Interaction between CXCR4 and CCL20 pathways regulates tumor growth
Katia Beider1, Michal Abraham, Michal Begin
1Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Abstract:
The chemokine receptor CXCR4 and its ligand CXCL12 is overexpressed in the majority of tumors and is critically involved in the development and metastasis of these tumors. CXCR4 is expressed in malignant tumor cells whereas its ligand SDF-1 (CXCL12) is expressed mainly by cancer associated fibroblasts (CAF). Similarly to CXCR4, the chemokine CCL20 is overexpressed in variety of tumors; however its role and regulation in tumors is not fully clear. Here, we show that the chemokine receptor CXCR4 stimulates the production of the chemokine CCL20 and that CCL20 stimulates the proliferation and adhesion to collagen of various tumor cells. Furthermore, overexpression of CCL20 in tumor cells promotes growth and adhesion in vitro and increased tumor growth and invasiveness in vivo. Moreover, neutralizing antibodies to CCL20 inhibit the in vivo growth of tumors that either overexpress CXCR4 or CCL20 or naturally express CCL20. These results reveal a role for CCL20 in CXCR4-dependent and -independent tumor growth and suggest a therapeutic potential for CCL20 and CCR6 antagonists in the treatment of CXCR4- and CCL20-dependent malignancies.
Insights
The chemokine receptor CXCR4 stimulates CCL20 production, promoting tumor cell proliferation and growth. Neutralizing CCL20 inhibits tumor growth, suggesting CCL20 antagonists as potential cancer therapeutics.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- CXCR4 and CXCL12 are overexpressed in many tumors, driving tumor development and metastasis.
- CXCL12 (SDF-1) is produced by cancer-associated fibroblasts (CAFs), while CXCR4 is on tumor cells.
- CCL20 is also overexpressed in tumors, but its specific role and regulation remain unclear.
Purpose of the Study:
- To investigate the role of the chemokine receptor CXCR4 in regulating CCL20 production.
- To determine the effects of CCL20 on tumor cell behavior, including proliferation and adhesion.
- To evaluate the therapeutic potential of targeting CCL20 in cancer treatment.
Main Methods:
- Investigated the relationship between CXCR4 and CCL20 production in tumor cells.
- Assessed the impact of CCL20 on tumor cell proliferation and collagen adhesion in vitro.
- Evaluated tumor growth and invasiveness in vivo following CCL20 overexpression.
- Utilized neutralizing antibodies against CCL20 to inhibit tumor growth in vivo.
Main Results:
- CXCR4 stimulation leads to increased production of CCL20.
- CCL20 enhances tumor cell proliferation and adhesion to collagen.
- Overexpression of CCL20 promotes tumor growth and invasiveness both in vitro and in vivo.
- CCL20-neutralizing antibodies effectively inhibit the growth of tumors overexpressing CXCR4, CCL20, or naturally expressing CCL20.
Conclusions:
- CCL20 plays a significant role in both CXCR4-dependent and -independent tumor progression.
- Targeting CCL20 and its receptor CCR6 offers a promising therapeutic strategy for various malignancies.
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