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Acidic extracellular microenvironment and cancer

Yasumasa Kato, Shigeyuki Ozawa, Chihiro Miyamoto and 4 more

Cancer Cell International · 2013 · Review

doi:10.1186/1475-2867-13-89

Abstract

Acidic extracellular pH is a major feature of tumor tissue, extracellular acidification being primarily considered to be due to lactate secretion from anaerobic glycolysis. Clinicopathological evidence shows that transporters and pumps contribute to H+ secretion, such as the Na+/H+ exchanger, the H+-lactate co-transporter, monocarboxylate transporters, and the proton pump (H+-ATPase); these may also be associated with tumor metastasis. An acidic extracellular pH not only activates secreted lysosomal enzymes that have an optimal pH in the acidic range, but induces the expression of certain genes of pro-metastatic factors through an intracellular signaling cascade that is different from hypoxia. In addition to lactate, CO2 from the pentose phosphate pathway is an alternative source of acidity, showing that hypoxia and extracellular acidity are, while being independent from each other, deeply associated with the cellular microenvironment. In this article, the importance of an acidic extracellular pH as a microenvironmental factor participating in tumor progression is reviewed.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The extracellular pH (pHe) of tumor tissues is often acidic, and acidic metabolites, e.g. lactic acid caused by anaerobic glycolysis in hypoxia, seem to be the main cause. Accumulating evidence shows that an acidic microenvironment is a regulator of cellular phenotype. Whereas Na+-HCO3- co-transporter and Cl-/HCO3- exchanger contribute a fall in intracellular pH, the Na+/H+ exchanger (NHE), the H+-lactate co-transporter, monocarboxylate transporters (MCTs), and the H+-ATPase (H+ pump) are responsible for the secretion of H+. Because carbonic anhydrase (CA) is widely distributed and can form H+ by catalyzing hydration of CO2, an excess amount of CO2 production through the pentose phosphate pathway in tumor cells is an alternative cause of a lower pH. Acidic pHe increases not only the activation of some lysosomal enzymes with acidic optimal pH, but also the expression of some genes involved with pro-metastatic factors. When melanoma cells pretreated with an acidic medium were injected into the tail vein of mice, a significantly higher frequency of them metastasized to the lungs. Thus, an acidic microenvironment is closely associated with tumor metastasis.

Acidity is found at the surface of skin and in inflammatory sites. It is also associated with bone resorption. Thus, an acidic microenvironment plays a role of homeostasis and the immune defense system. We will review the roles of acidic pHe in tumor progression along with other physiological and pathological conditions.

Lactate and tumor

The “Warburg effect” is a well-accepted theory that says that tumors tend to produce lactate by using the anaerobic glycolytic pathway, even in the presence of sufficient oxygen, rather than oxidative phosphorylation for energy production. High lactate levels indicate metastases, tumor recurrence, and prognosis in some cancer patients. In the molecular mechanism relating to these clinical contributions, lactate from tumor cells contributes to their immune escape. High lactate secretion from tumor cells inhibits its export from T cells, thereby disturbing their metabolism and function. Tumor-derived lactate affects inflammation and immune deficiency of tumor cells. Lactate itself functions as an intrinsic inflammatory mediator that increases interleukin (IL)-17A production by T-cells and macrophages, resulting in the promotion of chronic inflammation in tumor microenvironments. Lactate inhibits dendritic cell activation during antigen-specific autologous T-cell stimulation. It also enhances the motility of tumor cells and inhibits monocyte migration and cytokine release. It can contribute to angiogenesis through induction of IL-8 via nuclear factor-κB (NF-κB) and induction of vascular endothelial growth factor (VEGF/VEGF-A) via hypoxia-inducible transcription factor (HIF)-1. Furthermore, lactate production contributes to radio-resistance of tumors due to its antioxidant properties.

Inhibition of the lactate transporter has been considered a potential new therapeutic strategy. For example, α-cyano-4-hydroxycinnamate, a specific inhibitor of the lactate transporter MCT1, suppresses tumor angiogenesis. Quercetin (CYP2C9), which is an inhibitory flavonoid, inhibits lactate transport and acts as a hyperthermic sensitizer of HeLa cells.

