409. Expression of Mouse CD47 in Human Cancer Cells Profoundly Increases Tumor Metastasis in Murine Models

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Although there are many well established tumor cell lines that have been widely used as xenografts in murine models, many of them do not efficiently metastasize to other organ tissues after local inoculation. Lack of reliable metastatic human cancer models is hindering many aspects of cancer research, in particular, for drug development. The underlying reason for the inability of human xenografts to metastasize in immunodeficient mice is currently unclear. We hypothesize that innate immune cells such as macrophages play a pivotal role in dictating cancer cell metastasis. Specifically, macrophages can limit cancer cell metastasis by clearing tumor cells that do not express the correct CD47, the “don't eat me” signal.To test our hypothesis, we transduced the murine CD47 (mCD47) gene into the human prostate cancer cell line PC-3, to establish PC-3-CD47-GFP-Luc. A control cell line transduced with GFP-Luc only, PC-3-GFP-Luc, was also established. We then compared PC-3-CD47-GFP-Luc with PC-3-GFP-Luc and with PC-3M-Pro4, a more metastatic line established by repeatedly inoculating and harvesting PC-3 cells from prostates of athymic nude mice, for their metastatic efficiency in mice with different severity of immunodeficiency.In CB17Scid mice, which have an intact macrophage activity but lack functional T and B cells, tumor metastasis was detected in both sentinel lymph node and lung from subcutaneously implanted PC-3-CD47-GFP-Luc cells but not from the other two cell lines. In NOD-Scid and NSG mice, which have similar deficiency in T and B cells but have a diminished macrophage activity as compared to CB17Scid, tumor metastasis to the sentinel lymph node, lung and liver was detected from all the three cells implanted subcutaneously (in NOD-Scid mice) or orthotopically (in NSG mice). However, PC-3-CD47-GFP-Luc cells produced 2-3 times more tumor nodules than other two cells. The metastatic nodules from PC-3-CD47-GFP-Luc cell implantation were also visibly larger than in the other two groups. When quantified by luciferase activity, radiance from the metastatic tumor nodules in PC-3-CD47-GFP-Luc group was up to 11 times higher than that in the other two groups. Together, these data demonstrate that CD47 plays an important role in dictating tumor cell metastatic potential by providing the “don't eat me” signal to host's macrophages.