Tregs Promote Metastasis

Science Signaling  01 Mar 2011:
Vol. 4, Issue 162, pp. ec60
DOI: 10.1126/scisignal.4162ec60

Signaling by receptor activator of nuclear factor κB (RANK) in response to RANK ligand (RANKL) promotes the generation of osteoclasts. RANKL also stimulates the proliferation of mammary gland cells during pregnancy through activation of inhibitor of nuclear factor κB (NF-κB) kinase α (IKKα). Because the abundance of RANKL is increased in metastatic prostate cancer, Tan et al. investigated a role for RANKL in breast cancer metastasis. In a mouse model of breast cancer induced by the proto-oncogene Erbb2, heterozygosity in Rank had no effect on tumorigenesis but led to a 50% reduction in lung metastases compared with that in Erbb2/Rank+/+ mice. RANKL signaling induced the nuclear translocation of IKKα, and silencing of IKKα increased the number of apoptotic cells in late-stage tumors. Immunohistochemical analysis of Errb2-induced mammary tumors showed that RANKL was present in the stromal area of the tumor. CD4+ regulatory T cells (Tregs) localized to this same area, which also contained the chemokine CCL5, and tumor-infiltrating Tregs expressed the receptor for CCL5. Inoculation of CD4–/– mice with Errb2 tumor cells resulted in fewer lung metastases than occurred in inoculated wild-type mice. Transplantation of CD4+CD25+ Tregs restored the number of metastases in the CD4–/– mice, which was blocked with an antibody against RANK. RANKL increased the incidence of metastasis in nude mice that were inoculated with human breast carcinoma cells. Together, these data suggest that RANKL produced by tumor-infiltrating Tregs stimulates breast cancer metastasis, leading the authors to suggest that a combination of traditional therapy with targeting of RANK-RANKL signaling may reduce the extent of metastatic disease.

W. Tan, W. Zhang, A. Strasner, S. Grivennikov, J. Q. Cheng, R. M. Hoffman, M. Karin, Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011). [PubMed]