Manipulating the chemokine‐chemokine receptor network to treat cancer

Ruffini, Pier Adelchi; Morandi, Paolo; Cabıoğlu, Neslihan; Altundağ, Kadri̇; Cristofanilli, Massimo

doi:10.1002/cncr.22706

Cited by 104 publications

(77 citation statements)

References 108 publications

(143 reference statements)

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“…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 malignant cells along chemokine gradients towards secondary tumor sites in a manner that is similar to the process of lymphocyte homing.…”

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confidence: 54%

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

2009

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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...

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confidence: 54%

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

2009

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“…4 However, there have been no investigations of CXCR4 expression in a large series of soft-tissue sarcoma. This study firstly analyzed CXCR4 expression in soft-tissue sarcomas and compared it with detailed clinicopathological findings and prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] This CXCR4/SDF-1 pathway has been shown to be correlated with tumor progression and poor prognosis in several kinds of cancer. 4 Vascular endothelial growth factor (VEGF), a critical mediator of angiogenesis and tumor proliferation, 5 is frequently overexpressed in a variety of cancers. 6 This has meant that many therapeutic approaches targeting VEGF have been improved in several cancers.…”

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confidence: 99%

Chemokine receptor CXCR4 expression is correlated with VEGF expression and poor survival in soft‐tissue sarcoma

Oda

Tateishi

Matono

et al. 2009

Intl Journal of Cancer

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The expression of chemokine receptor CXCR4 has been associated with poor prognosis and VEGF expression in several kinds of human malignancy. We measured CXCR4 expression levels in soft‐tissue sarcoma and compared them with VEGF expression or microvessel density (MVD). We used real‐time quantitative PCR to examine the CXCR4 and VEGF expression levels in a total 176 tumors, including 24 intermediate tumors, 24 malignant round‐cell tumors (MRCTs) and 128 malignant non‐round‐cell tumors (MNRCTs). We also assessed their immunohistochemical expression of CXCR4 and VEGF, MVD and proliferative activities, as measured by the MIB‐1‐labeling index (LI). Furthermore, we evaluated their significance with respect to patient survival rates in MNRCTs, using the Cox regression model. Within the different types of tumor tissue, the expression levels of CXCR4 (p < 0.0001) and VEGF (p < 0.0001) in MNRCTs were significantly higher than those in intermediate tumors or MRCTs. Immunohistochemical expression levels of CXCR4 and VEGF were significantly correlated with their mRNA expression levels (p < 0.0001). Significant positive correlation was found between CXCR4 and VEGF expression in 112 primary MNRCTs (r = 0.434, p < 0.0001). Moreover, both univariate (p < 0.0001) and Cox multivariate analysis (p = 0.0001) revealed that overexpression of CXCR4 was an independent adverse prognostic factor, in addition to high stage according to the American Joint Committee on Cancer and a high MIB‐1‐LI. Determination of the CXCR4 expression level as a novel marker can provide useful prognostic information for patients and it could be a candidate for molecular targeting therapy in MNRCTs of soft‐tissue sarcomas. © 2008 Wiley‐Liss, Inc.

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“…This was the case for CCL5, CXCL9, CX3CL1, CCL16 and other [30,37,44,45]. In some experiments, the anti-tumor effect could be credited to the recruitment of T cells at the tumor site.…”

Section: Chemokine Regulation Of Leukocyte Attraction Within Tumorsmentioning

confidence: 96%

Chemokines in cancer related inflammation

Allavena

Germano

Marchesi

et al. 2011

Experimental Cell Research

197

137

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Chemokines are key players of the cancer-related inflammation. Chemokine ligands and receptors are downstream of genetic events that cause neoplastic transformation and are abundantly expressed in chronic inflammatory conditions which predispose to cancer. Components of the chemokine system affect multiple pathways of tumor progression including: leukocyte recruitment, neo-angiogenesis, tumor cell proliferation and survival, invasion and metastasis.Evidence in pre-clinical and clinical settings suggests that the chemokine system represents a valuable target for the development of innovative therapeutic strategies

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Manipulating the chemokine‐chemokine receptor network to treat cancer

Cited by 104 publications

References 108 publications

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

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

Chemokine receptor CXCR4 expression is correlated with VEGF expression and poor survival in soft‐tissue sarcoma

Chemokines in cancer related inflammation

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