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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-01-0031.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2597-2606
NEOPLASIA
CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and
regulates locomotion, chemotaxis, and adhesion
Jolanta Libura,
Justyna Drukala,
Marcin Majka,
Oana Tomescu,
Jean Marc Navenot,
Magda Kucia,
Leah Marquez,
Stephen C. Peiper,
Frederic G. Barr,
Anna Janowska-Wieczorek, and
Mariusz Z. Ratajczak
From the Stem Cell Biology Program at the James Graham
Brown Cancer Center, University of Louisville, KY; Department of
Pathology and Laboratory Medicine, University of Pennsylvania,
Philadelphia; Children's Hospital Laboratory of Cell and Tissue
Engineering, Jagiellonian University, Cracow, Poland; and Department of
Medicine, University of Alberta and Canadian Blood Services, Edmonton,
Canada.
We hypothesized that the CXC chemokine receptor-4
(CXCR4)-stromal-derived factor-1 (SDF-1) axis may be involved in
metastasis of CXCR4+ tumor cells into the bone marrow and
lymph nodes, which secrete the  -chemokine SDF-1. To explore this
hypothesis, we phenotyped by fluorescence-activated cell sorter
analysis various human tumor cell lines for expression of CXCR4 and
found that it was highly expressed on several rhabdomyosarcoma (RMS)
cell lines. We also observed that cell lines derived from alveolar RMS,
which is characterized by recurrent PAX3- and
PAX7-FKHR gene fusions and is associated with a
poor prognosis, expressed higher levels of CXCR4 than lines derived
from embryonal RMS. Furthermore, transfer of a PAX3-FKHR gene into embryonal RMS cell activates CXCR4 expression.
Because alveolar RMS frequently metastasizes to the bone marrow and
lymph nodes, it seems that the CXCR4-SDF-1 axis could play an
important role in this process. These findings prompted us to determine whether SDF-1 regulates the metastatic behavior of RMS cells. Accordingly, we found that, although SDF-1 did not affect proliferation or survival of these cell lines, it induced in several of them (1)
phosphorylation of mitogen-activated protein kinase p42/44; (2)
locomotion; (3) directional chemotaxis across membranes covered by
laminin, fibronectin, or Matrigel; (4) adhesion to laminin, fibronectin, and endothelial cells; and (5) increased MMP-2 and diminished tissue inhibitors of metalloproteinases secretion. The small-molecule CXCR4-specific inhibitor, T140, effectively blocked the in vitro responses of RMS cells to SDF-1. On the basis of
these observations we suggest that the CXCR4-SDF-1 axis may play an
important role in tumor spread and metastasis of RMS cells to bone
marrow and that molecular strategies aimed at inhibiting this axis
could thus prove to be useful therapeutic measures.
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