{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T05:38:59Z","timestamp":1793770739427,"version":"4.6.1"},"reference-count":166,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["AIRC IG 2018, grant number 21403."],"award-info":[{"award-number":["AIRC IG 2018, grant number 21403."]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In bone sarcomas, extracellular proton accumulation is an intrinsic driver of malignancy. Extracellular acidosis increases stemness, invasion, angiogenesis, metastasis, and resistance to therapy of cancer cells. It reprograms tumour-associated stroma into a protumour phenotype through the release of inflammatory cytokines. It affects bone homeostasis, as extracellular proton accumulation is perceived by acid-sensing ion channels located at the cell membrane of normal bone cells. In bone, acidosis results from the altered glycolytic metabolism of bone cancer cells and the resorption activity of tumour-induced osteoclasts that share the same ecosystem. Proton extrusion activity is mediated by extruders and transporters located at the cell membrane of normal and transformed cells, including vacuolar ATPase and carbonic anhydrase IX, or by the release of highly acidic lysosomes by exocytosis. To date, a number of investigations have focused on the effects of acidosis and its inhibition in bone sarcomas, including studies evaluating the use of photodynamic therapy. In this review, we will discuss the current status of all findings on extracellular acidosis in bone sarcomas, with a specific focus on the characteristics of the bone microenvironment and the acid-targeting therapeutic approaches that are currently being evaluated.<\/jats:p>","DOI":"10.3390\/cancers13153848","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"3848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Acid Microenvironment in Bone Sarcomas"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5121-4330","authenticated-orcid":false,"given":"Gemma","family":"Di Pompo","sequence":"first","affiliation":[{"name":"Biomedical Science and Technologies Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Cortini","sequence":"additional","affiliation":[{"name":"Biomedical Science and Technologies Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Baldini","sequence":"additional","affiliation":[{"name":"Biomedical Science and Technologies Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"},{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-0591","authenticated-orcid":false,"given":"Sofia","family":"Avnet","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.ejca.2012.09.011","article-title":"Descriptive epidemiology of sarcomas in Europe: Report from the RARE CARE project","volume":"49","author":"Stiller","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E508","DOI":"10.1002\/ijc.26426","article-title":"Incidence and survival of malignant bone sarcomas in England 1979\u20132007","volume":"131","author":"Whelan","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s10552-015-0607-3","article-title":"Bone cancer incidence by morphological subtype: A global assessment","volume":"26","author":"Valery","year":"2015","journal-title":"Cancer Causes Control"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/s00223-017-0372-2","article-title":"Biology of bone sarcomas and new therapeutic developments","volume":"102","author":"Brown","year":"2018","journal-title":"Calcif. Tissue Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1080\/13543784.2016.1237503","article-title":"Drugs in early clinical development for the treatment of osteosarcoma","volume":"25","author":"Heymann","year":"2016","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1517\/14728214.2013.823948","article-title":"Drugs targeting the bone microenvironment: New therapeutic tools in Ewing\u2019s sarcoma?","volume":"18","author":"Redini","year":"2013","journal-title":"Expert Opin. Emerg. Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e11131","DOI":"10.15252\/emmm.201911131","article-title":"Sarcoma treatment in the era of molecular medicine","volume":"12","author":"Grunewald","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s10555-019-09792-7","article-title":"Causes, consequences and therapy of tumors acidosis","volume":"38","author":"Pillai","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e229","DOI":"10.5301\/jbm.5000216","article-title":"Hypoxia-inducible factor-1 expression predicts osteosarcoma patients' survival: A meta-analysis","volume":"31","author":"Ouyang","year":"2016","journal-title":"Int. J. Biol. Markers"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yang, C., Tian, Y., Zhao, F., Chen, Z., Su, P., Li, Y., and Qian, A. (2020). Bone microenvironment and osteosarcoma metastasis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21196985"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hiraga, T. (2018). Hypoxic microenvironment and metastatic bone disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113523"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.semcancer.2017.01.008","article-title":"Therapeutic implications of tumor interstitial acidification","volume":"43","author":"Kolosenko","year":"2017","journal-title":"Semin. Cancer Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1016\/j.bbamem.2014.10.015","article-title":"Proton channels and exchangers in cancer","volume":"1848","author":"Spugnini","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.2174\/0929867323666161228142849","article-title":"Pathobiology and therapeutic implications of tumor acidosis","volume":"24","author":"Viklund","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3109\/02656739509022457","article-title":"Extracellular pH distribution in human tumours","volume":"11","author":"Engin","year":"1995","journal-title":"Int. J. Hyperth."