Abstract
BackgroundA growing body of work implicates chemokines, in particular CXCL12 and its receptors, in the progression and site-specific metastasis of various cancers, including breast cancer. Various agents have been used to block the CXCL12-CXCR4 interaction as a means of inhibiting cancer metastasis. However, as a potent chemotactic factor for leukocytes, CXCL12 also has the potential to enhance anti-cancer immunity. To further elucidate its role in breast cancer progression, CXCL12 and its antagonist CXCL12(P2G) were overexpressed in the syngeneic 4T1.2 mouse model of breast carcinoma.ResultsWhile expression of CXCL12(P2G) significantly inhibited metastasis, expression of wild-type CXCL12 potently inhibited both metastasis and primary tumor growth. The effects of wild-type CXCL12 were attributed to an immune response characterized by the induction of CD8+ T cell activity, enhanced cell-mediated cytotoxicity, increased numbers of CD11c+ cells in the tumor-draining lymph nodes and reduced accumulation of myeloid-derived suppressor cells in the spleen.ConclusionsThis study highlights the need to consider carefully therapeutic strategies that block CXCL12 signaling. Therapies that boost CXCL12 levels at the primary tumor site may prove more effective in the treatment of metastatic breast cancer.
Highlights
A growing body of work implicates chemokines, in particular CXCL12 and its receptors, in the progression and site-specific metastasis of various cancers, including breast cancer
CXCR4 was shown to be expressed by various human breast cancer cells, and metastasis of these cells in severe combined immunodeficient (SCID) mice could be inhibited with neutralizing CXCR4 antibodies [4]
Generation and in vitro characterization of CXCL12 construct-expressing 4T1.2 mammary carcinoma cell lines To determine if antagonizing CXCR4 by means of the CXCR4 antagonist CXCL12(P2G) would impact on growth and metastasis of 4T1.2 tumors, 4T1.2 cells were transfected with a DNA construct encoding CXCL12(P2G)
Summary
A growing body of work implicates chemokines, in particular CXCL12 and its receptors, in the progression and site-specific metastasis of various cancers, including breast cancer. CXCL12 is a highly pleiotropic chemokine, influencing a variety of biological processes through interaction with its receptors CXCR4 and CXCR7. It is prominent in the context of immune responses, acting as a potent chemotactic factor for mature T cells and monocytes [1], mature dendritic cells (DC) [2], natural killer (NK) cells and NKT cells [3]. CXCL12 and its receptors are involved in processes specific to metastasis; many of their functions promote primary tumor growth.
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