Targeting debris‐stimulated angiogenesis and primary tumor growth by resolvin mediated clearance

Background Standard cancer therapy reduces tumor burden by killing tumor cells, yet simultaneously creates tumor cell debris and associated inflammation in the tumor microenvironment. Thus, cancer therapy is inherently a double‐edged sword. Since tumor growth is angiogenesis‐dependent, we hypothesize that the accumulation of chemotherapy‐generated debris, stimulates tumor growth via tumor angiogenesis. ω‐3 fatty acid‐derived lipid autacoids termed ‘Specialized pro‐resolving mediators’ (SPMs), including resolvins, stimulate the resolution of inflammation by activating macrophage clearance of cell debris and promote wound healing and regeneration. While SPMs inhibit VEGFA‐mediated corneal and retinal neovascularization, the role of SPMs in tumor angiogenesis had not been studied to date. Thus, resolvins may represent a novel therapeutic approach to cancer through inhibition of tumor angiogenesis. Results Here, we show that co‐injecting tumor debris generated by the chemotherapeutic agent 5‐Fluorouracil (5‐FU), with living murine colon carcinoma (CT26) cells stimulated tumor growth in a dose‐dependent manner up to 100‐fold. In contrast, tumor cell debris alone did not produce any visible tumors, even at 100 days post‐injection. Next, we titrated the number of living tumor cells to a fixed quantity of 5‐FU‐generated tumor cell debris. The presence of debris promoted CT26 tumor growth even at an inoculum of 1×10 2 or 1×10 3 living tumor cells, which do not result in a visible tumor when injected alone, even at 150 days post‐injection. Tumor cell debris stimulated angiogenesis in a matrigel plug assay as measured by increased infiltration of CD31+ endothelial cells via flow cytometry analysis. 5‐FU‐generated debris also stimulated macrophage production of the pro‐angiogenic factors, MIP‐1α, serpin E1, and osteopontin. We also detected increased osteopontin levels in the plasma of mice bearing debris‐stimulated tumors compared to mice injected with living tumor cells alone. Systemic administration of resolvins inhibited primary growth of human colon xenografts (CCL‐188) via reduced microvessel density (as measured by CD31+ endothelial cells). Resolvins also stimulated macrophage phagocytosis of tumor cell debris. Conclusions We show that chemotherapy‐generated tumor cell debris stimulates tumor angiogenesis and primary tumor growth. Stimulating the clearance of tumor cell debris via SPMs, such as resolvins, represents a novel approach to preventing tumor growth and progression by inhibiting tumor angiogenesis. Support or Funding Information R01‐170549