{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T14:26:06Z","timestamp":1780496766959,"version":"3.54.1"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"9-10","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Resistance to cancer treatment, metastases, and rapid progression remain overwhelming factors for patients, their families, and health providers. One of the key mechanisms for the invasiveness and malignancy of cancer has been identified to be tumor acidity as a direct result of the Warburg effect observed during the continuous formation of cancerous tissue. This study describes the Warburg effect in cancer etiology, which causes lower pH levels in tumors compared to healthy tissues, and it also discusses the mechanisms and impact of tumor acidity on cancer progression and the damage it causes in healthy tissue while facilitating cancer invasion and dissemination.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Materials and Methods<\/jats:title>\n                  <jats:p>A review of the literature was conducted using search words such as: \u201cTumor acidity,\u201d \u201cCancer metabolism,\u201d \u201cWarburg effect,\u201d \u201cGlucose metabolism,\u201d and \u201cCancer cells,\u201d to analyze the effect tumor acidity has on healthy tissue, as well as the potential it has for cancer progression.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The review of the literature showed a high level of suggestive evidence of the negative impact of tumor acidity on healthy tissue. It furthermore confirmed some of the suspected ways of cancer progression induced by tumor acidity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Cancer is associated with massive complex metabolic reprogramming resulting in tumor acidity, which has the potential to further damage healthy tissues, as well as to induce cancer progression and dissemination. However, it also presents a metabolic vulnerability that can be used as a drug target to help enhance the efficiency of conventional cancer therapies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/milmed\/usaf119","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T12:06:16Z","timestamp":1744373176000},"page":"e1844-e1850","source":"Crossref","is-referenced-by-count":5,"title":["Tumor Acidity as a Result of the Warburg Effect in Cancer Glucose Metabolism and Its Role in Cancer Progression\u2014A Review"],"prefix":"10.1093","volume":"190","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4227-2626","authenticated-orcid":false,"given":"Nikoletta","family":"Vargas","sequence":"first","affiliation":[{"name":"University of Rochester , Rochester, NY 14642,","place":["United States"]},{"name":"Kimbrough Ambulatory Care Center, ARMY, MEDDAC , Fort Meade, MD 20755,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0025-2308","authenticated-orcid":false,"given":"Mary","family":"Rondeau","sequence":"additional","affiliation":[{"name":"Kimbrough Ambulatory Care Center, ARMY, MEDDAC , Fort Meade, MD 20755,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4416-8450","authenticated-orcid":false,"given":"Tatyana","family":"Fortune","sequence":"additional","affiliation":[{"name":"Kimbrough Ambulatory Care Center, ARMY, MEDDAC , Fort Meade, MD 20755,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7185-0307","authenticated-orcid":false,"given":"Tammy","family":"Luk","sequence":"additional","affiliation":[{"name":"Kimbrough Ambulatory Care Center, ARMY, MEDDAC , Fort Meade, MD 20755,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6126-8153","authenticated-orcid":false,"given":"Lars-Ove","family":"Brandenburg","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center , Rostock 18055,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"issue":"1-2","key":"2025092416182281300_R1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10555-019-09787-4","article-title":"Acidosis and cancer: from mechanism to neutralization","volume":"38","author":"Ibrahim-Hashim","year":"2019","journal-title":"Cancer Metastasis Rev"},{"issue":"1-2","key":"2025092416182281300_R2","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"},{"issue":"6","key":"2025092416182281300_R3","doi-asserted-by":"publisher","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":"2025092416182281300_R4","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1158\/jcr.1925.148","article-title":"The metabolism of carcinoma cells","volume":"9","author":"Warburg","year":"1925","journal-title":"J Cancer Res"},{"issue":"3","key":"2025092416182281300_R5","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg effect: how does it benefit cancer cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem Sci"},{"issue":"5930","key":"2025092416182281300_R6","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the Warburg effect: the metabolic requirements of cell proliferation","volume":"324","author":"Vander