Systemic neutralization of IL-17A significantly reduces breast cancer associated metastasis in arthritic mice by reducing CXCL12/SDF-1 expression in the metastatic niches

BMC Cancer

Lopamudra Das Roy⁴  Mahnaz Sahraei²  Jorge L Schettini¹  Helen E Gruber³  Dahlia M Besmer⁴  Pinku Mukherjee⁴ 

[1] Caris Life Science, 4610 S 44th Place, Phoenix, AZ 85040, USA

[2] Department of Pharmacology, Yale University, 10 Amistad St, New Haven, CT 06519, USA

[3] Department of Orthopedic Surgery, Carolinas Medical Center, Cannon Research Center, Room 304, PO Box 32861, Charlotte, NC 28232, USA

[4] Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC 28223, USA

关键词: IL-17A;    Autoimmune arthritis;    Breast cancer;    Lung metastasis;    Bone metastasis;    SDF-1;    CXCR4 CXCL12;   

Others  :  858932
DOI  :  10.1186/1471-2407-14-225

 received in 2014-01-05, accepted in 2014-03-11,  发布年份 2014

【 摘 要 】

Background

IL-17A is a pro-inflammatory cytokine that is normally associated with autoimmune arthritis and other pro-inflammatory conditions. Recently, IL-17A has emerged as a critical factor in enhancing breast cancer (BC)-associated metastases. We generated immune competent arthritic mouse models that develop spontaneous BC-associated bone and lung metastasis. Using these models, we have previously shown that neutralization of IL-17A resulted in significant reduction in metastasis. However, the underlying mechanism/s remains unknown.

Methods

We have utilized two previously published mouse models for this study: 1) the pro-arthritic mouse model (designated SKG) injected with metastatic BC cell line (4T1) in the mammary fat pad, and 2) the PyV MT mice that develop spontaneous mammary gland tumors injected with type II collagen to induce autoimmune arthritis. Mice were treated with anti-IL-17A neutralizing antibody and monitored for metastasis and assessed for pro-inflammatory cytokines and chemokines associated with BC-associated metastasis.

Results

We first corroborate our previous finding that in vivo neutralization of IL-17A significantly reduced metastasis to the bones and lungs in both models. Next, we report that treatment with anti-IL17A antibody significantly reduced the expression of a key chemokine, CXCL12 (also known as stromal derived factor-1 (SDF - 1)) in the bones and lungs of treated mice. CXCL12 is a ligand for CXCR4 (expressed on BC cells) and their interaction is known to be critical for metastasis. Interestingly, levels of CXCR4 in the tumor remained unchanged with treatment. Consequently, protein lysates derived from the bones and lungs of treated mice were significantly less chemotactic for the BC cells than lysates from untreated mice; and addition of exogenous SDF-1 to the lysates from treated mice completely restored BC cell migration. In addition, cytokines such as IL-6 and M-CSF were significantly reduced in the lung and bone lysates following treatment. The data presented suggests that systemic neutralization of IL-17A can block the CXCR4/SDF-1 signaling pathway by reducing the expression of SDF-1 in the metastatic niches and significantly reducing metastasis in both mouse models.

Conclusion

In our model, neutralization of IL-17A regulates SDF-1 expression in the metastatic niches either directly or indirectly via reducing levels of IL-6 and M-CSF.

【 授权许可】

   
2014 Das Roy et al.; licensee BioMed Central Ltd.

【 图 表 】

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