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Background: Cancer-related inflammation is recognized as a driver for tumor progression and chemokines are important players in both inflammation and the progression of many cancer types. CXC chemokines, especially CXCL8, have been implicated in melanoma growth and metastasis, while less is known for their roles in drug resistance., Methods: We generated drug-resistant cells by continuous exposure to chemotherapeutic drugs and analyzed the mechanism(s) of therapy resistance in malignant melanoma., Results: We report chemotherapies induced upregulation of a variety of chemokines in the CXCR1/CXCR2 network by an NF-κB-dependent mechanism. Notably, analysis of the drug-resistant melanoma cell line selected after prolonged exposure to chemotherapeutic drug dacarbazine revealed higher levels of CXCL8 and CXCR2 compared with parent cells as a signature of drug resistance. CXCR2 neutralization markedly improved sensitivity to dacarbazine in melanoma cells., Conclusion: These data provide insights into what drives melanoma cells to survive after chemotherapy treatment, thus pointing to strategies for developing combined drug therapies for combating the problem of chemotherapy resistance in melanoma., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.) more...

Tumor-induced immunosuppression is a fundamental problem in cancer immunotherapy and can occur by a variety of cellular and molecular mechanisms, affecting all arms of the immune system. Tumor-produced or elicited factors have been shown to inhibit antigen-specific immune effector function as well as impairment of the development, recruitment and maturation of dendritic cells (DCs) and T cells. A better understanding of the cross-talk between tumors and tumor-associated DCs and T cells is necessary to develop novel approaches for cancer immunotherapy. The recruitment of DCs to tumors, antigen processing and presentation, and migration of antigen-loaded DCs to secondary lymphoid organs are perturbed in tumor-bearing hosts. The ability of tumor-associated DCs to induce an anti-tumor response may be prevented by the tumor microenvironment due to inhibitory factors such as vascular endothelial growth factor (VEGF)-C, which are also known to regulate tumor angiogenesis and lymphangiogenesis. Strategies to inhibit tumor-induced angiogenesis and immunosuppression provide therapeutic approaches with the potential for synergism. In this review we will discuss the possibilities of developing novel approaches to concurrently inhibit angiogenesis, inhibit lymphangiogenesis, eliminate tumor-induced immunosuppression and augment the anti-tumor immune as potent multi-modality therapeutic strategies for metastatic cancer. more...