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We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. The model takes into account the dynamic interplay between glucose and\n \n \n $$\\hbox {O}_2$$<\/jats:tex-math>\n \n \n O<\/mml:mtext>\n 2<\/mml:mn>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n consumption with lactate and\n \n \n $$\\hbox {CO}_2$$<\/jats:tex-math>\n \n \n CO<\/mml:mtext>\n 2<\/mml:mn>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n production and connects these processes to\n \n \n $$\\hbox {H}^+$$<\/jats:tex-math>\n \n \n H<\/mml:mtext>\n +<\/mml:mo>\n <\/mml:msup>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n and\n \n \n $$\\hbox {HCO}_3^-$$<\/jats:tex-math>\n \n \n HCO<\/mml:mtext>\n 3<\/mml:mn>\n -<\/mml:mo>\n <\/mml:msubsup>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. The simulations show a dominance of the\n \n \n $$\\hbox {H}^+$$<\/jats:tex-math>\n \n \n H<\/mml:mtext>\n +<\/mml:mo>\n <\/mml:msup>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n exchanges in well-oxygenated regions, and of\n \n \n $$\\hbox {HCO}_3^-$$<\/jats:tex-math>\n \n \n HCO<\/mml:mtext>\n 3<\/mml:mn>\n -<\/mml:mo>\n <\/mml:msubsup>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. The model also includes the activity of the enzyme Carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear\n \n \n $$\\hbox {pH}_i$$<\/jats:tex-math>\n \n \n pH<\/mml:mtext>\n i<\/mml:mi>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n equalizer at any\n \n \n $$\\hbox {O}_2$$<\/jats:tex-math>\n \n \n O<\/mml:mtext>\n 2<\/mml:mn>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n level in cells that grow in acidic extracellular environments.\n <\/jats:p>","DOI":"10.1038\/s41598-020-70396-1","type":"journal-article","created":{"date-parts":[[2020,8,12]],"date-time":"2020-08-12T06:06:55Z","timestamp":1597212415000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["The control of acidity in tumor cells: a biophysical model"],"prefix":"10.1038","volume":"10","author":[{"given":"Nicola","family":"Piasentin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Milotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Chignola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,12]]},"reference":[{"key":"70396_CR1","doi-asserted-by":"crossref","first-page":"20130099","DOI":"10.1098\/rstb.2013.0099","volume":"369","author":"P Swietach","year":"2014","unstructured":"Swietach, P., Vaughan-Jones, R. 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