title: Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain.
abstract: Solid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Since acidosis is algogenic for sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid-sensing nociceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
authors: Department of Medicine, Hematology/Oncology, Indiana University School of Medicine, 980 W. Walnut Street, Indianapolis, IN 46202, USA. Electronic address: toshyone@iu.edu.
authors: Toshiyuki
authors: T
authors: Yoneda
authors: Department of Medicine, Hematology/Oncology, Indiana University School of Medicine, 980 W. Walnut Street, Indianapolis, IN 46202, USA. Electronic address: mhiasa@iu.edu.
authors: Masahiro
authors: M
authors: Hiasa
authors: Department of Medicine, Hematology/Oncology, Indiana University School of Medicine, 980 W. Walnut Street, Indianapolis, IN 46202, USA. Electronic address: nagatay@iu.edu.
authors: Yuki
authors: Y
authors: Nagata
authors: Department of Medicine, Hematology/Oncology, Indiana University School of Medicine, 980 W. Walnut Street, Indianapolis, IN 46202, USA. Electronic address: tokui@iupui.edu.
authors: Tatsuo
authors: T
authors: Okui
authors: Department of Anesthesia, Paul and Carole Stark Neurosciences Research Institute, Indiana University, 320 West 15th Street, Indianapolis, IN 46202, USA. Electronic address: fawhite@iu.edu.
authors: Fletcher
authors: F
authors: White
mesh_terms: D062565:Acid Sensing Ion Channels / Q000235:genetics / Q000378:metabolism; D000700:Analgesics / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010146:Pain / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011522:Protons; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D000700:Analgesics; D027501:Monocarboxylic Acid Transporters; D011522:Protons; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D019344:Lactic Acid
keywords: ASIC3; Bone metastasis; Monocarboxylate transporters; Osteoclastic bone resorption; TRPV1; Warburg effect