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Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences and The Ela Kodesz Institute for Research on Cancer Development and Prevention, Tel Aviv University, Tel Aviv, Israel;
Pediatric Hemato-Oncology Department, Chaim Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel-Hashomer, Israel
The homing of hemopoietic stem cells to the bone marrow is mediated
by specific interactions occurring between CXCR4, which is expressed on
hemopoietic 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 evaluated the possibility that neuroblastoma cells use
a mechanism similar to that used by hemopoietic stem 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 SDF-1,
as demonstrated by the ability of neutralizing Abs against human
SDF-1
to up-regulate CXCR4 expression on the tumor cells. The
reduction in CXCR4 expression following short term exposure to
recombinant human SDF-1
can be recovered as a result of de novo
receptor synthesis. Recombinant human SDF-1
induces the migration of
CXCR4-expressing SH-SY5Y neuroblastoma cells in CXCR4- and
heterotrimeric G protein-dependent manners. Furthermore, SH-SY5Y cells
interact at multiple levels with bone marrow components, as evidenced
by the fact that bone marrow-derived constituents promote SH-SY5Y cell
migration, adhesion to bone marrow stromal cells, and proliferation.
These results suggest that SH-SY5Y neuroblastoma cells are equipped
with adequate machinery to support their homing to the bone marrow.
Therefore, the ability of neuroblastoma tumors to preferentially form
metastases in the bone marrow may be influenced by a set of complex
CXCR4-SDF-1 interactions.
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