Abstract
Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. However, whether tumor‐draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis. Up‐regulation of oncogenic Il‐17rb in cancer cells derived from TDLNs contributes to their malignancy. TGF‐β1 secreted from regulatory T cells (Tregs) in the TDLNs mediated the up‐regulation of Il‐17rb through downstream Smad2/3/4 signaling. These phenotypes can be abolished by TGF‐β1 neutralization or depletion of Tregs. Consistently, clinical data showed that the up‐regulation of IL‐17RB in cancer cells from LN metastases correlated with the increased prevalence of Tregs as well as the aggressive growth of tumors in mouse xenograft assay. Together, these results indicate that Tregs in TDLNs play an important role in modulating the malignancy of breast cancer cells for distant metastasis. Blocking IL‐17RB expression could therefore be a potential approach to curb the process.
Highlights
Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients
We employed this syngeneic mouse breast tumor model, which has intact lymphoid organs and immune systems, to examine how tumor-draining LNs (TDLNs) play for systemic metastasis. 4T1 cells transduced with green fluorescent protein (GFP) and luciferase by lentivirus were used for following allograft assays
Some clinical evidence has suggested that metastasis to the LNs in breast cancer patients is strongly associated with distant organ metastasis, poor disease-free survival, and shorter overall survival (Rouzier et al, 2002; Ran et al, 2010)
Summary
Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. TGF-b1 secreted from regulatory T cells (Tregs) in the TDLNs mediated the up-regulation of Il-17rb through downstream Smad2/3/4 signaling. These phenotypes can be abolished by TGF-b1 neutralization or depletion of Tregs. Clinical data showed that the up-regulation of IL-17RB in cancer cells from LN metastases correlated with the increased prevalence of Tregs as well as the aggressive growth of tumors in mouse xenograft assay. Together, these results indicate that Tregs in TDLNs play an important role in modulating the malignancy of breast cancer cells for distant metastasis. Blocking IL-17RB expression could be a potential approach to curb the process
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