The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels

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Abstract

In a search for new therapeutic targets for treating epithelial ovarian cancer, we analyzed the Transforming Growth Factor Beta (TGFβ) signaling pathway in these tumors. Using a TMA with patient samples we found high Smad2 phosphorylation in ovarian cancer tumoral cells, independently of tumor subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human ovarian cancer orthotopically grown in nude mice (OVAs). Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumor size in all these models, affecting cell proliferation rate. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumor cell proliferation. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC-A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. When IGF1R levels were decreased by shRNA treatment, LY2109761 lost its capacity to block tumoral ovarian cell proliferation. At the molecular level TGFβ induced mRNA IGF1R levels. Overall, our results suggest an important role for the TGFβ signaling pathway in ovarian tumor cell growth through the control of IGF1R signaling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition.

What's new?

Several clinical trials are evaluating the effect of IGF1R inhibitors in different tumors, sometimes with modest results or evidence of toxicity. Meanwhile, an active TGFβ signaling pathway has been shown to correlate with poor patient outcome in advanced serous ovarian cancers. This study shows, for the first time, that high activation levels of the TGFβ pathway in epithelial ovarian cancers contributes to tumor cell proliferation by stimulating IGF1R expression. The authors, who used orthotopic models, patient samples and ovarian tumoral cells, propose the use of TGFβ inhibitors as an alternative to IGF1R inhibitors for the treatment of epithelial ovarian cancers.

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