Tapping Into Ovarian Cancer Signalling Network Can Limit Metastasis

A new treatment target for ovarian cancer aka "the silent killer", has raised hopes of tapping metastasis in ovarian cancer cells. Researchers at Cold Spring Harbor Laboratory arrived at "new insights into signalling events that underlie metastasis in ovarian cancer cells," said researcher Gaofeng Fan.

"The statistics point to the urgent need to address advanced disease - metastasis - in ovarian cancer," Fan noted, adding "The problem is especially difficult because of a feature specific to this form of cancer: ovarian cells move around readily within the peritoneal cavity, via the peritoneal fluid, both under normal conditions, and also, unfortunately, when cancer is present. Thus, in addition to being able to colonize other sites in the body via blood vessels, ovarian cancer cells have another way of migrating. It's very hard to render patients free of the disease via surgery due to this diffusion feature."

The team found a previously undiscovered pathway, through which ovarian cells can be transformed into cancer cells, one they think provides an excellent opportunity for targeting by new drugs, which, when combined with others now in development, may be able to stave off metastatic disease.

The newly uncovered pathway depends on activity of a protein called FER, a member of a family of proteins (called non-receptor tyrosine kinases) that add phosphate groups to other proteins.

FER can be found floating in the cytoplasm of cells, and in a series of initial experiments, Fan and the team demonstrated that it is both "upregulated," i.e., overproduced, in ovarian cancer cells, and, importantly, responsible for the elevated motility and invasiveness of such cells.

This was observed in human ovarian cancer cells grown in culture, and then in mouse models of the disease.

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The key discovery made by the team is that FER is able to activate a receptor on the surface of ovarian cells "from below," as it were - by interacting with a portion of the receptor that penetrates the cell membrane and plunges into the cytoplasm.

That receptor is a well known target in ovarian cancer. Called MET, it is typically activated when a growth factor called HGF binds it at the cell surface. MET is overexpressed in up to 60% of ovarian tumors and its activation has been implicated in both cancer initiation and in advanced cancers with poor prognosis. "We showed FER was essential for ovarian cancer cell motility and invasiveness, both in vitro and in vivo," Researcher Nicholas K. Tonks said.

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He added, "Considering that frequent amplification of MET accounts for resistance to therapies now in development and to poor prognosis, not only in ovarian cancer but in other cancers too, our findings pinpoint an important new signaling hub, involving the role of FER in MET activation.

This may provide a novel strategy for therapeutic intervention, perhaps a drug to suppress FER being administered along with a MET inhibitor." The study appears in the journal Genes and Development.

Source-ANI