Fibroblast-recruited, tumor-infiltrating CD4+ T cells stimulate mammary cancer metastasis through RANKL-RANK signaling

By Wei Tan, Weizhou Zhang, A. Strasner, S. Grivennikov, J. Cheng, R. Hoffman, M. Karin. Nature, 2011

637 citations recorded by the source corpus.

Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and lymphotoxin. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy through inhibitor of nuclear factor-κB (IκB) kinase-α (IKK-α), a protein kinase that is needed for the self-renewal of mammary cancer progenitors and for prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKK-α are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4+CD25+ T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)+ stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK+ human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4+ or FOXP3+ T cells on human breast cancer prognosis and suggest that the targeting of RANKL–RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/ce2064d20539f938795810330735e248285667fc

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Citations in the corpus

Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011 (2011, background): “Immunity and autoimmunity Tumor-infiltrating regulatory T cells stimulate mammary cancer metastases through receptor activator (RANKL-RANK) signaling [56].”
Systematic Analysis of Breast Cancer Morphology Uncovers Stromal Features Associated with Survival (2011, background): “This feature provided information about the relationship between stromal cellular composition and prognosis and suggested that the presence of inf lammatory cells in the stroma is associated with poor prognosis, a finding consistent with previous observations (32).”
Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “Moreover, the recruitment of CD4 + CD25 + Treg cells to CAFs also depends on the chemokine CCL5 according to studies examining breast cancer [209, 210].”
A CXCL1 paracrine network links cancer chemoresistance and metastasis (2012, neutral): “Hemann, 2010; Shree et al., 2011; Tan et al., 2011).”
The diverse and complex roles of NF-κB subunits in cancer (2012, background): “In this context, the function of NF-κB as a tumour promoter is not limited to intrinsic effects within transformed tumour cells — NF-κB also influences the function of infiltrating lymphocytes and macrophage”
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. (2018, neutral): “In addition, CAFs have been shown to contribute to drug resistance (Straussman et al., 2012; Paulsson et al., 2017) and to reduce anti-tumor immunity (Kraman et al., 2010; Tan et al., 2011; Feig et al., 2013; Denton et al., 2014; Ruhland et al., 2016; Yang et al., 2016).”