A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma

The homing of hemopoietic stem cells to the bone marrow is mediated by spec ific interactions occurring between CXCR4, which is expressed on hemopoieti c stem cells, and its ligand, stromal cell-derived factor-1 (SDF-1), a CXC chemokine secreted by bone marrow stromal cells. In the present study we ev aluated the possibility that neuroblastoma cells use a mechanism similar to that used by hemopoietic stern cells to home to the bone marrow and adhere to bone marrow stromal cells. Our study suggests that CXCR4 expression may be a general characteristic of neuroblastoma cells. SH-SY5Y neuroblastoma cells express not only CXCR4, but also its ligand, SDF-1. CXCR4 expression on SH-SY5Y neuroblastoma cells is tightly regulated by tumor cell-derived S DF-1, as demonstrated by the ability of neutralizing Abs against human SDF- 1 alpha to up-regulate CXCR4 expression on the tumor cells. The reduction i n CXCR4 expression following short term exposure to recombinant human SDF-1 alpha can be recovered as a result of de novo receptor synthesis. Recombin ant human SDF-1 alpha induces the migration of CXCR4-expressing SH-SY5Y neu roblastoma cells in CXCR4- and heterotrimeric G protein-dependent manners. Furthermore, SH-SY5Y cells interact at multiple levels with bone marrow com ponents, as evidenced by the fact that bone marrow-derived constituents pro mote SH-SY5Y cell migration, adhesion to bone marrow stromal cells, and pro liferation. These results suggest that SH-SY5Y neuroblastoma cells are equi pped with adequate machinery to support their homing to the bone marrow. Th erefore, the ability of neuroblastoma tumors to preferentially form metasta ses in the bone marrow may be influenced by a set of complex CXCR4-SDF-1 in teractions.