The results are being published in the latest issue of the journal Science Signaling.
“The signaling pathway that we have discovered helps tumor cells become invasive and invade surrounding tissues. We have also managed to stop the signaling pathway, and thus prevented the tumor cells’ aggressive behavior,” says Marene Landström, Professor of Pathology at Umeå University.
The focus of the study is a growth factor called transforming growth factor beta, TGF-ß. Aggressive tumor cells produce a high amount of TGF-ß. It was previously known that cancer patients who have high levels of TGF-ß in their blood run a higher risk of developing metastases that spread in the body.
In the study the researchers stimulated prostate cancer cells with TGF-ß. This activates an enzyme – γ-secretase – which plays a key role. The enzyme cleaves a particular receptor molecule that is bound to the cell membrane. The receptor’s cutted and intracellular part is then sent to the cell nucleus, where it starts directing the expression of genes that enables cancer cells to invade surrounding tissues. Interestingly enough, the cut-off receptor molecule also regulates its own gene expression, indicating that cancer cells continue to stimulate this pathway.
In the study now being published in Science Signaling, the researchers show where in the receptor molecule the cleavage occurs. They have also succeeded in finding out how the enzyme γ-secretase is activated. Their earlier studies have shown that TGF-ß activates a specific protein that regulates the cancer-specific behaviour of the receptor. This protein also triggers the activity of the enzyme γ-secretase. By making the enzyme ineffective, the researchers have now succeeded in preventing the aggressive behavior of the tumor cells in both animal models and in cell cultures.
Besides prostate cancer, the newly discovered pathway is also activated in breast and lung cancer. The researchers thus hope that the findings will lead to better treatment options for these forms of cancer.
“The signaling pathway could also be useful as a future biomarker to predict the prognosis of cancer patients and to choose the treatment that is most appropriate,” Landström says.
TRAF6 Stimulates the Tumor-Promoting Effects of TGF-ß Type I Receptor through Polyubiquitination and Activation of Presenilin. Shyam Kumar Gudey, Reshma Sundar, Yabing Mu, Anders Wallenius, Guangxiang Zang, Anders Bergh, Carl -Henrik Heldin, Marene Landström. Science Signaling 7 January 2014.
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Marene Landström, Professor of Pathology, Umeå University
Phone: 070-231 6342