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.bbadis.2013.04.003","article-title":"V-ATPase is a candidate therapeutic target for Ewing sarcoma","volume":"1832","author":"Avnet","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"435","DOI":"10.3389\/fcell.2020.00435","article-title":"Role of altered metabolic microenvironment in osteolytic metastasis","volume":"8","author":"Tiedemann","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1016\/j.bbadis.2017.08.030","article-title":"MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases","volume":"1863","author":"Lemma","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.ejso.2016.04.056","article-title":"Positron emission tomography (18)F-fluorodeoxyglucose uptake and prognosis in patients with bone and soft tissue sarcoma: A meta-analysis","volume":"42","author":"Li","year":"2016","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The metabolism of tumors in the body","volume":"8","author":"Warburg","year":"1927","journal-title":"J. Gen. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1002\/jcp.29921","article-title":"\u201cTake My Bone Away?\u201c hypoxia and bone: A narrative review","volume":"236","author":"Hannah","year":"2021","journal-title":"J. Cell Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nature13034","article-title":"Direct measurement of local oxygen concentration in the bone marrow of live animals","volume":"508","author":"Spencer","year":"2014","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1111\/cas.13990","article-title":"Hypoxia\/pseudohypoxia-mediated activation of hypoxia-inducible factor-1alpha in cancer","volume":"110","author":"Hayashi","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6463","DOI":"10.1158\/0008-5472.CAN-16-0825","article-title":"In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging","volume":"76","author":"Longo","year":"2016","journal-title":"Cancer Res."},{"key":"ref_26","first-page":"1215","article-title":"Quantitative [F-18] fluorodeoxyglucose positron emission tomography in pretreatment and grading of sarcoma","volume":"4","author":"Eary","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_27","first-page":"428","article-title":"Preclinical PET tracers for the evaluation of sarcomas: Understanding tumor biology","volume":"8","author":"Sigal","year":"2018","journal-title":"Am. J. Nucl. Med. Mol. Imaging"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrc.2017.77","article-title":"Tumour acidosis: From the passenger to the driver\u2019s seat","volume":"17","author":"Corbet","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1113\/JP278810","article-title":"Revisiting the Warburg effect: Historical dogma versus current understanding","volume":"599","author":"Vaupel","year":"2021","journal-title":"J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Van Uden, P., Kenneth, N.S., Webster, R., Muller, H.A., Mudie, S., and Rocha, S. (2011). Evolutionary conserved regulation of HIF-1\u03b2 by NF-kB. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1001285"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1042\/BJ20080476","article-title":"Regulation of hypoxia-inducible factor-1alpha by NF-kappaB","volume":"412","author":"Kenneth","year":"2008","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1002\/ijc.30540","article-title":"Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-kB activation","volume":"140","author":"Avnet","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1038\/sj.cdd.4401466","article-title":"Alterations of intracellular pH homeostasis in apoptosis: Origins and roles","volume":"11","author":"Huc","year":"2004","journal-title":"Cell Death Differ."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.yexcr.2013.10.011","article-title":"V-ATPase as an effective therapeutic target for sarcomas","volume":"320","author":"Perut","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Salerno, M., Avnet, S., Bonuccelli, G., Hosogi, S., Granchi, D., and Baldini, N. (2014). Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110340"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mboge, M.Y., Mahon, B.P., McKenna, R., and Frost, S.C. (2018). Carbonic anhydrases: Role in pH control and cancer. Metabolites, 8.","DOI":"10.3390\/metabo8010019"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"63408","DOI":"10.18632\/oncotarget.11503","article-title":"Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance","volume":"7","author":"Avnet","year":"2016","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"67482","DOI":"10.18632\/oncotarget.18713","article-title":"Restoring microenvironmental redox and pH homeostasis inhibits neoplastic cell growth and migration: Therapeutic efficacy of esomeprazole plus sulfasalazine on 3-MCA-induced sarcoma","volume":"8","author":"Balza","year":"2017","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"578","DOI":"10.5301\/tj.5000243","article-title":"Inhibition of hypoxia-inducible factor-1 alpha radiosensitized MG-63 human osteosarcoma cells in vitro","volume":"101","author":"Jin","year":"2015","journal-title":"Tumori"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1517\/14728222.2016.1086339","article-title":"Carbonic anhydrase IX inhibition is an effective strategy for osteosarcoma treatment","volume":"19","author":"Perut","year":"2015","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.bbrc.2019.03.040","article-title":"Hypoxia promotes osteosarcoma cell proliferation and migration through enhancing platelet-derived growth factor-BB\/platelet-derived growth factor receptor-beta axis","volume":"512","author":"Zhang","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7989","DOI":"10.1007\/s13277-015-4661-y","article-title":"Oncogenic roles of carbonic anhydrase 8 in human osteosarcoma cells","volume":"37","author":"Wang","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Staab, A., Loeffler, J., Said, H.M., Diehlmann, D., Katzer, A., Beyer, M., Fleischer, M., Schwab, F., Baier, K., and Einsele, H. (2007). Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer, 7.","DOI":"10.1186\/1471-2407-7-213"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1016\/j.bmc.2015.02.038","article-title":"Design, synthesis, and structure-activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors","volume":"23","author":"Yasuda","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/j.1365-2559.2010.03528.x","article-title":"Correlation of hypoxic signalling to histological grade and outcome in cartilage tumours","volume":"56","author":"Boeuf","year":"2010","journal-title":"Histopathology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.canlet.2013.08.042","article-title":"Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-kappaB pathway","volume":"342","author":"Zhao","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7575","DOI":"10.18632\/oncotarget.2243","article-title":"Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells","volume":"5","author":"Bonuccelli","year":"2014","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4278","DOI":"10.12659\/MSM.912272","article-title":"Monocarboxylate transporter 4 (MCT4) overexpression is correlated with poor prognosis of osteosarcoma","volume":"25","author":"Liu","year":"2019","journal-title":"Med. Sci. Monit."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nature19828","article-title":"Atomic model for the membrane-embedded VO motor of a eukaryotic V-ATPase","volume":"539","author":"Rohou","year":"2016","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s10555-019-09790-9","article-title":"Cause and effect of microenvironmental acidosis on bone metastases","volume":"38","author":"Avnet","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Supuran, C.T., and Nocentini, A. (2019). Chapter 8\u2014Human carbonic anhydrases: Tissue distribution, physiological role, and druggability. Carbonic Anhydrases, Academic Press.","DOI":"10.1016\/B978-0-12-816476-1.00008-3"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"825","DOI":"10.2174\/156802607780636690","article-title":"Carbonic anhydrases as drug targets\u2014An overview","volume":"7","author":"Supuran","year":"2007","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.1038\/s41598-020-63517-3","article-title":"The voltage-gated proton channel hHv1 is functionally expressed in human chorion-derived mesenchymal stem cells","volume":"10","author":"Meszaros","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.bbrc.2011.07.102","article-title":"Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis","volume":"412","author":"Wang","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Wang, Y., Wu, X., Li, Q., Zhang, S., and Li, S.J. (2013). Human voltage-gated proton channel hv1: A new potential biomarker for diagnosis and prognosis of colorectal cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070550"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"678532","DOI":"10.3389\/fcell.2021.678532","article-title":"Acid-Induced Inflammatory Cytokines in Osteoblasts: A Guided Path to Osteolysis in Bone Metastasis","volume":"9","author":"Errani","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"47675","DOI":"10.18632\/oncotarget.17544","article-title":"Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity","volume":"8","author":"McConnell","year":"2017","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"54478","DOI":"10.18632\/oncotarget.17091","article-title":"Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma","volume":"8","author":"Lemma","year":"2017","journal-title":"Oncotarget"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1158\/1078-0432.CCR-10-2507","article-title":"Molecular pathways: Osteoclast-dependent and osteoclast-independent roles of the RANKL\/RANK\/OPG pathway in tumorigenesis and