stable transfection of mutant and wildtype receptor constructs; luciferase reporter assays; cell proliferation and apoptosis assays; cell motility, invasion, and adhesion assays; short-hairpin RNA knockdown, gene manipulation, site-directed mutatgenesis, and quantitative real time-PCR.

Funding

National Health and Medical Research Council
Contributing to Australian Scholarship and Science (CASS) Foundation

Outcomes

demonstrated that human granulosa cell tumours exhibit significantly lower betaglycan expression than normal ovary and that loss of betaglycan on granulosa tumour cells is associated with more aggressive tumour behaviour in vitro

Selected Publications

Escalona RM, Stenvers KL, Farnworth PG, Findlay JK, and Ooi GT (2009) Reducing Betaglycan Expression by RNA interference (RNAi) Attenuates Inhibin Bio-Activity in LβT2 Gonadotropes (2009) Mol Cell Endocrinol. 2009 Aug 13;307(1-2):149-56. Epub 2009 Apr 8 PubMed Link

Bilandzic M, Chu S, Farnworth P, Harrison CA, Nicholls P, Wang Y, Escalona RM, Fuller PJ, Findlay JK, and Stenvers KL. (2009) Loss of betaglycan contributes to the malignant properties of human granulosa tumor cells. Mol Endocrinol. 23(4): 539-548.

Stenvers, KL, Tursky, ML, Harder, KW, Kountouri, N, Amatayakul-Chantler, S, Grail, D, Small, C, Weinberg, RA, Sizeland, A and Zhu, HJ (2003) Defective heart and liver development and reduced TGFbeta2 sensitivity in transforming growth factor-beta type III receptor-deficient embryos. Mol. Cell. Biol. 23(12): 4371-85.