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Articles in PresS. Am J Physiol Cell Physiol (May 25, 2011). doi:10.1152/ajpcell.00159.2011
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American Journal of Physiology Cell Physiology Theme: Ion Channels and Transporters in
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Cancer
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Annarosa Arcangeli1 and Jason X.-J. Yuan2
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Department of Experimental Pathology and Oncology, University of Firenze, and Istituto
Toscano Tumori, 50134 Firenze, Italy; and 2Departments of Medicine and Pharmacology,
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Institute for Personalized Respiratory Medicine, Center for Cardiovascular Research, University
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of Illinois at Chicago, Chicago, IL 60612, USA
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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.
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In this issue, the American Journal of Physiology Cell Physiology initiates the publication
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of a new Theme series of review articles that focus on the pathogenic role of ion channels and
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transporters in cancer. Ion channels, as an important family of membrane proteins that are highly
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expressed in virtually all types of cells, not only regulate cell excitability, muscle contraction,
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and glandular secretion. Activity of various ion channels in the plasma membrane and
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intracellular organelle membranes also plays an important role in regulating cell proliferation,
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migration, apoptosis and differentiation, cellular functions and processes that are traditionally
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considered to be regulated by intracellular signaling proteins and transcription factors. We hope
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that this series of reviews will bring to readers a new concept regarding the potential role of ion
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channels in cancer and help provide a rationale for the targeting of ion channels and their
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chaperones as a new approach for the treatment of cancer.
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A neoplasm as a result of neoplasia (from the Greek term meaning “new growth”), or the
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synonymous term “tumor” (from the Latin term meaning “swelling”), was defined by the British
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oncologist R.A. Willis in 1952 as “an abnormal mass of tissue, the growth of which exceeds and
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is uncoordinated with that of the normal tissue, and persists in the same excessive manner after
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cessation of the stimulus which evoked the change.” The basic characteristic of tumor (or a
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neoplasm) is hence its abnormal “growth”. To understand tumor growth, we must not forget
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what Theodor Boveri, an eminent pathologist, wrote in 1914: “When I published the results of
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my experiments on the development of double-fertilized sea-urchin eggs in 1902, I added the
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suggestion that malignant tumors might be the result of a certain abnormal condition of the
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chromosomes, which may arise from multipolar mitosis.”
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Indeed the excessive and uncoordinated growth of tumors relies on the fact that cancer
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cells are mutants. They often carry somatic mutations of specific (most likely growth-related)
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genes, although other modifications possibly caused by epigenetic mechanisms, such as gene
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amplification or inactivation, can also occur. The systematic search for genes that are particularly
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susceptible to mutation during carcinogenesis has helped in showing that cancer is a multistep
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process, a concept that and is summarized in the notion of “tumor progression.” The term
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“cancer”, synonymous of neoplasm (as a result of neoplasia) and tumor, more precisely includes
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the process of invading surrounding tissues by malignant cells during the course of tumor
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progression. The concept of “cancer” as a multistep process involves the progressive (but
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sometimes via very rapid progression) acquisition of genetic alterations, leading to the setting of
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malignancy. In this process, the early steps may involve alterations of a relatively small number
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of genes implicated in cell proliferation, apoptosis and differentiation. As a consequence, cell
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clones are produced that resist apoptosis and are capable of unlimited proliferation. However the
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tumor mass is restrained in its growth by the lack of an appropriate blood supply (the lack of
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which can create hypoxia) and by the hindrance operated by the surrounding tissue. Both these
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impediments need to be overcome. Hence tumor cells promote angiogenesis and, at later stages,
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undergo new genotypic (with new mutations/genetic alterations in different pathways) and
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phenotypic features are selected that enable cells to invade and colonize (metastasize)
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neighboring or even distant tissue, and eventually to evade and overcome immune response.
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The molecular dissection of neoplastic progression potentially opens the way to the
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development of drugs addressing tumor-specific processes. The many recent efforts devoted to
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this task have led to substantial improvement in treatment. For instance, novel selective
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inhibitors of tyrosine kinase receptors and non-receptor tyrosine kinases, pivotal regulators of
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cell survival and proliferation, as well as of the angiogenic process (e.g., inhibitors of vascular
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endothelial growth factor), have been developed for cancer treatment. By combining new
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targeted agents with traditional chemotherapy, survival of some patients can often be prolonged.
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Ion channels and transporters in the plasma membrane (and intracellular organelle
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membranes) are an emerging class of molecules or proteins that may represent good targets for
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developing antineoplastic therapy. Why ion channels? First of all, their expression is often
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grossly altered in human cancers. Secondly, channel dysfunction can have a strong impact on
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cell function and signaling, with ensuing effects on cancer progression. Thirdly, ion channels are
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a pharmaceutically tractable molecular class. A major advantage is their accessibility from the
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extracellular side. Thus, the study of the role of ion channels in the different aspects of tumor
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progression has the potential to unravel new therapeutic approaches.
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This Theme series includes review articles in which renowned experts discuss current
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findings and progress on: a) the functional role of ion channels (and transporters) in tumor cell
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proliferation, apoptosis, differentiation and migration; b) the role of ion channels in tumor cell-
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microenvironment cross talk; c) the role of intracellular Ca2+ signaling in tumorigenesis and
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tumor angiogenesis; d) the pathogenic role of ion channels and transporters in tumor progression;
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and e) the role of ion channels and membrane potential in cancer stem cell proliferation.
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There are more than 400 genes encoding ion channel subunits that regulate the flow of
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ions (e.g., Ca2+, Na+, K+, H+, Cl-, HCO3-) across the plasma membrane (and the intracellular
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organelle membrane). Many of the ion channel genes have been shown to play a critical role in
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the pathogenesis of various diseases including cancer. One of the grand challenges of ion
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channel research is to identify the specific subtype of ion channels that plays a pathogenic role in
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cancer (tumorigenesis, tumor progression, tumor metastasis, and tumor angiogenesis) and to
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develop specific blockers (and openers) for the channel as tumor suppressants.
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The topic “Ion channels and transporters in cancer” is a broad field that fits in quite well
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with the mission of American Journal of Physiology Cell Physiology. We invite your feedback
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about this series of review articles on this topic, and sincerely encourage readers to submit
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original work on ion channels in cancer to the American Journal of Physiology Cell Physiology.
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