metastasis","volume":"18","author":"Dougall","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1126\/science.289.5484.1504","article-title":"Bone resorption by osteoclasts","volume":"289","author":"Teitelbaum","year":"2000","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1126\/science.2528207","article-title":"Osteoclastic bone resorption by a polarized vacuolar proton pump","volume":"245","author":"Blair","year":"1989","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.biocel.2016.08.034","article-title":"Energy metabolism in osteoclast formation and activity","volume":"79","author":"Lemma","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/j.biocel.2012.05.014","article-title":"V-ATPases in osteoclasts: Structure, function and potential inhibitors of bone resorption","volume":"44","author":"Qin","year":"2012","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1097\/00003086-199309000-00003","article-title":"Recent advances toward understanding osteoclast physiology","volume":"294","author":"Blair","year":"1993","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1074\/jbc.270.5.2203","article-title":"Regulation of cytoplasmic pH in osteoclasts. Contribution of proton pumps and a proton-selective conductance","volume":"270","author":"Nordstrom","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s00424-016-1931-5","article-title":"Extracellular phosphates enhance activities of voltage-gated proton channels and production of reactive oxygen species in murine osteoclast-like cells","volume":"469","author":"Li","year":"2017","journal-title":"Pflugers Arch. Eur. J. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1007\/s00424-016-1796-7","article-title":"Acid-inducible proton influx currents in the plasma membrane of murine osteoclast-like cells","volume":"468","author":"Kuno","year":"2016","journal-title":"Pflugers Arch. Eur. J. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/sj.clpt.6100450","article-title":"Cathepsin K inhibitors: A novel target for osteoporosis therapy","volume":"83","author":"Stoch","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_69","first-page":"169","article-title":"Management in the context of incomplete evidence","volume":"86","author":"Levallois","year":"1995","journal-title":"Can. J. Public Health"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.canlet.2011.09.023","article-title":"Hypoxia, stem cells and bone tumor","volume":"313","author":"Zeng","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_71","first-page":"1231","article-title":"Increased osteoclast activity is associated with aggressiveness of osteosarcoma","volume":"33","author":"Avnet","year":"2008","journal-title":"Int. J. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1567-5769(01)00134-5","article-title":"Human osteosarcoma-derived cell lines produce soluble factor(s) that induces differentiation of blood monocytes to osteoclast-like cells","volume":"2","author":"Miyamoto","year":"2002","journal-title":"Int. Immunopharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.bone.2015.01.013","article-title":"Intravital bone imaging by two-photon excitation microscopy to identify osteocytic osteolysis in vivo","volume":"74","author":"Sano","year":"2015","journal-title":"Bone"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1002\/jbmr.3167","article-title":"Osteocytes acidify their microenvironment in response to PTHrP in vitro and in lactating mice in vivo","volume":"32","author":"Jahn","year":"2017","journal-title":"J. Bone Miner. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s11914-019-00514-0","article-title":"Investigating osteocytic perilacunar\/canalicular remodeling","volume":"17","author":"Yee","year":"2019","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Petho, Z., Najder, K., Carvalho, T., McMorrow, R., Todesca, L.M., Rugi, M., Bulk, E., Chan, A., Lowik, C., and Reshkin, S.J. (2020). pH-Channeling in cancer: How ph-dependence of cation channels shapes cancer pathophysiology. Cancers, 12.","DOI":"10.3390\/cancers12092484"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1523-1755.2005.00069.x","article-title":"pH dependence of extracellular calcium sensing receptor activity determined by a novel technique","volume":"67","author":"Doroszewicz","year":"2005","journal-title":"Kidney Int."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3389\/fonc.2020.00293","article-title":"Calcium Homeostasis: A potential vicious cycle of bone metastasis in breast cancers","volume":"10","author":"Yang","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"C382","DOI":"10.1152\/ajpcell.2001.280.2.C382","article-title":"Expression of extracellular calcium-sensing receptor in human osteoblastic MG-63 cell line","volume":"280","author":"Yamaguchi","year":"2001","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/978-94-007-2888-2_41","article-title":"Calcium signaling in osteoclast differentiation and bone resorption","volume":"740","author":"Kajiya","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1016\/j.bbamem.2014.08.016","article-title":"Altered calcium signaling in cancer cells","volume":"1848","author":"Stewart","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Cortini, M., Armirotti, A., Columbaro, M., Longo, D.L., Di