Purpose: The inability to intraoperatively distinguish the primary tumor, as well as lymphatic spread, increases the probability of positive surgical margins, tumor recurrence, and surgical toxicity. The goal of this study was to develop a tumor-specific optical probe for real-time fluorescence-guided surgery. Experimental design: A humanized antibody fragment against PSCA (A11 minibody, A11 Mb) was conjugated with a near-infrared fluorophore, IRDye800CW. The integrity and binding of the probe to PSCA were confirmed by gel electrophoresis, size exclusion chromatography, and flow cytometry, respectively. The ability of the probe to detect tumor infiltrated lymph nodes and metastatic lesions was evaluated in two xenograft models, and in transgenic mice expressing human PSCA (hPSCA). An invasive intramuscular model was utilized to evaluate the efficacy of the A11 Mb-IRDye800CW-guided surgery. Results: A11 Mb was successfully conjugated with IRDye800CW and retained specific binding to PSCA. In vivo imaging showed maximal signal to background ratios at 48 hours. The A11 Mb-IRDye800CW specifically detected PSCA positive primary tumors, tumor infiltrated lymph nodes, and distant metastases with high contrast. Fluorescence guidance facilitated more complete tumor resection, reduced tumor recurrence, and improved overall survival, compared with conventional white light surgery. The probe successfully identified primary orthotopic tumors and metastatic lesions in hPSCA transgenic mice. Conclusions: Real-time fluorescence image-guided surgery with A11 Mb-IRDye800CW enabled detection of lymph node metastases and positive surgical margins, facilitated more complete tumor removal, and improved survival, compared to white light surgery. These results may be translatable into clinical practice to improve surgical and patient outcomes.

Background-M2-like macrophages are associated with the pathogenesis of castrate resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω−3 FAs) delay the development and progression of CRPC and inhibit tumor associated M2-like macrophages. Methods-MycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300mm 3. To study effects of dietary ω−3 FAs on development of CRPC, ω−3 or ω−6 diets were started two days after castration and mice sacrificed after early regrowth of tumors. To study ω−3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω−3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages was studied by RTqPCR and a migration/ invasion assay. Results-The ω−3 diet combined with castration lead to greater MycCap tumor regression (182.2±33.6 mm 3) than the ω−6 diet (148.3±35.2; p=0.003) and significantly delayed the time to CRPC (p=0.006). Likewise, the ω−3 diet significantly delayed progression of established castrate resistant MycCaP tumors (p=0.003). The ω−3 diet (as compared to the ω−6 diet) significantly reduced tumor associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω−3). Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Host GPR120 plays a central role in the anti-prostate cancer effects of dietary ω-3 FAs. Future studies are required to determine if the anticancer effects of ω-3 FAs are mediated through inhibition of M2-like macrophages and if host GPR120 status predicts anticancer effects of dietary ω-3 FAs in men with prostate cancer.

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