TGF-β Is Critical for Ovarian Cancer Migration, Invasion, and Chemosensitivity

Background/Objectives: Standard treatment for ovarian cancer includes surgery and chemotherapy, either as primary "debulking" surgery followed by adjuvant chemotherapy or neoadjuvant chemotherapy followed by interval debulking surgery. The degree of surgical resection correlates with overall survival, with "suboptimal debulking" (visible remaining cancer) being a poor prognostic variable. TGF-β pathway activation is associated with ovarian cancers that cannot be optimally debulked. To test the role of this pathway in ovarian cancer biology, modulation of the pathway was performed in in vitro and in vivo ovarian cancer model systems. Methods: A small molecule TGF-β receptor 1 (TGFBR1) kinase inhibitor, LY2157299, was used to test the in vitro cellular adhesion, proliferation, migration and invasive ability of ovarian cancer cells in culture. A TGF-β responsive reporter construct was used to determine the role of TGF-β pathway in those interactions. To test the effects of TGF-β inhibition in vivo, TGFBR1 and TGFBR2 CRISPR knockout cells were generated and examined for growth and sensitivity to chemotherapy. Results: For ovarian cancer cells responsive to exogenous TGF-β1 treatment, LY2157299-mediated the TGF-β pathway inhibition decreased cell migration and invasion, as well as mesothelial cell to cancer cell adhesion, proliferation, and migration. TGFBR1 and TGFBR2 CRISPR knockout cells showed decreased proliferation baseline or when treated with TGF-β and LY2157299. TGFBR2 CRISPR cells also showed increased sensitivity to cisplatin, with a significant decrease in tumor weight in vivo. Conclusions: TGF-β pathway inhibition successfully targeted many of the cancer cell behaviors that could contribute to suboptimally debulked patients and showed an additive anti-tumor effect in conjunction with cisplatin. LY2157299 treatment is clinically limited due to solubility, but other TGF-β inhibitors could be highly efficacious treatment options.