CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion

Abstract

Breast cancer (BrCa) is one of the most frequently diagnosed cancers and the second leading cause of cancer-related deaths in North American women. Most deaths are caused by metastasis, and BrCa is characterized by a distinct metastatic pattern involving lymph nodes, bone marrow, lung, liver and brain. Migration of metastatic cells share many similarities with leukocyte trafficking, which are regulated by chemokines and their receptors. The current study evaluates the expression and functional role of CCR9, and its only known ligand, CCL25, in BrCa cell migration and invasion. Quantitative immunohistochemical analysis showed that both moderately and poorly differentiated BrCa tissue expressed significantly more (P<0.0001) CCR9 compared to non-neoplastic breast tissue. Interestingly, poorly differentiated BrCa tissue expressed significantly more (P<0.0001) CCR9 compared to moderately differentiated BrCa tissue. Similarly, CCR9 was highly expressed by the aggressive breast cancer cell line (MDA-MD-231) compared to the less aggressive MCF-7. Migration as well as invasion assays were used to evaluate the functional interaction between CCR9 and CCL25 in BrCa cell lines (MDA-MB-231 and MCF-7). Neutralizing CCR9-CCL25 interactions significantly impaired the migration and invasion of BrCa cells. Furthermore, CCL25 enhanced the expression of MMP-1, -9, -11 and -13 active proteins by BrCa cells in a CCR9-dependent fashion. These studies show CCR9 is functionally and significantly expressed by BrCa (poorly > moderately differentiated) tissue and cells as well as that CCL25 activation of this receptor promotes breast tumor cell migration, invasion and MMP expression, which are key components of BrCa metastasis.

Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

“…CCR9 signalling in tumour cells increases their resistance to chemotherapy 116,117 and their expression of MMPs, which promote cancer invasion and metastasis 118–122 . CCL25 can also promote metastasis by recruiting CCR9 + cancer cells into CCL25-expressing tissues, such as the small intestine.…”

Chemokines in tumor progression and metastasis

“…Some breast cancer cell lines also express CCR9 [159]. A recent study suggests that CCR9 may promote metastasis in breast cancer by enhancing cell migration, increasing matrix-metalloproteinase-9 (MMP-9) expression via CCL25 and supporting tumor cell survival in metastatic sites [159].…”

“…A recent study suggests that CCR9 may promote metastasis in breast cancer by enhancing cell migration, increasing matrix-metalloproteinase-9 (MMP-9) expression via CCL25 and supporting tumor cell survival in metastatic sites [159]. Certain ovarian cancer cell lines and tumors also express CCR9 [160]; however, further research is needed to elucidate the role of CCR9 in other cancers and to determine the mechanism by which it promotes metastasis.…”

Antitumor effects of a monoclonal antibody to human CCR9 in leukemia cell xenografts

“…Aberrant CCR9 expression in prostate cancer, 18 breast cancer 19 and melanomas 7 is correlated with in vitro invasiveness in response to CCL25. CCR9 provides competitive advantages to tumor cells.…”