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Utilizing fibroblast recruitment for detection and targeted therapy of ovarian tumors - Roni Oren

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. We have previously demonstrated specific homing of labeled fibroblasts to solid ovarian tumors. Here, we demonstrate the feasibility of using naive fibroblasts for detection and therapy of ovarian metastasis in mouse xenograft model. We used fresh human and mouse ascites to demonstrate fibroblasts recruitment 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, using fibroblasts cells over expressing the soluble receptor variant of VEGFR1 (s-Flt1). Mice bearing tumors were injected with two doses (day 7 and 14) of control or s-Flt1 expressing fibroblasts. Injection of s-Flt1 expressing fibroblasts resulted in significant reduction in the ascites volume in the mice and in reduced vascularization of adherent metastases. Using 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 debulking surgery. Fluorescently labeled fibroblasts may serve as a beacon pointing to the otherwise invisible metastases in the peritoneal cavity of ovarian cancer patients. These results suggest a novel approach for targeting ovarian tumor metastases for both tumor detection and therapy.

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Figure 1 | Fibroblasts recruitment to ovarian ES2 micro metastases. ES2 spheroids were injected IP in left side of the abdomen. One week later MRC5 fibroblasts, were injected IP in the other side of the abdomen. One day after MRC5 injection mice were sacrificed and imaged using stereo microscope. A,B Fibroblasts recruitment to tumor nodule next to intestine (A) and tumor patches attached to the peritoneal/abdominal wall (B). C. Scattered fibroblast(s) in the abdomen of control mouse in which tumor was not injected. Scale bar 1 mm. D. High resolution image of recruited fibroblasts to tumor nodule (two photon microscope). Scale bar 100µm. E. A scheme describing the experiment design.