Utilizing Fibroblasts Recruitment for Detection and Targeted Therapy of Ovarian Tumors

Ovarian cancer is the most lethal gynecologic malignancy. It is often diagnosed at late stage when metastases are widely spread. Currently, patients diagnosed with ovarian cancer are treated by debulking surgery and chemotherapy and survival rate remains low. We have previously demonstrated specific homing of labeled fibroblasts to solid ovarian tumors in mouse xenograft model. In this work, we demonstrate the feasibility of using naive fibroblasts for detection and therapy of ovarian metastasis in mouse model. We used fresh human and mouse ascites to demonstrate that fibroblasts are recruited to tumor cells in vitro. Using an in vivo metastatic model for ovarian cancer in mice, we demonstrated that fluorescently labeled fibroblasts injected intra-peritoneally, were specifically recruited to tumor nodules (resulting in 93-100% co-localization). We further used fibroblasts recruitment for targeted therapy. Fibroblasts cells over expressing the soluble receptor variant of VEGFR1 (s-Flt1) were injected to mice bearing tumors. The mice received two doses (day 7 and 14) of control or s-Flt1 expressing fibroblasts. The injection of s-Flt1 expressing fibroblasts resulted in significant reduction in the ascites volume in the mice and in reduced vascularization of adherent metastases. These results suggest fibroblasts could be a novel tool for targeting ovarian tumor metastases for detection and therapy. Fluorescently labeled fibroblasts could serve as a beacon for surgeons to identify otherwise invisible metastases in ovarian patients using available intra-operative fluorescence imaging tools. The fibroblasts could assist in directed biopsies, advancing surgical efforts and in delivery of anti angiogenic or anti tumor molecules.