Liver cancer: Two signaling pathways decide on "good" or "bad"

Linkage makes tumor cells resistant to chemotherapy

Metastatic liver cancer cells in a 3-dimensional gel matrix. © Wolfgang Mikulits
Read out

Linking two signaling pathways in liver tumor cells has a significant impact on its malignancy. Crucial for this connection is the activation of the messenger molecule "Platelet-Derived Growth Factor" (PDGF). Scientists from Austria have now discovered this in the context of a current project of the Austrian Science Fund FWF.

As reported in the journal Oncogene, liver tumor cells that have been linked to signaling pathways actually take on characteristics of cancer stem cells that are fundamentally resistant to chemotherapy. The researchers hope to gain new approaches to modified therapies by better understanding the signaling pathways involved.

When epithelial cells become cells of the mesenchyme, it can be good or bad. This is good during embryonic development, inflammation or tissue regeneration. It is very bad when this epithelial to mesenchymal transition (EMT) transformation into cancer cells occurs. This is because cancer cells gain the ability to migrate to other tissues, ie the ability to form metastases.

Suppressor or aggressor?

The involvement of a signaling pathway of the transforming growth factor (TGF) beta at the EMT was already known. However, since this messenger substance rather prevents cell proliferation and even makes cells susceptible to an endogenous protective mechanism, it had hitherto been regarded more as a tumor suppressor. Recently, however, it is also known that TGF-beta in cells that are already degenerate, contributes to their aggressiveness. How exactly this happened, but so far was not known.

Now the team led by Professor Wolfgang Mikulits from the Institute for Cancer Research of the Medical University of Vienna, took a big step towards a better understanding of these processes. They found that the signaling pathway of TGF-beta via the activation of Platelet-Derived Growth Factor (PGDF) causes the accumulation of another messenger that has not previously been linked to the signaling pathway of TGF-beta: beta-catenin. display

Mikulits comments: "PGDF is thus virtually a bridge connecting two signaling pathways that were previously considered independent. This discovery was intriguing in itself. But when we further investigated the effect of beta-catenin, we were completely surprised. "

Slow and insensitive

So far, beta-catenin has been associated more with an increased cell division rate, ie faster tumor growth. However, the team led by Mikulits found cell behaviors quite different in response to beta-catenin: "We observed that it was actually beta-catenin that caused the reduction in cell division rate. In itself this is not a bad thing for a tumor, but this makes the cells unsuitable as a target for chemotherapy. In addition, the cells that contained beta-catenin had yet another property. They were less susceptible to a natural protective mechanism of the body, eliminating cells that migrate out of organs. "

However, these two features - low rate of division and escape of the protective mechanisms - are known in tumor cells as typical properties of cancer stem cells - cells that can spread through the bloodstream and produce new tumors elsewhere: metastases.

The association of TGF-beta and beta-catenin signaling pathways with PGDF contributes significantly to the aggressiveness of the liver tumor, thus providing a new target for future liver cancer therapies. But already now, the results of this FWF project show ways to optimize the treatment of liver cancer. The accumulation of beta-catenin in cancer cells can be diagnosed before the onset of therapy. Subsequently, the treatment could then be adapted to the aggressiveness of the tumor.

(Science Fund FWF / University of Vienna, 31.07.2007 - DLO)