Appearance of acidic microenvironments under physiological and pathological conditions

An oncogenic transformation assay by oncogenic-virus infection shows that lactate production is correlated with an increase in the number of transformed foci by viral infection in a presence of 5% CO2 in 95% air. Since high lactate corresponds to a high proton concentration, an acidic pHe is a major feature of the solid tumor tissue. Lactic acid is a product of the anaerobic glycolysis including the activity of lactate dehydrogenase (LDH) 5 that generates lactic acid from pyruvate and the expression of which has been strongly associated with the poor prognosis of patients with non-small cell lung and colorectal cancers.

CO2 is a major source of acid in glycolytically impaired mice. The pentose phosphate pathway is seen as a major productive pathway for CO2 which can be processed to H+ and HCO3- by the catalytic activity of CA. In osteoclasts, CA II, a CA isozyme, is a major enzyme producing H+ to decalcify bone hydroxyapatite. Osteoclasts secrete H+ and create an acidic microenvironment below pH 5.5, which is critical for the bone resorption and the proton can be secreted through H+-ATPase. Induction of CA II expression itself is also induced by an acidic pHe. Thus, secretion of acidic metabolites and/or the pentose phosphate pathway-mediated CO2 production, and CA-mediated production of H2CO3 form acidic microenvironments.

Extracellular acidity is a pathological feature of inflammation and solid tumor tissue. Acidity in inflammatory tissue is due to production of proton from macrophages, whereas tumor tissue acidity is due to acidic metabolites, e.g., lactate, caused by anaerobic glycolysis under the hypoxia. The acidic microenvironment acts as a trigger for pain in both inflammation and in cancer patients.

Ovarian cancer G-protein-coupled receptor 1 (OGR1), a receptor for sphingosylphosphorylcholine, and GPR4, a close relative of OGR1, also act as a proton-sensing receptor in osteosarcoma cells and primary human osteoblast precursors. OGR1 (GPR68) stimulates cyclooxygenase-2 expression and prostaglandin (PG) E2 production in response to acidic pHe in a human osteoblastic cell line. Because PGE2 is involved in osteoclastic differentiation of precursor cells, inhibition of the OGR1 signaling negatively regulates osteoclastogenesis. Another type of G-protein-coupled receptor, TDAG8 (GPR65), also senses pHe.

Breast cancer frequently metastasizes to bone. Osteoclasts can be activated by breast cancer-derived H+ such that osteolysis occurs when cancer cells metastasize to bone. During this process, patients feel pain through acid-sensing ion channels (ASIC) 1a, 1b and 3.

An acidic pHe is also found in the epidermis and plays an important protective role against bacterial infection. Using the conditional knockout (KO) mice for focal adhesion kinase (FAK) in keratinocytes, Ilic et al. showed that the stratum corneum pHe gradient of keratinocytes in these mice had significantly more neutral pH values, and that NHE1 failed to localize to the plasma membrane. Thus, FAK controls pH-dependent epidermal barrier homeostasis by regulating actin-directed NHE1 plasma membrane localization.

Lung liquid is acidic, which is worse in patients with cystic fibrosis, although the airway pH is not known for certain because different detecting methods have been used.

CA expression in cancer

CA isoforms are associated with tumor malignancy, including CA I, CA II, CA IX, CA XII, and CA XIII. Among them, CA IX in particular has been well studied in association with hypoxia and tumor survival through regulating intracellular pH. In ovarian cancer, high expression of CA IX with a concomitant increase in VEGF-A is associated with overall survival rates positively. Overexpression of CA IX increases tumor cell migration and invasion. CA inhibitor suppresses invasion of renal cancer cells in vitro. Based on the accumulated evidence, a new therapeutic strategy targeting CA has been considered.

Acidic pHe activates proteinase activity and induces gene expression

Acidic pHe activates some proteinases. Although caries is due to some bacterial acidic metabolites, Tjäderhane et al. found that host-derived pro-matrix metalloproteinase-9 (proMMP-9), proMMP-2 and proMMP-8 in saliva could be activated by acid, and thereby suggested that these MMPs contribute to the disruption of dentin in caries. Alternatively, host derived proMMP-9 could be activated in the stomach, and this suggests it functions as a digestive enzyme for collagenous foods. Activation of proMMP-9 by an acidic pHe also occurs in a human melanoma model.

