FOXC2 Promotes Vasculogenic Mimicry in Ovarian Cancer

Simple Summary Tumors need a continuous supply of oxygen and nutrients to sustain growth. One coping mechanism is to secret factors that promote the development of new blood vessels. However, this may not be sufficient for the growth of highly aggressive tumors. Vasculogenic mimicry is another coping mechanism whereby cancer cells form vascular-like structures capable of carrying blood and nutrients. Expression of nuclear FOXC2 has been associated with aggressiveness and advanced stage in most cancers, including ovarian cancer. We confirmed most of the known mechanisms by which FOXC2 promotes cancer aggressiveness. Additionally, we found evidence that FOXC2 expression is associated with vasculogenic mimicry in ovarian cancer samples and that FOXC2 overexpression promotes vasculogenic mimicry in cell culture. FOXC2 is a forkhead family transcription factor that plays a critical role in specifying mesenchymal cell fate during embryogenesis. FOXC2 expression is associated with increased metastasis and poor survival in various solid malignancies. Using in vitro and in vivo assays in mouse ovarian cancer cell lines, we confirmed the previously reported mechanisms by which FOXC2 could promote cancer growth, metastasis, and drug resistance, including epithelial-mesenchymal transition, stem cell-like differentiation, and resistance to anoikis. In addition, we showed that FOXC2 expression is associated with vasculogenic mimicry in mouse and human ovarian cancers. FOXC2 overexpression increased the ability of human ovarian cancer cells to form vascular-like structures in vitro, while inhibition of FOXC2 had the opposite effect. Thus, we present a novel mechanism by which FOXC2 might contribute to cancer aggressiveness and poor patient survival.