Chemokine receptors and melanoma metastasis
ABSTRACT Cancer metastasis is the end result of a complex series of biologic events that leads to the formation of clinically significant secondary tumors at distant sites. The sites of distant metastasis are not random since certain tumors show a tendency to develop metastases in specific organs. Human melanoma, for example, demonstrates frequent metastasis to brain, lungs, lymph nodes, and skin. Herein, we review the evidence that suggests that a limited number of chemokine receptors may play critical roles in determining organ-selective metastasis in melanoma by regulating diverse processes such as chemoattraction, adhesion, and survival. In particular, we describe roles for CC chemokine receptor 7 (CCR7) in lymph node metastasis, CXC chemokine receptor 4 (CXCR4) in pulmonary metastasis, and CCR10 in skin metastasis, using a mouse model of melanoma. Preliminary evidence in this preclinical model suggests that inhibiting the function of these receptors may decrease the ability of cancer cells to disseminate to other sites and/or block their ability to survive and form tumors. Therefore, manipulation of the chemokine network could have therapeutic potential in human malignancies.
SourceAvailable from: María Vela[Show abstract] [Hide abstract]
ABSTRACT: The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on direct-ing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize sig-naling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications.Frontiers in Immunology 01/2015; 6. DOI:10.3389/fimmu.2015.00012
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ABSTRACT: Metastasis is the main cause of cancer treatment failure and death. However, current therapies are designed to impair carcinoma metastasis mainly by impairing initial dissemination events. CXCR4 is a G-protein coupled receptor that exclusively binds its ligand CXCL12, which can stimulate cells to metastasize to distant sites. As the antagonist of chemokine receptor CXCR4, Peptide S exhibited anti-metastasis effect. In order to enhance treatment efficiency through destroying primary tumors and inhibiting their metastases, we combined PEGylated doxorubicin-loaded liposomes (DOX-Lip) with anti-metastasis Peptide S for tumor therapy for the first time. DOX-Lip exhibited similar cytotoxic activity compared to free DOX in vitro, and Peptide S showed no toxic effect on cell viability. However, the Peptide S sensitized CXCR4-positive B16F10 melanoma cells to DOX-Lip (5 μM) when cocultured with stromal cells (50.18 ± 0.29% of viable cells in the absence of Peptide S vs 33.70 ± 3.99% of viable cells in the presence of Peptide S). Both Peptide S and DOX-Lip inhibited the adhesion of B16F10 cells to stromal cells. We further confirmed that the inhibition of phosphorylated Akt (pAkt) by Peptide S played a key role due to the fact that activation of pAkt by DOX-Lip promoted resistance to chemotherapy. Migration and invasion assays showed that DOX-Lip enhanced anti-metastasis effect of Peptide S in vitro because of the cytotoxicity of doxorubicin. In vivo studies also showed that the combined treatment with DOX-Lip and Peptide S not only retarded primary tumor growth, but also reduced lung metastasis. Both the DOX-Lip and DOX-Lip + Peptide S exhibited even more outstanding tumor inhibition effect (with tumor growth inhibition rates of 32.1% and 37.9% respectively). In conclusion, our combined treatment with CXCR4 antagonist and liposomal doxorubicin was proved to be promising for antitumor and anti-metastasis therapy.Journal of Controlled Release 12/2014; 196. DOI:10.1016/j.jconrel.2014.10.017 · 7.26 Impact Factor
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ABSTRACT: Chemokines mediate numerous physiological and pathological processes related primarily to cell homing and migration. The chemokine CXCL12, also known as stromal cell-derived factor-1, binds the G-protein-coupled receptor CXCR4, which, through multiple divergent pathways, leads to chemotaxis, enhanced intracellular calcium, cell adhesion, survival, proliferation, and gene transcription. CXCR4, initially discovered for its involvement in HIV entry and leukocytes trafficking, is overexpressed in more than 23 human cancers. Cancer cell CXCR4 overexpression contributes to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance. CXCR4 antagonism has been shown to disrupt tumor-stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden. As such, CXCR4 is a target not only for therapeutic intervention but also for noninvasive monitoring of disease progression and therapeutic guidance. This review provides a comprehensive overview of the biological involvement of CXCR4 in human cancers, the current status of CXCR4-based therapeutic approaches, as well as recent advances in noninvasive imaging of CXCR4 expression.Advances in Cancer Research 01/2014; 124:31-82. DOI:10.1016/B978-0-12-411638-2.00002-1 · 4.26 Impact Factor