Lysosomal enzymes have an acidic optimal pH. Some tumor cells have the ability to secrete them, such as cathepsin B and cathepsin L. Cathepsin K plays an important role in osteoclast-mediated bone resorption; its inhibition prevents breast cancer-induced osteolysis and skeletal tumor burden. Thus, osteoclast-mediated acidic pHe leads to mineral dissolution and activation of cathepsins to digest bone matrix, such as type I collagen. Podgorski et al. reported that SPARC/osteonectin, a major non-collagenous protein in bone, is digested by cathepsin K and its fragments are associated with bone-metastasis. Another lysosomal enzyme, heparanase, has an acidic optimal pH; it degrades heparan sulfate in the basement membrane and contributes to tumor invasion and metastasis.

Also, acidic microenvironments affect the expression of some genes, such as MMP-9 and acidic sphingomyelinase in mouse B16 melanoma, platelet-derived endothelial cell growth factor (thymidine phosphorylase) in human breast cancer cells, the inducible isoform of nitric oxide synthase (iNOS) in macrophages, VEGF-A in glioma and glioblastoma cells, and IL-8 expression in human pancreatic adenocarcinoma and ovarian carcinoma cells.

Acidic pHe signal transduction pathway

Thus, although acidic pHe occurs in several physiological and pathological conditions, information on its signaling remains limited. Transcription factors AP-1 and NF-κB, independent of hypoxia, have important roles in the acidic pHe-induced expression of VEGF-A and IL-8. p38 mitogen-activated protein kinase (MAPK) is involved in acidic pHe signaling that induces IL-8.

We also found involvement of phospholipase D (PLD) in the acidic pHe-intracellular signaling to induce MMP-9 production. Acidic pHe-induced PLD activation was prolonged for at least for 24 h, different from general growth factor signaling. Inhibition of PLD activity by 1-butanol and Myr-ARF6 suppresses acidic pHe-induced MMP-9 expression. Acidic pHe increases the steady-state levels of phosphorylated ERK1/2 and p38, and PLD inhibitors prevent these increases. Using 5′-deleted constructs of the MMP-9 promoter, we found that the acidic pHe-responsive region was located at nucleotides -670 to -531, a region containing the NF-κB binding site. A mutation in the NFκB binding site reduced acidic pHe-induced MMP-9 promoter activity, and NF-κB activity was induced by acidic pHe. Pharmacological inhibitors specific for MEK1/2 (PD098059) and p38 (SB203580) attenuated acidic pHe-induced NF-κB activity and MMP-9 expression. The data suggest that PLD, MAPKs including ERK 1/2 and p38, and NF-κB mediate acidic pHe signaling thereby inducing MMP-9 expression. Activation of ERK1/2 and p38, followed by the NF-κB axis, which is stimulated by tumor necrosis factor-α (TNF-α), also occurs in cholangiocarcinoma. This suggests that acidic pHe signaling is, at least in part, the signaling pathway for TNF-α. However, it has been reported that acidic pHe activates p38, but not ERK1/2, in T-cell receptor signaling in Jurkat cells. This may be cell-type specific. In a further contribution dealing with the intracellular substances of acidic pHe, we have found that calcium influx triggers acidic pHe-induced PLD activation and that acidic sphingomyelinase mediates acidic pHe signaling to activate NF-κB independently of the PLD-MAPK pathway.

OGR1 stimulates cyclooxygenase-2 expression and PGE2 production in response to an acidic pHe in a human osteoblastic cell line through G(q/11)/phospholipase C/protein kinase C pathway and in human aortic smooth muscle cells through the phospholipase C/cyclooxygenase/PGI2 pathway.

Acidic pH directly affects transcription factor activity; DNA binding activity of the transcription factor, SP1, is enhanced by intracellular acidic pH. Intracellular pH is maintained a constitutively neutral state but known to become transiently acidic when pHe decreases to acidic. Therefore an acidic pH can activate SP1.

Acidic pHe stimulates disruption of adherence junctions

When tumor cells move into their surrounding tissue, cell-cell junctions become dissociated. Acidic pH disrupts adherence junction by Src activation, resulting in E-cadherin degradation through the protein kinase Cδ pathway. Acidic pHe also induces motility of tumor cells, and inhibits monocyte migration and cytokine release.

Acidic pHe stimulates metastatic potential

Brockton et al. have shown that high stromal CA IX expression is associated with nodal metastasis. The high activity produces an acidic microenvironment that leads to increased metastatic ability of the tumor cells. We have reported that induction rate of MMP-9 secretion correlates with metastatic potential of mouse B16 melanoma clones, and an acidic pHe stimulates invasion through a type-IV collagen barrier. In human melanoma models, an acidic pHe increases both migration and invasiveness in vitro, accompanied by MMP-9 activation. NHE1 is also associated with the metastatic ability of tumor cells; it is accumulated in leading edge of the cell and is activated by CD44 (a hyaluronan (HA) receptor) -binding to HA. Because HA directs membrane-type 1 matrix metalloproteinase (MT1-MMP) to the invasion front (invadopodia), NHE1 might interact with MT1-MMP through CD44 at an acidic pHe.

