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Multiple functions of CXCL12 in a syngeneic model of breast cancer
Sharon A Williams1, Yuka Harata-Lee, Iain Comerford
1School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
Background:
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. 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.
Results:
While 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.
Conclusions:
This 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.
Insights
Boosting CXCL12 levels, not blocking it, may be a more effective strategy for treating metastatic breast cancer by enhancing anti-tumor immunity and inhibiting tumor growth.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis
Background:
- Chemokines like CXCL12 and its receptors are implicated in breast cancer progression and metastasis.
- Current therapies aim to block the CXCL12-CXCR4 interaction to inhibit cancer spread.
- CXCL12 also functions as a chemotactic factor for leukocytes, potentially enhancing anti-cancer immunity.
Purpose of the Study:
- To investigate the role of CXCL12 in breast cancer progression.
- To compare the effects of overexpressing wild-type CXCL12 versus its antagonist CXCL12(P2G) in a mouse model.
Main Methods:
- Overexpression of CXCL12 and CXCL12(P2G) in the 4T1.2 mouse model of breast carcinoma.
- Assessment of metastasis, primary tumor growth, and immune responses.
Main Results:
- CXCL12(P2G) significantly inhibited metastasis.
- Wild-type CXCL12 potently inhibited both metastasis and primary tumor growth.
- Wild-type CXCL12 induced CD8+ T cell activity, enhanced cytotoxicity, increased CD11c+ cells, and reduced myeloid-derived suppressor cells.
Conclusions:
- Blocking CXCL12 signaling may not be the optimal therapeutic strategy.
- Therapies that increase CXCL12 levels at the primary tumor site could be more effective for metastatic breast cancer.
- The immune-modulating effects of CXCL12 are crucial for its anti-cancer activity.
