title: Fibroblast recruitment as a tool for ovarian cancer detection and targeted therapy.
abstract: Metastatic ovarian cancer, the most lethal of gynecologic malignancies, is typically managed by debulking surgery, followed by chemotherapy. However, despite significant efforts, survival rate remains low. We have previously demonstrated, in mouse models, a specific systemic homing of labeled fibroblasts to solid ovarian tumors. Here, we demonstrate the feasibility of utilizing this specific homing of genetically modified fibroblasts for detection and targeted therapy of orthotopic metastatic ovarian carcinoma model in immune-deficient mice. Using an in vivo metastatic mouse model for ovarian cancer, we demonstrated that fibroblasts expressing fluorescent reporters injected intra-peritoneally, were specifically recruited to peritoneal tumor nodules (resulting in 93-100% co-localization). We further used fibroblasts over expressing the soluble receptor variant of VEGFR1 (s-Flt1). Mice bearing tumors were injected weekly with either control or s-Flt1 expressing fibroblasts. Injection of s-Flt1 expressing fibroblasts resulted in a significant reduction in the ascites volume, reduced vascularization of adherent metastases, and improved overall survival. Using fluorescently labeled fibroblasts for tumor detection with readily available intra-operative fluorescence imaging tools may be useful for tumor staging and directing biopsies or surgical efforts during exploratory or debulking surgery. Fibroblasts may serve as a beacon pointing to the otherwise invisible metastases in the peritoneal cavity of ovarian cancer patients. Utilizing the recruited fibroblasts also for targeted delivery of anti angiogenic or antitumor molecules may aid in controlling tumor progression. Thus, these results suggest a novel approach for targeting ovarian tumor metastases for both tumor detection and therapy.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Roni
authors.initials: R
authors.lastname: Oren
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Addadi
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Lian
authors.initials: L
authors.lastname: Narunsky Haziza
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Dafni
authors.affiliation: Department of Biological Services, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Rotkopf
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Gila
authors.initials: G
authors.lastname: Meir
authors.affiliation: Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Ami
authors.initials: A
authors.lastname: Fishman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D000882:Haplorhini; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis
chemical_list: D005456:Fluorescent Dyes; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: cell based therapy; fibroblasts; image guided therapy; ovarian carcinoma; s-FLT1