Pompo, G., Cannas, E., Maresca, A., Errani, C., Longhi, A., and Righi, A. (2021). Exploring metabolic adaptations to the acidic microenvironment of osteosarcoma cells unveils sphingosine 1-phosphate as a valuable therapeutic target. Cancers, 13.","DOI":"10.3390\/cancers13020311"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Holzer, P. (2009). Acid-sensitive ion channels and receptors. Sensory Nerves, Springer.","DOI":"10.1007\/978-3-540-79090-7_9"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.molmed.2010.01.005","article-title":"Ion channels and the hallmarks of cancer","volume":"16","author":"Prevarskaya","year":"2010","journal-title":"Trends Mol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1152\/physrev.00044.2016","article-title":"Ion Channels in cancer: Are cancer hallmarks oncochannelopathies?","volume":"98","author":"Prevarskaya","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fncel.2015.00086","article-title":"Cancer as a channelopathy: Ion channels and pumps in tumor development and progression","volume":"9","author":"Litan","year":"2015","journal-title":"Front. Cell Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"20130098","DOI":"10.1098\/rstb.2013.0098","article-title":"Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment","volume":"369","author":"Andersen","year":"2014","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"19245","DOI":"10.3390\/ijms140919245","article-title":"Voltage-gated potassium channel Kv1.3 is highly expressed in human osteosarcoma and promotes osteosarcoma growth","volume":"14","author":"Wu","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.3892\/ol.2016.4764","article-title":"High expression of TRPM8 predicts poor prognosis in patients with osteosarcoma","volume":"12","author":"Zhao","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.12659\/MSM.906959","article-title":"The function of the novel mechanical activated ion channel piezo1 in the human osteosarcoma cells","volume":"23","author":"Jiang","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"220","DOI":"10.2478\/s11658-006-0067-6","article-title":"The influence of protons and zinc ions on the steady-state inactivation of Kv1.3 potassium channels","volume":"12","author":"Teisseyre","year":"2007","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/sj.bjp.0705652","article-title":"Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay","volume":"141","author":"Behrendt","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1074\/jbc.M114.604033","article-title":"Protonation of the human PIEZO1 ion channel stabilizes inactivation","volume":"290","author":"Bae","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1242\/jcs.008037","article-title":"Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation","volume":"121","author":"Ayala","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_95","first-page":"1127","article-title":"Acid microenvironment promotes cell survival of human bone sarcoma through the activation of cIAP proteins and NF-kB pathway","volume":"9","author":"Avnet","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_96","first-page":"859","article-title":"Tumour-Specific metabolic adaptation to acidosis is coupled to epigenetic stability in osteosarcoma cells","volume":"6","author":"Chano","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/S0006-2952(99)00021-0","article-title":"pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs","volume":"57","author":"Raghunand","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3751","DOI":"10.1038\/sj.onc.1204500","article-title":"Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells","volume":"20","author":"Shi","year":"2001","journal-title":"Oncogene"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/ncb1144","article-title":"HIF activation by pH-dependent nucleolar sequestration of VHL","volume":"6","author":"Mekhail","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"20188","DOI":"10.1074\/jbc.M116.738799","article-title":"Acidic pH Is a Metabolic Switch for 2-Hydroxyglutarate Generation and Signaling","volume":"291","author":"Nadtochiy","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Perut, F., Roncuzzi, L., Zini, N., Massa, A., and Baldini, N. (2019). Extracellular nanovesicles secreted by human osteosarcoma cells promote angiogenesis. Cancers, 11.","DOI":"10.3390\/cancers11060779"},{"key":"ref_102","first-page":"321","article-title":"Tumor microenvironment: Bone marrow-mesenchymal stem cells as key players","volume":"1836","author":"Gori","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1097\/JTO.0b013e3181f8a1bd","article-title":"The role of tumor stroma in cancer progression and prognosis: Emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer","volume":"6","author":"Bremnes","year":"2011","journal-title":"J. Thorac. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.canlet.2009.02.022","article-title":"Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis","volume":"281","author":"Xu","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Perrot, P., Rousseau, J., Bouffaut, A.L., Redini, F., Cassagnau, E., Deschaseaux, F., Heymann, M.F., Heymann, D., Duteille, F., and Trichet, V. (2010). Safety concern between autologous fat graft, mesenchymal stem cell and osteosarcoma recurrence. