Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis

Abstract

Mesenchymal stromal cells (MSCs) are one of major components of the tumour microenvironment. Recent studies have shown that MSC tumour residence and their close interactions with inflammatory factors are important factors that affect tumour progression. Among tumour-associated inflammatory factors, transforming growth factor β (TGFβ) is regarded as a key determinant of malignancy. By employing a lung metastasis model of a murine breast cancer, we show here that the prometastatic effect of MSCs was dependent on their response to TGFβ. Interestingly, we found that MSC-produced CXCL12, an important chemokine in tumour metastasis, was markedly inhibited by TGFβ. Furthermore, silencing of CXCL12 in TGFβ-unresponsive MSCs restored their ability to promote tumour metastasis. We found that 4T1 breast cancer cells expressed high levels of CXCR7, but not of CXCR4, both of which are CXCL12 receptors. In presence of CXCL12, CXCR7 expression on tumour cells was decreased. Indeed, when CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, our data demonstrated that sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGFβ, this CXCL12 effect of MSCs on tumour cells is relieved. Importantly, elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival. Our findings reveal a novel mechanism of MSC effects on malignant cells through which crosstalk between MSCs and TGFβ regulates tumour metastasis.

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…However, CXCL12 and CXCR4 have disparate functions on breast tumorigenesis and outcomes depending on the specific immune cell type and conditions present [51]. Yu et al demonstrated that transforming growth factor β (TGFβ) impairs MSCs ability to secrete CXCL12 and therefore promotes breast cancer metastasis [52], consistent with our findings. Recently, Xia et al found that B cells directly kill BC cells using CXCR4/CXCL12 pathways, indicating that CXCL12 functions as a tumor suppressor [53].…”

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

“…5F). This is consistent with our recent report that TGFβ1 degrades TRAF3 in MSCs to increase RANKL production through activation of NF-κB 17 and www.nature.com/scientificreports www.nature.com/scientificreports/ that expression of RANKL by MSCs (OBs/fibroblasts) mediates the interactions of circulating cancer cells with the host microenvironment not only in bone 13,14 , but also in lung 18,40 to promote cancer metastasis. Debio1143, and the bivalent agent, TL32711/birinapant, have been tested in clinical trials for the treatment of cancers, including breast, lung, ovarian and colon carcinomas, melanoma, lymphoma, and leukemia [41][42][43][44][45][46] .…”

Gene expression profiling in aggressive digital papillary adenocarcinoma sheds light on the architecture of a rare sweat gland carcinoma

“…A cluster consistently downregulated in tumours contains FZD5 and, surprisingly, CXCL12 , which is reported to be associated with tumour growth and metastasis . Interestingly, there have recently been reports of CXCL12 downregulation promoting breast cancer metastasis . The rare ADPA investigated here is to be annotated in a KEGG pathway, as only projections to other cancer pathways could be identified in our study.…”