Heiden","year":"2009","journal-title":"Science"},{"issue":"3","key":"2025092416182281300_R7","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1042\/AN20090011","article-title":"In vitro growth environment produces lipidomic and electron transport chain abnormalities in mitochondria from non-tumorigenic astrocytes and brain tumours","volume":"1","author":"Kiebish","year":"2009","journal-title":"ASN Neuro"},{"key":"2025092416182281300_R8","doi-asserted-by":"crossref","DOI":"10.1177\/1759091418818261","article-title":"Mitochondrial substrate-level phosphorylation as energy source for glioblastoma: review and hypothesis","volume":"10","author":"Chinopoulos","year":"2018","journal-title":"ASN Neuro"},{"issue":"34","key":"2025092416182281300_R9","doi-asserted-by":"publisher","first-page":"57813","DOI":"10.18632\/oncotarget.18175","article-title":"The reverse Warburg effect is likely to be an Achilles\u2019 heel of cancer that can be exploited for cancer therapy","volume":"8","author":"Fu","year":"2017","journal-title":"Oncotarget"},{"issue":"5","key":"2025092416182281300_R10","doi-asserted-by":"crossref","DOI":"10.3390\/cancers15051417","article-title":"How Warburg-associated lactic acidosis rewires cancer cell energy metabolism to resist glucose deprivation","volume":"15","author":"Daverio","year":"2023","journal-title":"Cancers"},{"issue":"3191","key":"2025092416182281300_R11","doi-asserted-by":"publisher","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"},{"issue":"6","key":"2025092416182281300_R12","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.ccr.2006.04.023","article-title":"Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance","volume":"9","author":"Fantin","year":"2006","journal-title":"Cancer Cell"},{"issue":"1","key":"2025092416182281300_R13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1148\/114.1.89","article-title":"A positron-emission transaxial tomograph for nuclear imaging (PETT)","volume":"114","author":"Ter-Pogossian","year":"1975","journal-title":"Radiology"},{"issue":"2","key":"2025092416182281300_R14","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22020764","article-title":"Anti-Warburg effect of melatonin: a proposed mechanism to explain its inhibition of multiple diseases","volume":"22","author":"Reiter","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"6","key":"2025092416182281300_R15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3390\/cancers12061616","article-title":"How and why are cancers acidic? carbonic anhydrase IX and the homeostatic control of tumour extracellular pH","volume":"12","author":"Lee","year":"2020","journal-title":"Cancers"},{"issue":"7","key":"2025092416182281300_R16","doi-asserted-by":"publisher","DOI":"10.1007\/s11538-021-00914-3","article-title":"A mathematical study of the influence of hypoxia and acidity on the evolutionary dynamics of cancer","volume":"83","author":"Fiandaca","year":"2021","journal-title":"Bull Math Biol"},{"key":"2025092416182281300_R17","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9752","article-title":"Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane","volume":"6","author":"Damaghi","year":"2015","journal-title":"Nat Commun"},{"key":"2025092416182281300_R18","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00004","article-title":"Hypoxia-modified cancer cell metabolism","volume":"7","author":"Al Tameemi","year":"2019","journal-title":"Front Cell Dev Biol"},{"issue":"4","key":"2025092416182281300_R19","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1002\/jcb.22313","article-title":"An acidic extracellular pH disrupts adherens junctions in HepG2 cells by Src kinases-dependent modification of E-cadherin","volume":"108","author":"Chen","year":"2009","journal-title":"J Cell Biochem"},{"issue":"1-2","key":"2025092416182281300_R20","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s10555-018-09777-y","article-title":"Tumor pH and metastasis: a malignant process beyond hypoxia","volume":"38","author":"Thews","year":"2019","journal-title":"Cancer Metastasis Rev"},{"key":"2025092416182281300_R21","first-page":"1","article-title":"Epithelial-mesenchymal transition in cancer: An overview","volume":"4(3)","author":"Ramos","year":"2017","journal-title":"Icst"},{"issue":"2","key":"2025092416182281300_R22","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/BF00121214","article-title":"Acidic pH enhances the invasive behavior of human melanoma cells","volume":"14","author":"Mart\u00ednez-Zaguil\u00e1n","year":"1996","journal-title":"Clin Exp Metastasis"},{"issue":"6","key":"2025092416182281300_R23","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1158\/0008-5472.CAN-08-2394","article-title":"The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion","volume":"69","author":"Silva","year":"2009","journal-title":"Cancer Res"},{"issue":"9","key":"2025092416182281300_R24","doi-asserted-by":"crossref","first-page":"5205","DOI":"10.1073\/pnas.0935978100","article-title":"Acidic