{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T11:08:42Z","timestamp":1762081722340,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T00:00:00Z","timestamp":1671235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>The present perspective article proposes that cachexia, muscle wasting in cancer, is mediated by dysregulated phosphate metabolism and phosphate toxicity that can damage tissues in most major organ systems. A diet high in phosphorus fed to mice deficient in klotho, a cofactor that regulates phosphate metabolism, accelerates aging, sarcopenia, general organ atrophy, kyphosis, and osteoporosis. Similar effects are seen in phenotypes of mutant p53 mice that overexpress the p53 tumor suppressor gene. Although mutant p53 mice do not develop tumors compared to wild-type mice, mutant p53 mice have shorter mean lifespans. Furthermore, tumorigenesis is associated with the sequestration of excessive inorganic phosphate, and dangerous levels of phosphate are released into circulation during tumor lysis syndrome. In total, this evidence implies that tumorigenesis may be a compensatory mechanism that provides protective effects against systemic exposure to dysregulated phosphate metabolism and phosphate toxicity related to cachexia in cancer. Moreover, the hypothetical protection against phosphate toxicity afforded by tumorigenesis also provides an alternate explanation for putative tumor evasion of the immune system. Insights proposed in this perspective paper provide new directions for further research, with potential to develop novel interventions and clinical applications that modify dietary phosphate intake to reduce cachexia in cancer patients.<\/jats:p>","DOI":"10.3390\/metabo12121284","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T04:54:13Z","timestamp":1671425653000},"page":"1284","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cancer Cachexia and Dysregulated Phosphate Metabolism: Insights from Mutant p53 and Mutant Klotho Mouse Models"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9473-2274","authenticated-orcid":false,"given":"Ronald B.","family":"Brown","sequence":"first","affiliation":[{"name":"School of Public Health Sciences, University of Waterloo, Waterloo, ON N2L 3G1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,17]]},"reference":[{"key":"ref_1","unstructured":"Singh, A.K., and Williams, G.H. (2018). Chapter 31\u2014Endocrine Regulation of Phosphate Homeostasis. Textbook of Nephro-Endocrinology, Academic Press. [2nd ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.bbcan.2018.04.007","article-title":"Phosphate toxicity and tumorigenesis","volume":"1869","author":"Brown","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Rev. Cancer"},{"key":"ref_3","first-page":"1","article-title":"Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey","volume":"00","author":"Qiao","year":"2022","journal-title":"Cancer Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7094","DOI":"10.1038\/onc.2008.292","article-title":"Klotho: A tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer","volume":"27","author":"Wolf","year":"2008","journal-title":"Oncogene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/36285","article-title":"Mutation of the mouse klotho gene leads to a syndrome resembling ageing","volume":"390","author":"Matsumura","year":"1997","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3562","DOI":"10.1096\/fj.09-152488","article-title":"Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging","volume":"24","author":"Ohnishi","year":"2010","journal-title":"FASEB J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3904\/kjim.2011.26.2.113","article-title":"Klotho and the aging process","volume":"26","year":"2011","journal-title":"Korean J. Intern. Med."},{"key":"ref_8","first-page":"39","article-title":"Muscle wasting in cancer and ageing: Cachexia versus sarcopenia","volume":"18","author":"Busquets","year":"2006","journal-title":"Adv. Gerontol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1200\/JOP.2016.016832","article-title":"Cancer Cachexia: Beyond Weight Loss","volume":"12","author":"Bruggeman","year":"2016","journal-title":"J. Oncol. Pract."},{"key":"ref_10","unstructured":"National Cancer Institute (2022, November 18). Treating Cancer Cachexia: Progress Looks Possible, Available online: https:\/\/www.cancer.gov\/about-cancer\/treatment\/research\/cachexia."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Advani, S.M., Advani, P.G., VonVille, H.M., and Jafri, S.H. (2018). Pharmacological management of cachexia in adult cancer patients: A systematic review of clinical trials. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-5080-4"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1634\/theoncologist.2010-0019","article-title":"More is better: A multimodality approach to cancer cachexia","volume":"15","year":"2010","journal-title":"Oncologist"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/415045a","article-title":"p53 mutant mice that display early ageing-associated phenotypes","volume":"415","author":"Tyner","year":"2002","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1177\/1758834017698643","article-title":"Cancer-induced muscle wasting: Latest findings in prevention and treatment","volume":"9","author":"Aversa","year":"2017","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1057\/ejis.2011.51","article-title":"Using grounded theory as a method for rigorously reviewing literature","volume":"22","author":"Wolfswinkel","year":"2013","journal-title":"Eur. J. Inf. Syst."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Brown, R.B. (2020). Breakthrough knowledge synthesis in the Age of Google. Philosophies, 5.","DOI":"10.3390\/philosophies5010004"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e101","DOI":"10.1097\/GOX.0000000000000045","article-title":"Klotho Mice: A Novel Wound Model of Aged Skin","volume":"2","author":"Yamashita","year":"2014","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., and Giordano, A. (2020). Role of p53 in the Regulation of Cellular Senescence. Biomolecules, 10.","DOI":"10.3390\/biom10030420"},{"key":"ref_19","first-page":"73","article-title":"Mitochondrial reactive oxygen species, endoplasmic reticulum stress and phosphate toxicity in impairment of pancreatic cells","volume":"1","author":"Nguyen","year":"2016","journal-title":"TTU Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"576110","DOI":"10.3389\/fcell.2020.576110","article-title":"Disorders of Calcium and Phosphorus Metabolism and the Proteomics\/Metabolomics-Based Research","volume":"8","author":"Sun","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/S0140-6736(96)06184-3","article-title":"A new biological framework for cancer research","volume":"348","author":"Schipper","year":"1996","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1056\/NEJMra0904569","article-title":"The tumor lysis syndrome","volume":"364","author":"Howard","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"868695","DOI":"10.3389\/fphar.2022.868695","article-title":"The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment","volume":"13","author":"Kim","year":"2022","journal-title":"Front. Pharmacol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/12\/1284\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:43:20Z","timestamp":1760147000000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/12\/1284"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,17]]},"references-count":23,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["metabo12121284"],"URL":"https:\/\/doi.org\/10.3390\/metabo12121284","relation":{},"ISSN":["2218-1989"],"issn-type":[{"type":"electronic","value":"2218-1989"}],"subject":[],"published":{"date-parts":[[2022,12,17]]}}}