Recently, there are two articles which reported the study on CXCL12 and breast cancer. Let’s take a glance on these new results.

Breast cancer (BC) remains the most frequent cancer and the major cause of cancer-associated death in women. Based on histopathological analysis commonly used in clinical practice, BC has been identified as a heterogeneous disease classified into three main subtypes: Luminal (Lum), HER2 and triple-negative (TN), which have been further confirmed and extended by gene expression profiling.

Many types of cells, such as immune cells, endothelial progenitor cells and mesenchymal stromal cells (MSCs), are recruited to the stroma of developing tumors. Experimental evidence has shown that the direct effects of MSCs on tumor cells can enhance tumor metastasis. Thus, the metastatic phenotype of tumor cells is not only dependent on autonomous changes in tumor cells, but is also influenced by tumor stroma cells in tumor microenvironment.

Mesenchymal stromal cells (MSCs) are one of major components of the tumor microenvironment. Recent studies have shown that MSC tumor residence and their close interactions with inflammatory factors are important factors that affect tumor progression. Among tumor-associated inflammatory factors, transforming growth factor β (TGFβ) is regarded as a key determinant of malignancy.

The functions of MSCs in breast cancer metastasis have not been fully elucidated. Investigations on MSCs within the stroma of breast cancer xenografts show that MSCs can enhance the xenograft metastatic ability to the lungs and the bones. The contributions of MSCs to breast cancer metastasis are mostly mediated through their ability to produce a number of factors, such as CCL5, CXCL12, which in turn exert paracrine actions on breast cancer cells that resulted in their invasion and/or distant organ metastasis.

CXCL12 (also known as stromal cell-derived factor 1) and its receptor CXCR4 have essential roles in hematopoiesis: they regulate hematopoietic stem cells homing in bone marrow and lymphocytes trafficking to sites of inflammation. Beside its role in supporting tumor growth and angiogenesis, CXCL12 was demonstrated to be important in helping select metastatic tumor cells for bone metastasis. More interestingly, breast cancer cells with high expression of CXCR4 and CXCR7, the chemokine receptors for CXCL12, are apt to migrate to the distant sites where CXCL12 is highly expressed.

Fig.1 Representative views of smooth-muscle actin (SMA),CXCR4 and CXCL12 immunostaining (IHC) in PDX models derived from Luminal A (LumA, Left), HER2 (Middle) and Triple-Negative (TN, Right) breast cancers (BC).

At the normal state, CXCR4 is found at the surface of most leukocytes, endothelial and epithelial cells. In cancer, CXCR4 is expressed in many types of solid tumors including breast, prostate, brain, colon and lung. Moreover, CXCR4 surface expression is an independent prognostic factor for disease relapse and survival in BC. Previous studies have assessed efficacy of targeting CXCR4/CXCL12 pathway on breast primary tumor growth and metastasis using syngenic models or various human breast cancer cell lines. Still, the therapeutic interest of targeting CXCR4/ CXCL12 axis in the different BC subtypes remained unclear.

The article result shows that CXCL12 protein staining was strongly up-regulated in the stroma of HER2 patients. This chemokine, mostly produced by carcinoma-associated fibroblasts, enhances tumor growth through mechanisms such as proliferation, survival, migration and drug resistance. Moreover, CXCL12 strongly modifies tumor microenvironment by promoting angiogenesis through hypoxia-induced CXCR4 expression and recruitment of endothelial progenitors.

All these tumor and metastasis-promoting functions of CXCL12/CXCR4 make this ligand-receptor association appealing for new therapeutic avenues, in particular in BC. Given the crucial role of the CXCR4/CXCL12 axis in tumor microenvironment, the scientists investigated if targeting this signaling pathway could be of potential therapeutic interest in invasive BC.

 

In contrast to previous CXCR4 BC studies using subcutaneous xenograft models or transgenic mouse models, BC patient-derived xenografts (PDX) models maintain cell differentiation, morphology, architecture, and molecular signatures of original patient tumors.

Systemically blocking CXCR4 with specific antagonists can impair metastasis of breast tumor cells to the lung. However, the role of CXCL12 produced by MSCs in tumor metastasis remains unclear.
Except CXCL12/CXCR4 axis, CXCL12 could also influence tumor through another receptor -CXCR7.

It has been reported that CXCL12 produced by MSCs can be inhibited in presence of TGFβ. TGFβ that is highly produced by MSCs, tumor cells, as well as suppressive immune cells can facilitate tumor cell migration and invasion by the induction of the EMT process of tumor cells. Classically, TGFβ binds to the type 2 TGFβ receptor (TGFBR2), causing the recruitment and phosphorylation of TGFBR1, and then activates the downstream signalling.

Fig.2  Mechanisms for enhanced tumour metastasis through TGFβ–CXCL12–CXCR7 axis.

In the current study, the author found that the prometastatic effect of MSCs in breast cancer model was abolished when the TGFβ signaling pathway was blocked in MSCs, suggesting the pivotal roles of TGFβ-mediated regulation of MSCs on tumor metastasis. The author found that TGFβ down-regulated the expression of CXCL12, which restricted tumor metastasis. Double knock-down of the expression of TGFBR2 and CXCL12 in MSCs was shown to reverse the effect of TGFβ-unresponsive MSCs on tumor metastasis to the lung, providing the evidence of the role of TGFβ–CXCL12 axis in tumor metastasis. More importantly, this regulation of tumor metastasis by CXCL12 was related to its regulation of CXCR7 in 4T1 cells. Blocking of CXCR7 expression in 4T1 cells by shRNA inhibited breast cancer metastasis. Thus, our data demonstrated that CXCL12 produced by MSCs in the primary tumor site impedes breast cancer metastasis via inhibiting CXCR7 expression in 4T1 cells, however, TGFβ can diminish the restriction of MSC produced CXCL12 on tumor cells. The author also described that up-regulation of TGFβ and CXCR7, and repression of CXCL12 are prominent features of aggressive clinical breast cancer, and the author found that they are prognostic parameters for patient survival, indicative of their critical roles in breast cancer pathogenesis. Our study implicates a role for a TGFβ–CXCL12–CXCR7 regulatory network between MSCs and tumor cells in breast cancer metastasis.

 

References

1. CXCR4 inhibitors could benefit to HER2 but not to triple-negative breast cancer patients. Oncogene. 2016 Sep 26. doi: 10.1038/onc.2016.284.

2. Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis. Oncogene. 2016 Sep 26. doi: 10.1038/onc.2016.252.