Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

Abstract

Expression of the chemokine receptor CXCR4 has been linked with increased metastasis and decreased clinical prognosis in breast cancer. The current paradigm dictates that CXCR4 fosters carcinoma cell metastasis along a chemotactic gradient to organs expressing the ligand CXCL12. The present study asked if alterations in autocrine CXCR4 signaling via dysregulation of CXCL12 in mammary carcinoma cells modulated their metastatic potential. While CXCR4 was consistently detected, expression of CXCL12 characteristic of human mammary epithelium was silenced by promoter hypermethylation in breast cancer cell lines and primary mammary tumors. Stable re-expression of functional CXCL12 in ligand null cells increased orthotopic primary tumor growth in the mammary fat-pad model of tumorigenesis. Those data parallel increased carcinoma cell proliferation measured in vitro with little-to-no-impact on apoptosis. Moreover, re-expression of autocrine CXCL12 markedly reduced metastatic lung invasion assessed using in vivo bioluminescence imaging following tail vein injection. Consistent with those data, decreased metastasis reflected diminished intracellular calcium signaling and chemotactic migration in response to exogenous CXCL12 independent of changes in CXCR4 expression. Together these data suggest that an elevated migratory signaling response to ectopic CXCL12 contributes to the metastatic potential of CXCR4-expressing mammary carcinoma cells, subsequent to epigenetic silencing of autocrine CXCL12.

Constitutive CXCL12 Expression Induces Anoikis in Colorectal Carcinoma Cells

“…2,29 Further, differences in mutational status contributing to increased resistance to CXCL12-induced anoikis is evidenced by our work showing CXCL12 re-expression in Ras mutated mammary carcinoma cells does not affect anoikis, but instead increases cellular proliferation. 18 Together with previous reports our data support the notion that the Ras, Raf, MEK, ERK pathway is a key regulator of intestinal epithelial and colorectal carcinoma cell anoikis.…”

DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts

“…In cancers, however, it has been shown that DNA hypermethylation of the CXCL12 promoter in colon carcinomas, mammary carcinomas and the MCF7 breast cancer cell line promotes tumor metastasis. [37][38][39] In the current study basal levels of CXCL12 were higher in RASFs compared with OASFs. Even though these changes were not dramatic, we believe that they are of clinical significance as CXCL12 expression positively correlated with levels of C-reactive protein.…”

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

“…Our refined model for chemokine-directed metastasis includes epigenetic silencing of the ligand that confers a leukocyte migratory phenotype to carcinoma cells that is diminished by reexpression of the suppressed chemokine (13)(14)(15)25). The purpose of our study was to test whether exogenous CXCL12 treatment would also reduce metastasis.…”

“…We discovered that changes in the oligomeric state of CXCL12 dictated the migratory outcome of monocytic cells in vitro, with monomer, but not dimer, inducing cellular migration (17). Congruently, restoration of CXCL12 expression in colonic and mammary carcinoma cells markedly reduced their metastatic potential in vivo (14,15), in part, through increased sensitivity to detachment-induced cell death (15,19). We therefore speculate that local CXCL12 secretion acts as a tumor suppressor, preventing metastasis by shielding the primary tumor from remote chemotactic gradients.…”

“…However, this avenue has proven difficult to move into the clinic (5,12), suggesting alternative strategies to interfere with CXCR4-guided metastatic homing (for example, by the use of agonists rather than antagonists) are required. Our previous data indicate that epigenetic silencing of the Cxcl12 promoter enhances metastasis of colonic and mammary carcinoma, implicating the chemokine ligand as a key variable governing metastatic potential (13)(14)(15).…”