Pretreatment of the tumor cells in an acidic medium induces production of proteinases (MMPs and cathepsins) and proangiogenic factors (VEGF-A and IL-8) and promotes experimental metastasis to the lung after injection into the tail vein of nude mice; elevation of pH by one unit following injection of sodium bicarbonate prevents spontaneous metastases. Furthermore, using P-31 magnetic resonance spectroscopic evaluation, it was found that acidic pHe in spontaneous soft tissue sarcomas predicts metastasis in dogs.

Acidic pHe sensing systems

ASICs are voltage-independent and proton-activated channels found in tumor cells and associated tumor malignancy. Transient receptor potential (TRP) V isoforms, TRPV1, TRPV5 and TRPV6, also act as acid-sensitive channels. ERK1/2 plays as a downstream target of ASICs and TRPVs. Another subfamily of TRP, TRPM7 has proton conductivity. TRPM7 regulates EGF signaling to induce STAT3 activation and vimentin expression during epithelial-mesenchymal transition. OGR1 also acts as a proton-sensing receptor, stimulating inositol phosphate formation.

pHe gradient formation by H+ pumps and exchangers

NHE1 accumulates at the leading edge to make a pHe gradient associated with cell migration. The Rho-ROCK pathway contributes to NHE1 activation and focal adhesions. Protons stabilize the collagen–α2β1 integrin bond, but alkalosis, a lack of protons or an inhibited NHE activity, prevents adhesion. Furthermore, the cell forms an individual pHe gradient to facilitate movement: i.e. at leading edge or invadopodia, cells preferentially attach to the substrate due to the acidic pHe induced by NHE1, while cell-matrix interaction at the rear end is weak due to a mid-alkaline pHe. Mutation studies clearly showed that downregulation of NHE1 function suppresses cell polarity, migration, and invasion through matrigel™. Inhibition of NHE1 activity by HOE642 (cariporide) reduced migration and adhesion activities.

To secrete acidic metabolites, NHE1 and the H+-lactate co-transporter are involved. H+-ATPase (the H+ pump) and cell surface ATP synthase also play a role in extracellular acidification, thereby contributing to tumor metastasis. Therefore, inhibition of the H+ pump can be a new strategy for cancer treatment. Angiostatin has anti-tumor efficacy by inhibiting cell surface ATP synthase activity through binding its β subunit. In particular, treatment of the cells with angiostatin proved more cytotoxicity at an acidic pHe than a neutral pHe.

Drug efficacy and acidic pHe

Two analogues of camptothecin (CPT), topotecan (TPT) and irinotecan (CPT-11), have significant anti-tumor activity in the clinic, although their abilities depend on the CPT E ring lactone, which forms an inactive hydroxy acid at physiological pH. The reaction is reversible at an acidic pHe, which provides a rationale for selectivity because many solid tumors, while creating an acidic extracellular environment, maintain a normal intracellular pH. An acidic pHe inhibits cellular uptake of mitoxantrone and topotecan, so that elevation of pHe in tumor tissue enhances those drugs’ efficacy. Because the buffer action is weaker in tumor tissue than normal tissue, NaHCO3 has much potential to raise pHe relatively specifically in tumor tissue. Acidic pHe also plays a role in the resistance of tumor cells to drugs by increasing the expression of p-glycoprotein, thereby increasing drug efflux. Recently, an acidic pHe-specific drug-releasing system has been developed. A novel polymeric micelle constituted of 2 block copolymers of poly (L-lactic acid)-b-poly(ethylene glycol) b-poly (L-histidine) - TAT (transactivator of transcription) and poly(L-histidine)-b-poly(ethylene glycol) increases the cytotoxicity of doxorubicin in several multidrug-resistant tumor cell lines. To measure pHe, a magnetic resonance image technique has been developed using acidic pHe specific probes. Thus, clinicians should pay attention to tumor pHe in selecting drugs and helping to maximize their chemotherapeutic action. Vasodilating drugs, such as hydralazine and captopril, inhibit tumor growth rate in vivo by reducing tumor blood flow. Although the reduction in tumor growth by those drugs also reduces the oxygen supply, it reduces pHe. In patients given vasodilating drugs, anti-tumor drugs with weak acidic pKa value, such as 5-fluorouracil (5FU) and cyclophosphamide, may have increased efficacy at an acidic pHe. In contrast, the anti-tumor drugs with weak base pKa values, such as doxorubicin, mitoxantrone and daunorubicin, may not be fully functioned because acidic pHe reduces their cytotoxicity. In early-stage breast cancer, high CAIX is a predictive marker of doxorubicin resistance.