pH induces topoisomerase II-mediated DNA damage","volume":"100","author":"Xiao","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"21","key":"2025092416182281300_R25","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1038\/sj.onc.1202660","article-title":"An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis","volume":"18","author":"Williams","year":"1999","journal-title":"Oncogene"},{"issue":"18","key":"2025092416182281300_R26","first-page":"3910","article-title":"p53-dependent induction of WAF1 by a low-pH culture condition in human glioblastoma cells","volume":"57","author":"Ohtsubo","year":"1997","journal-title":"Cancer Res"},{"issue":"3","key":"2025092416182281300_R27","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"},{"issue":"21","key":"2025092416182281300_R28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21218363","article-title":"lactic acid and an acidic tumor microenvironment suppress anticancer Immunity","volume":"21","author":"Wang","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2025092416182281300_R29","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1158\/1538-7445.AM2015-3213","article-title":"Abstract 3213: extracellular acidosis alters polarization of macrophages","volume":"75","author":"El-Kenawi","year":"2015","journal-title":"Cancer Res"},{"issue":"6","key":"2025092416182281300_R30","doi-asserted-by":"publisher","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":"Pilon-Thomas","year":"2016","journal-title":"Cancer Res"},{"issue":"12","key":"2025092416182281300_R31","doi-asserted-by":"publisher","first-page":"3687","DOI":"10.1016\/j.cclet.2021.06.032","article-title":"Sodium bicarbonate, an inorganic salt and a potential active agent for cancer therapy","volume":"32","author":"Wang","year":"2021","journal-title":"Chin Chem Lett"},{"issue":"3","key":"2025092416182281300_R32","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/mco2.55","article-title":"Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment","volume":"2","author":"Liu","year":"2021","journal-title":"MedComm(2020)"},{"issue":"3","key":"2025092416182281300_R33","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.radonc.2015.08.012","article-title":"AMPK-independent autophagy promotes radioresistance of human tumor cells under clinical relevant hypoxia in vitro","volume":"116","author":"Chaachouay","year":"2015","journal-title":"Radiother Oncol"},{"issue":"4","key":"2025092416182281300_R34","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.21037\/tcr.2019.07.42","article-title":"Acid-induced autophagy protects human gastric cancer cells from apoptosis by activating Erk1\/2 pathway","volume":"8","author":"Gao","year":"2019","journal-title":"Transl Cancer Res"},{"issue":"5","key":"2025092416182281300_R35","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1158\/1535-7163.MCT-06-0024","article-title":"Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics","volume":"5","author":"Gerweck","year":"2006","journal-title":"Mol Cancer Ther"},{"issue":"4","key":"2025092416182281300_R36","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15041143","article-title":"Cancer resistance to immunotherapy: comprehensive insights with future perspectives","volume":"15","author":"Said","year":"2023","journal-title":"Pharmaceutics"},{"issue":"8","key":"2025092416182281300_R37","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1016\/j.joen.2020.04.005","article-title":"Moderately acidic ph promotes angiogenesis: an in vitro and in vivo study","volume":"46","author":"Saghiri","year":"2020","journal-title":"J Endod"},{"issue":"7","key":"2025092416182281300_R38","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1158\/0008-5472.CAN-10-2828","article-title":"Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-\u03baB\/IL-8 pathway that drives tumor angiogenesis","volume":"71","author":"V\u00e9gran","year":"2011","journal-title":"Cancer Res"},{"issue":"9","key":"2025092416182281300_R39","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1007\/s00018-019-03351-7","article-title":"Tumor angiogenesis: causes, consequences, challenges and opportunities","volume":"77","author":"Lugano","year":"2020","journal-title":"Cell Mol Life Sci"},{"issue":"3","key":"2025092416182281300_R40","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/sj.neo.7900037","article-title":"Causes and effects of heterogeneous perfusion in tumors","volume":"1","author":"Gillies","year":"1999","journal-title":"Neoplasia"},{"key":"2025092416182281300_R41","doi-asserted-by":"publisher","DOI":"10.3390\/cells10051056","article-title":"Mechanisms of metabolic reprogramming in cancer cells supporting enhanced growth and proliferation","volume":"10","author":"Schiliro","year":"2021","journal-title":"Cells"},{"key":"2025092416182281300_R42","doi-asserted-by":"crossref","DOI":"10.1038\/bonekey.2015.58","article-title":"Acidic