title: Acidity generated by the tumor microenvironment drives local invasion.
abstract: The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium-hydrogen exchanger-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis. Cancer Res; 73(5); 1524-35. ©2012 AACR.
authors.affiliation: Departments of Cancer Imaging and Metabolism, Radiology, and Analytic Microscopy Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Estrella
authors.forename: Tingan
authors.initials: T
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Lloyd
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wojtkowiak
authors.forename: Heather H
authors.initials: HH
authors.lastname: Cornnell
authors.forename: Arig
authors.initials: A
authors.lastname: Ibrahim-Hashim
authors.forename: Kate
authors.initials: K
authors.lastname: Bailey
authors.forename: Yoganand
authors.initials: Y
authors.lastname: Balagurunathan
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Rothberg
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
authors.forename: Joseph
authors.initials: J
authors.lastname: Johnson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gatenby
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000818:Animals; D004365:Drugs, Chinese Herbal; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017693:Sodium Bicarbonate / Q000494:pharmacology; D059016:Tumor Microenvironment
chemical_list: D004365:Drugs, Chinese Herbal; C551434:yun-chang; D017693:Sodium Bicarbonate