title: Mechanisms of buffer therapy resistance.
abstract: Many studies have shown that the acidity of solid tumors contributes to local invasion and metastasis. Oral pH buffers can specifically neutralize the acidic pH of tumors and reduce the incidence of local invasion and metastatic formation in multiple murine models. However, this effect is not universal as we have previously observed that metastasis is not inhibited by buffers in some tumor models, regardless of buffer used. B16-F10 (murine melanoma), LL/2 (murine lung) and HCT116 (human colon) tumors are resistant to treatment with lysine buffer therapy, whereas metastasis is potently inhibited by lysine buffers in MDA-MB-231 (human breast) and PC3M (human prostate) tumors. In the current work, we confirmed that sensitive cells utilized a pH-dependent mechanism for successful metastasis supported by a highly glycolytic phenotype that acidifies the local tumor microenvironment resulting in morphological changes. In contrast, buffer-resistant cell lines exhibited a pH-independent metastatic mechanism involving constitutive secretion of matrix degrading proteases without elevated glycolysis. These results have identified two distinct mechanisms of experimental metastasis, one of which is pH-dependent (buffer therapy sensitive cells) and one which is pH-independent (buffer therapy resistant cells). Further characterization of these models has potential for therapeutic benefit.
authors.affiliation: Department of Cancer Imaging and Metabolism, Tampa, FL, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Bailey
authors.affiliation: Department of Cancer Imaging and Metabolism, Tampa, FL, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wojtkowiak
authors.affiliation: Department of Cancer Imaging and Metabolism, Tampa, FL, USA.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Cornnell
authors.affiliation: Department of Cancer Imaging and Metabolism, Tampa, FL, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ribeiro
authors.affiliation: Department of Cancer Imaging and Metabolism, Tampa, FL, USA.
authors.forename: Yoganand
authors.initials: Y
authors.lastname: Balagurunathan
authors.affiliation: Department of Cancer Imaging and Metabolism, Tampa, FL, USA.
authors.forename: Arig Ibrahim
authors.initials: AI
authors.lastname: Hashim
authors.affiliation: Department of Cancer Imaging and Metabolism, Tampa, FL, USA; Department of Radiology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. Electronic address: robert.gillies@moffitt.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000818:Animals; D002021:Buffers; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000737:chemistry / Q000494:pharmacology; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy
chemical_list: D002021:Buffers; D008239:Lysine