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CXCL12/CXCR4 blockade induces multimodal anti-tumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer
The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers including ovarian cancer, where they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here we used an immunocompetent mouse model of intraperitoneal papilla...
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Published in: | Cancer research (Chicago, Ill.) Ill.), 2011-07, Vol.71 (16), p.5522-5534 |
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Main Authors: | , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human
cancers including ovarian cancer, where they are associated with disease
progression at the levels of tumor cell proliferation, invasion, and
angiogenesis. Here we used an immunocompetent mouse model of intraperitoneal
papillary epithelial ovarian cancer to demonstrate that modulation of the
CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis
associated with induction of antitumor immunity. siRNA-mediated knockdown of
CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell
proliferation in vitro and tumor growth in vivo. Similarly, treatment of
BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in
increased tumor apoptosis and necrosis, reduction in intraperitoneal
dissemination, and selective reduction of intratumoral FoxP3+ regulatory T-cells
(T-regs). Compared to controls, CXCR4 blockade greatly increased T cell-mediated
antitumor immune responses, conferring a significant survival advantage to
AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on
intratumoral T regulatory cells was associated with both higher CXCR4 expression
and increased chemotactic responses to CXCL12, a finding that was also confirmed
in a melanoma model. Together, our findings reinforce the concept of a critical
role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a
definitive preclinical validation of CXCR4 as a therapeutic target in this
disease. |
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ISSN: | 0008-5472 1538-7445 |
DOI: | 10.1158/0008-5472.CAN-10-3143 |