Tumor self-seeding by circulating tumor cells in nude mouse models of human osteosarcoma and a preliminary study of its mechanisms

Purpose The purpose of this study is to determine whether and how tumor self-seeding by circulating tumor cells (CTCs) plays a role in the initiation and progression of osteosarcoma. Methods Two different nude mouse models of human osteosarcoma were established for detecting tumor self-seeding by fluorescently labeled CTCs. Various tumor growth indicators were quantitated for seeded and unseeded groups. Growth mechanisms were characterized using cell proliferation assays and immunohistochemical staining. Conditioned media of primary osteosarcoma cells was characterized in a Transwell migration assay and enzyme-linked immunosorbent assay. The effect of cytokines secreted by primary tumor cells was verified by small interfering RNA and recombinant human cytokine experiments. Results Red fluorescent protein-labeled CTCs seeded primary tumors in both models. Seeded primary tumors groups grew faster than control groups (P < 0.05), which was partially attributed to the CTCs having a higher proliferation rate and higher vascular endothelial growth factor expression after self-seeding. Conditioned media of primary osteosarcoma cells attracted CTCs, through an IL-6-dependent mechanism. Conclusions CTC tumor self-seeding occurs in osteosarcoma and promotes the growth of primary osteosarcoma. CTCs appear to be recruited by cytokines secreted by primary osteosarcoma cells, particularly IL-6.