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010999"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00223-004-0285-8","article-title":"Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization","volume":"77","author":"Utting","year":"2005","journal-title":"Calcif. Tissue Int."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"252","DOI":"10.22203\/eCM.v033a19","article-title":"The effect of extracellular acidosis on the behaviour of mesenchymal stem cells in vitro","volume":"33","author":"Massa","year":"2017","journal-title":"Eur. Cells Mater."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Granchi, D., Torreggiani, E., Massa, A., Caudarella, R., Di Pompo, G., and Baldini, N. (2017). Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181230"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.abb.2010.07.021","article-title":"Acidosis, hypoxia and bone","volume":"503","author":"Arnett","year":"2010","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/jbmr.5650080310","article-title":"Effect of medium pH on osteoclast activity and osteoclast formation in cultures of dispersed rabbit osteoclasts","volume":"8","author":"Shibutani","year":"1993","journal-title":"J. Bone Miner. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3389\/fphys.2016.00222","article-title":"The Roles of acidosis in osteoclast biology","volume":"7","author":"Yuan","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.bbrc.2005.09.054","article-title":"Identification of acid-sensing ion channels in bone","volume":"337","author":"Jahr","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nature01905","article-title":"Proton-Sensing G-protein-coupled receptors","volume":"425","author":"Ludwig","year":"2003","journal-title":"Nature"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1359\/jbmr.080236","article-title":"Cyclooxygenase-2 expression and prostaglandin E2 production in response to acidic pH through OGR1 in a human osteoblastic cell line","volume":"23","author":"Tomura","year":"2008","journal-title":"J. Bone Miner. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.bbrc.2015.01.142","article-title":"Involvement of the G-protein-coupled receptor 4 in RANKL expression by osteoblasts in an acidic environment","volume":"458","author":"Okito","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3389\/fendo.2012.00099","article-title":"The involvement of TRP channels in bone homeostasis","volume":"3","author":"Lieben","year":"2012","journal-title":"Front. Endocrinol."},{"key":"ref_117","first-page":"33","article-title":"Promotion of osteoclast differentiation and activation in spite of impeded osteoblast-lineage differentiation under acidosis: Effects of acidosis on bone metabolism","volume":"7","author":"Kato","year":"2013","journal-title":"Biosci. Trends"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s00424-005-1457-8","article-title":"Structure and function of TRPV1","volume":"451","author":"Tominaga","year":"2005","journal-title":"Pflugers Arch."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"C699","DOI":"10.1152\/ajpcell.00188.2012","article-title":"Structure and activity of the acid-sensing ion channels","volume":"303","author":"Sherwood","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0896-6273(02)01130-3","article-title":"Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade","volume":"37","author":"Immke","year":"2003","journal-title":"Neuron"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.cmet.2008.08.002","article-title":"TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts","volume":"8","author":"Masuyama","year":"2008","journal-title":"Cell Metab."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3389\/fonc.2020.00397","article-title":"Tumor microenvironment: Extracellular matrix alterations influence tumor progression","volume":"10","author":"Brezillon","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"30599","DOI":"10.1038\/srep30599","article-title":"Excessive collagen turnover products are released during colorectal cancer progression and elevated in serum from metastatic colorectal cancer patients","volume":"6","author":"Kehlet","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"11424","DOI":"10.1016\/S0021-9258(19)49927-4","article-title":"Induction of 103-kDa gelatinase\/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell lines","volume":"267","author":"Kato","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"6244","DOI":"10.1038\/onc.2017.219","article-title":"The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia\/MMP14-mediated invasion","volume":"36","author":"Swayampakula","year":"2017","journal-title":"Oncogene"},{"key":"ref_126","first-page":"7693","article-title":"Immunotherapeutic strategies for sarcoma: Current perspectives","volume":"12","author":"Li","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1097\/CCO.0000000000000651","article-title":"Immunotherapy in sarcoma: Combinations or single agents? In