Pharma Focus Asia

Cytokines In Cancer Drug Resistance: Cues To New Therapeutic Strategies

Authors: Valerie Sloane Jones, Ren-Yu Huang, Li-Pai Chen, Zhe-Sheng Chend, Liwu Fu, Ruo-Pan Huang

Abstract:

The development of oncoprotein-targeted anticancer drugs is an invaluable weapon in the war against cancer. However, cancers do not give up without a fight. They may develop multiple mechanisms of drug resistance, including apoptosis inhibition, drug expulsion, and increased proliferation that reduce the effectiveness of the drug. The collective work of researchers has highlighted the role of cytokines in the mechanisms of cancer drug resistance, as well as in cancer cell progression. Furthermore, recent studies have described how specific cytokines secreted by cancer stromal cells confer resistance to chemotherapeutic treatments. In order to gain a better understanding of mechanism of cancer drug resistance and a prediction of treatment outcome, it is imperative that correlations are established between global cytokine profiles and cancer drug resistance. Here we discuss the recent discoveries in this field of research and discuss their implications for the future development of effective anti-cancer medicines.

Abbreviations

 AM, adrenomedullin; AMF, autocrine motility factor; AML, acute myeloid leukemia; BCL, B-cell lymphoma; BCR, breakpoint cluster region; BM, bone marrow; CCL, chemokine (C?C motif) ligand; CML, chronic myeloid leukemia; ECM, extracellular matrix; EGF, epidermal growth factor; EMT, epithelial–mesenchymal transition; FGF, fibroblast growth factor; G-CSF, granulocyte colony stimulating factor; GEM, gemcitabine monotherapy; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; IL, interleukin; Mcl-1, myeloid cell leukemia-1; MDR, multidrug resistance; MMP, matrix metalloproteinase; MRCC, metastatic renal cell carcinoma; NGAL, neutrophil gelatinase-associated lipocalin; PARP, poly ADP-ribose polymerase; PFS, progression-free survival; PI3, phosphoinositide 3; PSCs, pancreatic stellate cells; RANTES, regulated on activation, normal T cell expressed and secreted; SDF-1, stromal cell-derived factor-1; STAT3, signal transducer and activator of transcription 3; TGF, transforming growth factor; TKI, tyrosine kinase inhibitor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor

Keywords

Cytokine; Cancer drug resistance; Stromal cells; Tumor microenvironment; Antibody array; Multiplex immunoassay

Citation: Valerie Sloane Jones, Ren-Yu Huang, Li-Pai Chen, Zhe-Sheng Chend, Liwu Fu, Ruo-Pan Huang Cytokines In Cancer Drug Resistance: Cues To New Therapeutic Strategies doi:10.1016/j.bbcan.2016.03.005.

Received: 27 December 2015, Revised: 11 March 2016, Accepted: 13 March 2016, Available online: 16 March 2016

Copyright:© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Conclusion

Resistance to chemotherapy and oncoprotein-targeted drugs remains the biggest impediment in oncology, disrupting the long term success of treatment of cancer patients. In this review, we described and assessed examples of the mechanisms by which cells and tissues develop resistance against chemotherapy drugs, particularly those involving altered cytokine expression and their downstream signaling networks. As mentioned earlier, our understanding of the molecular mechanisms of chemoresistance is woefully incomplete. The studies described here however, have contributed foundational insights, identifying several key pathways which cancer cells commonly hyperactivate or block in order to evade targeted therapeutic agents. These pathway perturbations are caused by (or result in) a telltale cytokine signature. Individually, these cytokines can stimulate tumor-promoting pathways through autocrine loops and/or paracrine mechanisms emanating from re-educated stromal cells. Collectively, these cytokines contribute to a TME which is permissive to tumor progression and drug resistance

Acknowledgments

We would like to express our thanks to the following for the support of RayBiotech: The Innovative Research Fund, Guangdong innovative research team program (201001s0104659419), Foundation of Enterprise University Research Institute Cooperation of Guangdong Province and Ministry of Education of China (2012B090600021), Special program for the development of technology business incubators in Guangzhou (2013J4200016), Foundation of Enterprise University Research Institute Cooperation of Guangdong Province and Ministry of Education of China (2012B091000145), National High Technology Research and Development Program 863 (2014AA020905), ‘Five-twelfth’ National Science and Technology Support Program (2012EP001000), UK-China (Guangzhou) Healthtech Open Innovation (2014Q-P037), and the Guangdong Provincial Science and Technology SME Technology Innovation Fund Program (2015A010101492).

Statement of conflict of interest

All of the authors of this paper are employees of RayBiotech, Inc., a company producing commercial antibody arrays which were used in some cited references.

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