Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

Abstract

Chemokine receptors are essential mediators of the metastatic spread in various cancer types; however their precise function in the development of secondary tumors remains poorly understood. We report here a novel property of the chemokine receptors CXCR4 and CCR7 in inhibiting detachment-induced cell death -anoikis, which is believed to be one of the major blocks in the metastatic spread of various neoplasms. Activation of these chemokine receptors by their respective ligands, CXCL12 and CCL21 specifically reduced the sensitivity of metastatic breast cancer cells to anoikis by a distinct mechanism of selective regulation of pro-apoptotic Bmf and anti-apoptotic Bcl-xL proteins. Consequently, functional CXCR4 and CCR7 increased cell survival in the absence of correct ECM attachment both in vitro and in vivo. We also demonstrated that preventing chemokineinduced reduction in Bmf levels significantly attenuated breast cancer metastasis in an experimental mouse model. These results provide evidence for a previously unknown axis in malignant tumors, which connects chemokine receptors with deregulated apoptosis in the absence of the appropriate cell -ECM interaction and may offer novel targets for therapeutic intervention for the treatment of metastatic breast and potentially other tumors. Cell Death and Differentiation (2009) 16, 664-673; doi:10.1038/cdd.2008; published online 9 January 2009The main cause of cancer-related deaths is the spread of tumor cells to sites distant from the primary locus and the subsequent establishment of secondary lesions. The heterogeneity and complexity of malignant transformation make it difficult to identify common molecular mechanisms governing the metastatic progression of cancer and potentially account for the lack of effective treatments for malignant cancers. Recently, members of the chemokine receptor family of G-protein-coupled receptors (GPCRs) have been assigned a major role in this process (reviewed in Zlotnik 1 ). It is becoming increasingly clear that many members of this family regulate a complex milieu of interactions between tumor cells, stromal cells, tumor infiltrating leukocytes and endothelial cells and that better understanding of the specific actions of chemokines and their receptors in promoting malignancy will significantly contribute to combating cancer. 2 CXCR4 and CCR7 are the major chemokine receptors found on a wide range of tumor cells and high levels of these receptors are associated with higher grade and poor prognosis of breast, lung, colon and other cancers. 3 Blocking the interaction between CXCR4 and its ligand CXCL12, dramatically reduces breast and other cancer metastases in mouse models. 4 Our recent results have also provided a direct correlation between functional activation of CXCR4 and CCR7 and the invasive, metastatic phenotype of breast cancer cells 5 further supporting a highly important role for these molecules in tumor dissemination to distant sites. Initial studies suggested that these surface molecules induce directional migration of ma...

Interstitial flow influences direction of tumor cell migration through competing mechanisms

“…MDA-MB-231 cells are known to express CCR7 (23,24) and migrate toward increasing concentration of CCL21 when cultured in 2D and exposed to a CCL21 gradient (25). The system consists of two channels separated by a region containing single cells suspended in a collagen I gel (Fig.…”

Different Expression Patterns of CXCR4, CCR7, Maspin and FOXP3 in Luminal Breast Cancers and Their Sentinel Node Metastases

“…Cooperation of CXCR4 and CCR7 in close association with their respective ligands have been reported to be responsible for anoikis, meaning reduced sensitivity to apoptosis normally caused by detachment of neoplastic cells from cellcell and cell-matrix contacts (29). This may implicate enhanced survival of mobile cancer cells in circulating blood or extracellular matrix.…”

Inhibition of gap junction transfer sensitizes thyroid cancer cells to anoikis

“…Our findings are consistent with previously reported data. Formation of cancer cell aggregates has been reported in hepatoma, breast, prostate, and lung cancer cell lines growing in suspension (Berezovskaya et al 2005, Zhang et al 2008, Kochetkova et al 2009). It has also been reported that formation of multi-cellular aggregates in non-adherent conditions is associated with overexpression of adhesion molecules (Zhang et al 2008).…”