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Articles in PresS. Am J Physiol Cell Physiol (May 25, 2011). doi:10.1152/ajpcell.00159.2011 1 2 3 American Journal of Physiology Cell Physiology Theme: Ion Channels and Transporters in 4 Cancer 5 6 Annarosa Arcangeli1 and Jason X.-J. Yuan2 7 8 9 1 Department of Experimental Pathology and Oncology, University of Firenze, and Istituto Toscano Tumori, 50134 Firenze, Italy; and 2Departments of Medicine and Pharmacology, 10 Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University 11 of Illinois at Chicago, Chicago, IL 60612, USA 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Address for reprint requests and other correspondence: Dr. Annarosa Arcangeli Dipartimento di Patologia e Oncologia Sperimentali, Università di Firenze, Viale GB Morgagni, 50, 50134, Firenze, Italy E-mail: [email protected] Tel: +39-055-4598206 Fax: +39-055-4598900 Dr. Jason X-J. Yuan Department of Medicine, Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue (MC 719), COMRB 3131, Chicago, IL 60612, USA E-mail: [email protected] Tel: (312)355-5911 Fax: (312)996-7193 Copyright © 2011 by the American Physiological Society. 35 36 In this issue, the American Journal of Physiology Cell Physiology initiates the publication 37 of a new Theme series of review articles that focus on the pathogenic role of ion channels and 38 transporters in cancer. Ion channels, as an important family of membrane proteins that are highly 39 expressed in virtually all types of cells, not only regulate cell excitability, muscle contraction, 40 and glandular secretion. Activity of various ion channels in the plasma membrane and 41 intracellular organelle membranes also plays an important role in regulating cell proliferation, 42 migration, apoptosis and differentiation, cellular functions and processes that are traditionally 43 considered to be regulated by intracellular signaling proteins and transcription factors. We hope 44 that this series of reviews will bring to readers a new concept regarding the potential role of ion 45 channels in cancer and help provide a rationale for the targeting of ion channels and their 46 chaperones as a new approach for the treatment of cancer. 47 48 A neoplasm as a result of neoplasia (from the Greek term meaning “new growth”), or the 49 synonymous term “tumor” (from the Latin term meaning “swelling”), was defined by the British 50 oncologist R.A. Willis in 1952 as “an abnormal mass of tissue, the growth of which exceeds and 51 is uncoordinated with that of the normal tissue, and persists in the same excessive manner after 52 cessation of the stimulus which evoked the change.” The basic characteristic of tumor (or a 53 neoplasm) is hence its abnormal “growth”. To understand tumor growth, we must not forget 54 what Theodor Boveri, an eminent pathologist, wrote in 1914: “When I published the results of 55 my experiments on the development of double-fertilized sea-urchin eggs in 1902, I added the 56 suggestion that malignant tumors might be the result of a certain abnormal condition of the 57 chromosomes, which may arise from multipolar mitosis.” 58 59 Indeed the excessive and uncoordinated growth of tumors relies on the fact that cancer 60 cells are mutants. They often carry somatic mutations of specific (most likely growth-related) 61 genes, although other modifications possibly caused by epigenetic mechanisms, such as gene 62 amplification or inactivation, can also occur. The systematic search for genes that are particularly 63 susceptible to mutation during carcinogenesis has helped in showing that cancer is a multistep 64 process, a concept that and is summarized in the notion of “tumor progression.” The term 65 “cancer”, synonymous of neoplasm (as a result of neoplasia) and tumor, more precisely includes 66 the process of invading surrounding tissues by malignant cells during the course of tumor 67 progression. The concept of “cancer” as a multistep process involves the progressive (but 68 sometimes via very rapid progression) acquisition of genetic alterations, leading to the setting of 69 malignancy. In this process, the early steps may involve alterations of a relatively small number 70 of genes implicated in cell proliferation, apoptosis and differentiation. As a consequence, cell 71 clones are produced that resist apoptosis and are capable of unlimited proliferation. However the 72 tumor mass is restrained in its growth by the lack of an appropriate blood supply (the lack of 73 which can create hypoxia) and by the hindrance operated by the surrounding tissue. Both these 74 impediments need to be overcome. Hence tumor cells promote angiogenesis and, at later stages, 75 undergo new genotypic (with new mutations/genetic alterations in different pathways) and 76 phenotypic features are selected that enable cells to invade and colonize (metastasize) 77 neighboring or even distant tissue, and eventually to evade and overcome immune response. 78 79 The molecular dissection of neoplastic progression potentially opens the way to the 80 development of drugs addressing tumor-specific processes. The many recent efforts devoted to 81 this task have led to substantial improvement in treatment. For instance, novel selective 82 inhibitors of tyrosine kinase receptors and non-receptor tyrosine kinases, pivotal regulators of 83 cell survival and proliferation, as well as of the angiogenic process (e.g., inhibitors of vascular 84 endothelial growth factor), have been developed for cancer treatment. By combining new 85 targeted agents with traditional chemotherapy, survival of some patients can often be prolonged. 86 87 Ion channels and transporters in the plasma membrane (and intracellular organelle 88 membranes) are an emerging class of molecules or proteins that may represent good targets for 89 developing antineoplastic therapy. Why ion channels? First of all, their expression is often 90 grossly altered in human cancers. Secondly, channel dysfunction can have a strong impact on 91 cell function and signaling, with ensuing effects on cancer progression. Thirdly, ion channels are 92 a pharmaceutically tractable molecular class. A major advantage is their accessibility from the 93 extracellular side. Thus, the study of the role of ion channels in the different aspects of tumor 94 progression has the potential to unravel new therapeutic approaches. 95 96 This Theme series includes review articles in which renowned experts discuss current 97 findings and progress on: a) the functional role of ion channels (and transporters) in tumor cell 98 proliferation, apoptosis, differentiation and migration; b) the role of ion channels in tumor cell- 99 microenvironment cross talk; c) the role of intracellular Ca2+ signaling in tumorigenesis and 100 tumor angiogenesis; d) the pathogenic role of ion channels and transporters in tumor progression; 101 and e) the role of ion channels and membrane potential in cancer stem cell proliferation. 102 103 There are more than 400 genes encoding ion channel subunits that regulate the flow of 104 ions (e.g., Ca2+, Na+, K+, H+, Cl-, HCO3-) across the plasma membrane (and the intracellular 105 organelle membrane). Many of the ion channel genes have been shown to play a critical role in 106 the pathogenesis of various diseases including cancer. One of the grand challenges of ion 107 channel research is to identify the specific subtype of ion channels that plays a pathogenic role in 108 cancer (tumorigenesis, tumor progression, tumor metastasis, and tumor angiogenesis) and to 109 develop specific blockers (and openers) for the channel as tumor suppressants. 110 111 The topic “Ion channels and transporters in cancer” is a broad field that fits in quite well 112 with the mission of American Journal of Physiology Cell Physiology. We invite your feedback 113 about this series of review articles on this topic, and sincerely encourage readers to submit 114 original work on ion channels in cancer to the American Journal of Physiology Cell Physiology. 115