Because cis-diamminedichloroplatinum (II) (CDDP) solution has an acidic pH, NaHCO3 is used to prevent the angialgia in the cancer patients coming from the acidic pH solution injection because it increases pH. However, CDDP is frequently used for co-injection with other chemotherapeutic drugs, such as 5FU. In some cases, co-injection of NaHCO3 (depends on the concentration) may reduce the clinical efficacy of 5FU + CDDP regimen.

Hyperthermia and acidic pHe

Hyperthermic treatment (42.5°C) for JB-1-E plasmacytoma tumor cells in vitro enhances the colony formation index when cells are maintained at pH 6.4, regardless oxygen tensions. Melanoma cells growing at low pH are sensitized to hyperthermia because of the altered intracellular pH threshold for the heat sensitization in vitro.

Conclusion

Acidic pHe is toxic to many cells, including tumors. However, if tumors have successfully adapted to their condition, and use it for their own cellular activation, this increases drug resistance and leads to more aggressive behavior. Therefore, management of tumor pHe and inhibition of blockade of proton-sensing system are important in not only raising drug efficacy, e.g. mitoxantrone, but in preventing metastasis.

Abbreviations

pHe: Extracellular pH; NHE: Na+/H+ exchanger; MCT: Monocarboxylate transporter; CA: Carbonic anhydrase; IL: Interleukin; NF-κB: Nuclear factor κB; VEGF: Vascular endothelial growth factor; HIF: Hypoxia inducible factor; LDH: Lactate dehydrogenase; OGR: Ovarian cancer G-protein-coupled receptor; PG: Prostaglandin; ASIC: Acid-sensing ion channel; KO: Knockout; FAK: Focal adhesion kinase; MMP: Matrix-metalloproteinase; iNOS: Nitric oxide synthase; PLD: Phospholipase D; MAPK: Mitogen-activated protein kinase; TNF-α: Tumor necrosis factor-α; HA: Hyaluronan; MT1-MMP: Membrane-type 1 matrix metalloproteinase; TRP: Transient receptor potential; CDDP: cis-Diamminedichloroplatinum (II).

Competing interests

The authors declare no competing financial interests.

Authors’ contributions

YK designed the study. SO, CM, YM, AS and TM were involved in discussion. YK drafted the manuscript. YB revised the manuscript. All authors read and approved the final manuscript.

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    Nagae M Hiraga T Wakabayashi H Wang L Iwata K Yoneda T Osteoclasts play a part in pain due to the inflammation adjacent to boneBone2006 39511071115

    Not in our library10.1016/j.bone.2006.04.033

  44. 44.

    Jasti J Furukawa H Gonzales EB Gouaux E Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pHNature2007 4497160316323

    Not in our library10.1038/nature06163

  45. 45.

    Marples MJ The ecology of human skin1965 Springfield, IL: Charles C. Thomas

    Not in our library

  46. 46.

    Behne MJ Barry NP Hanson KM Aronchik I Clegg RW Gratton E Feingold K Holleran WM Elias PM Mauro TM Neonatal development of the stratum corneum pH gradient: localization and mechanisms leading to emergence of optimal barrier functionJ Invest Dermatol2003 12069981006

    Not in our library10.1038/jid.2003.11

  47. 47.

    Ilic D Mao-Qiang M Crumrine D Dolganov G Larocque N Xu P Demerjian M Brown BE Lim ST Ossovskaya V Focal adhesion kinase controls pH-dependent epidermal barrier homeostasis by regulating actin-directed Na+/H+ exchanger 1 plasma membrane localizationAm J Pathol2007 170620552067

    Not in our library10.2353/ajpath.2007.061277

  48. 48.

    Adamson TM Boyd RD Platt HS Strang LB Composition of alveolar liquid in the foetal lambJ Physiol1969 2041159168

    Not in our library10.1113/jphysiol.1969.sp008905

  49. 49.