whom?","volume":"32","author":"Dufresne","year":"2020","journal-title":"Curr. Opin. Oncol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/S1470-2045(17)30624-1","article-title":"Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial","volume":"18","author":"Tawbi","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1634\/theoncologist.2016-0025","article-title":"Immunotherapy: A new (and old) approach to treatment of soft tissue and bone sarcomas","volume":"23","author":"Nathenson","year":"2018","journal-title":"Oncologist"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"439053","DOI":"10.1155\/2011\/439053","article-title":"From tumor immunosuppression to eradication: Targeting homing and activity of immune effector cells to tumors","volume":"2011","author":"Draghiciu","year":"2011","journal-title":"Clin. Dev. Immunol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1038\/ni.2392","article-title":"Immunology beats cancer: A blueprint for successful translation","volume":"13","author":"Pardoll","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1158\/0008-5472.CAN-12-3696","article-title":"The emerging \u201challmarks\u201d of metabolic reprogramming and immune evasion: Distinct or linked?","volume":"73","author":"Kareva","year":"2013","journal-title":"Cancer Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/2049-3002-1-23","article-title":"Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress","volume":"1","author":"Lamonte","year":"2013","journal-title":"Cancer Metab."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1158\/0008-5472.CAN-15-1743","article-title":"Neutralization of tumor acidity improves antitumor responses to immunotherapy","volume":"76","author":"Kodumudi","year":"2016","journal-title":"Cancer Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.4049\/jimmunol.1202702","article-title":"Tumor-derived lactate modifies antitumor immune response: Effect on myeloid-derived suppressor cells and NK cells","volume":"191","author":"Husain","year":"2013","journal-title":"J. Immunol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1189\/jlb.70.4.478","article-title":"Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors","volume":"70","author":"Crowther","year":"2001","journal-title":"J. Leukoc. Biol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4849","DOI":"10.4049\/jimmunol.162.8.4849","article-title":"Extracellular acidification induces human neutrophil activation","volume":"162","author":"Trevani","year":"1999","journal-title":"J. Immunol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.4049\/jimmunol.176.2.1163","article-title":"Extracellular acidosis induces neutrophil activation by a mechanism dependent on activation of phosphatidylinositol 3-kinase\/Akt and ERK pathways","volume":"176","author":"Martinez","year":"2006","journal-title":"J. Immunol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"3196","DOI":"10.4049\/jimmunol.172.5.3196","article-title":"Acidosis improves uptake of antigens and MHC class I-restricted presentation by dendritic cells","volume":"172","author":"Vermeulen","year":"2004","journal-title":"J. Immunol."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Lemma, S., Avnet, S., Meade, M.J., Chano, T., and Baldini, N. (2018). Validation of suitable housekeeping genes for the normalization of mRNA expression for studying tumor acidosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102930"},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Shinoda, H., Shannon, M., and Nagai, T. (2018). Fluorescent proteins for investigating biological events in acidic environments. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061548"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"412","DOI":"10.3389\/fbioe.2020.00412","article-title":"pHLuc, a ratiometric luminescent reporter for in vivo monitoring of tumor acidosis","volume":"8","author":"Ong","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1002\/mrm.28676","article-title":"Evaluation of a similarity anisotropic diffusion denoising approach for improving in vivo CEST-MRI tumor pH imaging","volume":"85","author":"Romdhane","year":"2021","journal-title":"Magn. Reson. Med."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"104166","DOI":"10.1016\/j.phrs.2019.02.005","article-title":"A molecular view of the function and pharmacology of acid-sensing ion channels","volume":"154","author":"Vullo","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"9852","DOI":"10.18632\/oncotarget.23955","article-title":"Prominent role of RAB39A-RXRB axis in cancer development and stemness","volume":"9","author":"Chano","year":"2018","journal-title":"Oncotarget"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1007\/s00228-008-0538-y","article-title":"Proton pump inhibitors: An update of their clinical use and pharmacokinetics","volume":"64","author":"Shi","year":"2008","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1006\/bbrc.1993.2306","article-title":"Evidence for a common binding site for omeprazole and N-ethylmaleimide in subunit A of chromaffin granule vacuolar-type H+-ATPase","volume":"196","author":"Moriyama","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0005-2736(91)90238-4","article-title":"Omeprazole and bafilomycin, two proton pump inhibitors: Differentiation of their effects on gastric, kidney and bone H+-translocating ATPases","volume":"1065","author":"Mattsson","year":"1991","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1186\/1479-5876-11-268","article-title":"Proton pump inhibitor chemosensitization in human osteosarcoma: From the bench to the patients\u2019 bed","volume":"11","author":"Ferrari","year":"2013","journal-title":"J. Transl. Med."