Microenvironment and Bone Pain in Cancer-colonized Bone","volume":"4","author":"Yoneda","year":"2015","journal-title":"Bonekey Rep"},{"issue":"1\u20132","key":"2025092416182281300_R43","doi-asserted-by":"publisher","first-page":"e58","DOI":"10.1093\/milmed\/usac297","article-title":"Cancer incidence and etiology in the active duty population of U.S.Military","volume":"189","author":"Lovejoy","year":"2022","journal-title":"Mil Med"},{"issue":"7","key":"2025092416182281300_R44","first-page":"23","article-title":"Incident diagnoses of cancers in the active component and cancer-related deaths in the active and reserve components, U.S. Armed Forces, 2005\u20132014","volume":"23","author":"Lee","year":"2016","journal-title":"Msmr"},{"issue":"3","key":"2025092416182281300_R45","doi-asserted-by":"publisher","first-page":"247","DOI":"10.7205\/MILMED-D-13-00356","article-title":"Melanoma incidence rates in active duty military personnel compared with a population-based registry in the United States, 2000-2007","volume":"179","author":"Lea","year":"2014","journal-title":"Mil Med"},{"issue":"1","key":"2025092416182281300_R46","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1002\/cncr.34978","article-title":"Cancer incidence in the US military: an updated analysis","volume":"130","author":"Bytnar","year":"2024","journal-title":"Cancer"},{"issue":"Suppl 3","key":"2025092416182281300_R47","first-page":"S23","article-title":"Agent orange exposure, transformation from MGUS to multiple myeloma, and outcomes in veterans","volume":"39","author":"Dodlapati","year":"2022","journal-title":"Fed Pract"},{"issue":"12","key":"2025092416182281300_R48","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.46380","article-title":"Exposure to agent orange and hepatocellular carcinoma among US Military personnel","volume":"6","author":"Benhammou","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"2","key":"2025092416182281300_R49","first-page":"8","article-title":"Incidence rates of malignant melanoma in relation to years of military service, overall and in selected military occupational groups, active component, U.S. Armed Forces, 2001\u20132015","volume":"24","author":"Brundage","year":"2017","journal-title":"Msmr"},{"issue":"1","key":"2025092416182281300_R50","article-title":"How to use the Surveillance, Epidemiology, and End Results (SEER) data: research design and methodology","volume":"10","author":"Che","year":"2023","journal-title":"Mil Med Res"},{"issue":"1","key":"2025092416182281300_R51","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"2025092416182281300_R52","article-title":"Metabolism of amino acids in cancer","volume":"8","author":"Wei","year":"2020","journal-title":"Front Cell Dev Biol"},{"issue":"4","key":"2025092416182281300_R53","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/path.4218","article-title":"Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite?","volume":"230","author":"Choi","year":"2013","journal-title":"J Pathol"},{"key":"2025092416182281300_R54","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.979154","article-title":"Tumor acidity: from hallmark of cancer to target of treatment","volume":"12","author":"Bogdanov","year":"2022","journal-title":"Front Oncol"},{"key":"2025092416182281300_R55","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.freeradbiomed.2014.10.732","article-title":"The metabolic state of cancer stem cells-a valid target for cancer therapy?","volume":"79","author":"Vlashi","year":"2015","journal-title":"Free Radic Biol Med"},{"issue":"1","key":"2025092416182281300_R56","first-page":"11","article-title":"Cancer prevention: past, present, and future","volume":"8","author":"Young","year":"2002","journal-title":"Clin Cancer Res"},{"issue":"1","key":"2025092416182281300_R57","doi-asserted-by":"crossref","first-page":"3, 11","DOI":"10.3390\/sports6010010","article-title":"Cancer and exercise: Warburg hypothesis, tumour metabolism and high-intensity anaerobic exercise","volume":"6","author":"Hofmann","year":"2018","journal-title":"Sports"}],"container-title":["Military Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/milmed\/article-pdf\/190\/9-10\/e1844\/62916084\/usaf119.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/milmed\/article-pdf\/190\/9-10\/e1844\/62916084\/usaf119.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T20:18:30Z","timestamp":1758745110000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/milmed\/article\/190\/9-10\/e1844\/8111548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":57,"journal-issue":{"issue":"9-10","published-online":{"date-parts":[[2025,4,11]]},"published-print":{"date-parts":[[2025,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/milmed\/usaf119","relation":{},"ISSN":["0026-4075","1930-613X"],"issn-type":[{"value":"0026-4075","type":"print"},{"value":"1930-613X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,4,11]]}}}