Ion Channels in Cancer: Orchestrators of Electrical Signaling and Cellular Crosstalk
Ion channels are pore-forming transmembrane proteins that govern ion flux to regulate a myriad of biological processes in development, physiology, and disease. Across various types of cancer, ion channel expression and activity are often dysregulated. We
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Ion Channels in Cancer: Orchestrators of Electrical Signaling and Cellular Crosstalk Jerry J. Fan and Xi Huang
Contents 1 Introduction 1.1 Tumor Heterogeneity and the Multi-Step Tumorigenic Process Are Necessary Considerations for Personalized Cancer Medicine 1.2 Why Target Ion Channels in Cancer? 1.3 Criteria for Selection of Studies in this Review 2 Ion Channel Expression in Human Cancer 2.1 Dysregulated Expression 2.2 Structural Variations and Copy Number Alterations 2.3 Mutations 2.4 Ion Channel Expression and Tumor Heterogeneity 3 Ion Channel Functions in Tumorigenesis 3.1 Ion Channels in Tumor Initiation 3.2 Ion Channels in Tumor Progression 3.3 Ion Channels in Metastasis 3.4 Ion Channels in Therapeutic Resistance and Tumor Recurrence 3.5 Therapeutic Potential of Targeting Ion Channels 4 Emergent Areas of Ion Channels in Cancer and Outlook 4.1 Ion Channels in Governing Local Ion Milieu 4.2 Ion Channels in Regulating Cell-Cell Interactions 4.3 Ion Channels in Sensing and Responding to Mechanical Environment References
Abstract Ion channels are pore-forming transmembrane proteins that govern ion flux to regulate a myriad of biological processes in development, physiology, and disease. Across various types of cancer, ion channel expression and activity are often J. J. Fan (*) and X. Huang (*) Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada e-mail: [email protected]; [email protected]
J. J. Fan and X. Huang
dysregulated. We review the contribution of ion channels to multiple stages of tumorigenesis based on data from in vivo model systems. As intertumoral and intratumoral heterogeneities are major obstacles in developing effective therapies, we provide perspectives on how ion channels in tumor cells and their microenvironment represent targetable vulnerabilities in the areas of tumor-stromal cell interactions, cancer neuroscience, and cancer mechanobiology. Keywords Bioelectrical signaling · Cancer · Ion channels · Mechanobiology · Membrane potential · Metastasis · Tumor heterogeneity · Tumor initiation · Tumor microenvironment · Tumor progression
1 Introduction 1.1
Tumor Heterogeneity and the Multi-Step Tumorigenic Process Are Necessary Considerations for Personalized Cancer Medicine
Cancer is the second leading cause of death worldwide. Current standard-of-care is often non-specific and toxic to normal cells, causing side effects which reduce quality of life in survivors. Targeted therapeutic strategies have been developed through efforts in cancer genomics. Identification of oncogenic mutations, cellular mechanisms, and signaling networks have aided risk stratification and prediction of therapeutic response (The Cancer Genome Atlas Research Network 2008, 2011, 2012; The Cancer Genome Atlas Network 2012a, b). Tumorigenesis is a multi-step process which drives normal ce
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