Extracellular Matrix Protein Modulates Taxane Resistance in Ovarian Cancer

They do this by stabilizing GDP-bound tubulin in the microtubule. As microtubules are essential to cell division, mitosis freezes and cell replication is prevented. However, many tumors develop resistance to treatment with taxanes such as paclitaxel, and investigators at the Cambridge Research Institute (UK) looked to the extracellular matrix (ECM) for an explanation.

ECM is a filamentous structure of glycoproteins and proteoglycans that is attached to the cell surface and provides cells with anchorage, traction for movement, and positional recognition. Furthermore, in ovarian cancer cells, taxane resistance is associated with a loss of stable microtubules that is influenced by signals from the ECM.

The investigators worked with lines of ovarian cancer cells that were either sensitive or resistant to paclitaxel. They reported in the December 2007 issue of the journal Cancer Cell that loss of the ECM protein TGFBI (transforming growth factor beta-induced) was sufficient to induce specific resistance to paclitaxel. TGFBI induced microtubule stabilization that was dependent on integrin-mediated FAK and Rho signaling. Analysis of ovarian cancer samples taken after treatment with paclitaxel revealed that paclitaxel-induced cell death was associated with high levels of TGFBI expression.

"Our findings have potentially significant clinical applications, as TGFBI protein expression is lost in one-third of primary ovarian and lung cancers and FAK is low or absent in one-third of ovarian cancer patients,” explained senior author Dr. James D. Brenton, a researcher at the Cambridge Research Institute. "It is possible that TGFBI could be used as a biomarker for selecting patients likely to respond to taxane therapy. In addition, proteins that activate TGFBI or mimic its action may be an effective strategy for modulating the response to widely used drugs like paclitaxel or docetaxel.”


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Cambridge Research Institute