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1016\/j.bmcl.2014.04.077","article-title":"Dual carbonic anhydrase\/matrix metalloproteinase inhibitors incorporating bisphosphonic acid moieties targeting bone tumors","volume":"24","author":"Tauro","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_151","first-page":"971","article-title":"Intracellular binding sites of acridine orange in living osteosarcoma cells","volume":"20","author":"Kusuzaki","year":"2000","journal-title":"Anticancer Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1007\/BF01941777","article-title":"Fluorescence response of acridine orange to changes in pH gradients across liposome membranes","volume":"42","author":"Cools","year":"1986","journal-title":"Experientia"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jphotobiol.2006.08.003","article-title":"Vesicle disruption, plasma membrane bleb formation, and acute cell death caused by illumination with blue light in acridine orange-loaded malignant melanoma cells","volume":"86","author":"Hiruma","year":"2007","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"370","DOI":"10.3389\/fphys.2013.00370","article-title":"pH sensing and regulation in cancer","volume":"4","author":"Damaghi","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1699-0463.1993.tb00091.x","article-title":"Acridine orange-mediated photodamage to cultured cells","volume":"101","author":"Zdolsek","year":"1993","journal-title":"APMIS"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1159\/000048251","article-title":"Acridine orange excited by low-dose radiation has a strong cytocidal effect on mouse osteosarcoma","volume":"62","author":"Hashiguchi","year":"2002","journal-title":"Oncology"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/S0891-5849(97)00007-5","article-title":"Photo-oxidative disruption of lysosomal membranes causes apoptosis of cultured human fibroblasts","volume":"23","author":"Brunk","year":"1997","journal-title":"Free Radic. Biol. Med."},{"key":"ref_158","first-page":"1225","article-title":"Clinical trial of photodynamic therapy using acridine orange with\/without low dose radiation as new limb salvage modality in musculoskeletal sarcomas","volume":"25","author":"Kusuzaki","year":"2005","journal-title":"Anticancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1562\/2004-06-27-RA-218.1","article-title":"Clinical outcome of a novel photodynamic therapy technique using acridine orange for synovial sarcomas","volume":"81","author":"Kusuzaki","year":"2005","journal-title":"Photochem. Photobiol."},{"key":"ref_160","first-page":"279","article-title":"Periosteal Ewing\u2019s sarcoma treated by photodynamic therapy with acridine orange","volume":"13","author":"Yoshida","year":"2005","journal-title":"Oncol. Rep."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"8275935","DOI":"10.1155\/2019\/8275935","article-title":"Photodynamic Surgery for Feline Injection-Site Sarcoma","volume":"2019","author":"Martano","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1302\/0301-620X.92B6.23788","article-title":"Photodynamic therapy with acridine orange in musculoskeletal sarcomas","volume":"92","author":"Matsubara","year":"2010","journal-title":"J. Bone Joint Surg."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/jso.21602","article-title":"Clinical outcomes of minimally invasive surgery using acridine orange for musculoskeletal sarcomas around the forearm, compared with conventional limb salvage surgery after wide resection","volume":"102","author":"Matsubara","year":"2010","journal-title":"J. Surg. Oncol."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Saito, T., Tsukahara, T., Suzuki, T., Nojima, I., Tadano, H., Kawai, N., Kubo, T., Hirohashi, Y., Kanaseki, T., and Torigoe, T. (2020). Spatiotemporal metabolic dynamics of the photosensitizer talaporfin sodium in carcinoma and sarcoma. Cancer Sci.","DOI":"10.1111\/cas.14735"},{"key":"ref_165","first-page":"5374","article-title":"Effects of photodynamic therapy using mono-L-aspartyl chlorin e6 on vessel constriction, vessel leakage, and tumor response","volume":"54","author":"McMahon","year":"1994","journal-title":"Cancer Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.pdpdt.2014.10.009","article-title":"Low-Level light therapy potentiates NPe6-mediated photodynamic therapy in a human osteosarcoma cell line via increased ATP","volume":"12","author":"Tsai","year":"2015","journal-title":"Photodiagn. Photodyn. Ther."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/15\/3848\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:37:24Z","timestamp":1760164644000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/15\/3848"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,30]]},"references-count":166,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cancers13153848"],"URL":"https:\/\/doi.org\/10.3390\/cancers13153848","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,30]]}}}