    Tate S MacGregor G Davis M Innes JA Greening AP Airways in cystic fibrosis are acidified: detection by exhaled breath condensateThorax2002 5711926929

    Not in our library10.1136/thorax.57.11.926

  50. 50.

    Ricciardolo FL Gaston B Hunt J Acid stress in the pathology of asthmaJ Allergy Clin Immunol2004 1134610619

    Not in our library10.1016/j.jaci.2003.12.034

  51. 51.

    Bekku S Mochizuki H Yamamoto T Ueno H Takayama E Tadakuma T Expression of carbonic anhydrase I or II and correlation to clinical aspects of colorectal cancerHepatogastroenterology2000 47349981001

    Not in our library

  52. 52.

    Leppilampi M Koistinen P Savolainen ER Hannuksela J Parkkila AK Niemela O Pastorekova S Pastorek J Waheed A Sly WS The expression of carbonic anhydrase II in hematological malignanciesClin Cancer Res2002 8722402245

    Not in our library

  53. 53.

    Chiche J Ilc K Laferriere J Trottier E Dayan F Mazure NM Brahimi-Horn MC Pouyssegur J Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pHCancer Res2009 691358368

    Not in our library10.1158/0008-5472.can-08-2470

  54. 54.

    Brockton NT Klimowicz AC Bose P Petrillo SK Konno M Rudmik L Dean M Nakoneshny SC Matthews TW Chandarana S High stromal carbonic anhydrase IX expression is associated with nodal metastasis and decreased survival in patients with surgically-treated oral cavity squamous cell carcinomaOral Oncol2012 487615622

    Not in our library10.1016/j.oraloncology.2012.01.018

  55. 55.

    Parkkila S Parkkila AK Saarnio J Kivela J Karttunen TJ Kaunisto K Waheed A Sly WS Tureci O Virtanen I Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumorsJ Histochem Cytochem2000 481216011608

    Not in our library10.1177/002215540004801203

  56. 56.

    Kummola L Hamalainen JM Kivela J Kivela AJ Saarnio J Karttunen T Parkkila S Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosaBMC cancer2005 541

    Not in our library10.1186/1471-2407-5-41

  57. 57.

    Swietach P Wigfield S Cobden P Supuran CT Harris AL Vaughan-Jones RD Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growthsJ Biol Chem2008 283292047320483

    Not in our library10.1074/jbc.m801330200

  58. 58.

    Williams E Martin S Moss R Durrant L Deen S Co-expression of VEGF and CA9 in ovarian high-grade serous carcinoma and relationship to survivalVirchows Arch2012 46113339

    Not in our library10.1007/s00428-012-1252-9

  59. 59.

    Shin HJ Rho SB Jung DC Han IO Oh ES Kim JY Carbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasionJ Cell Sci2011 124Pt 710771087

    Not in our library10.1242/jcs.072207

  60. 60.
    Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro · 2000
    Not checked
  61. 61.

    Zatovicova M Jelenska L Hulikova A Csaderova L Ditte Z Ditte P Goliasova T Pastorek J Pastorekova S Carbonic anhydrase IX as an anticancer therapy target: preclinical evaluation of internalizing monoclonal antibody directed to catalytic domainCurr Pharm Des2010 162932553263

    Not in our library10.2174/138161210793429832

  62. 62.

    Muselaers S Mulders P Oosterwijk E Oyen W Boerman O Molecular imaging and carbonic anhydrase IX-targeted radioimmunotherapy in clear cell renal cell carcinomaImmunotherapy2013 55489495

    Not in our library10.2217/imt.13.36

  63. 63.

    Oosterwijk-Wakka JC Boerman OC Mulders PF Oosterwijk E Application of Monoclonal Antibody G250 Recognizing Carbonic Anhydrase IX in Renal Cell CarcinomaInt J Mol Sci2013 1461140211423

    Not in our library10.3390/ijms140611402

  64. 64.

    Tjäderhane L Larjava H Sorsa T Uitto VJ Larmas M Salo T The activation and function of host matrix metalloproteinases in dentin matrix breakdown in caries lesionsJ Dent Res1998 77816221629

    Not in our library10.1177/00220345980770081001

  65. 65.

    Davis GE Martin BM A latent Mr 94,000 gelatin-degrading metalloprotease induced during differentiation of HL-60 promyelocytic leukemia cells: a member of the collagenase family of enzymesCancer Res1990 50411131120

    Not in our library

  66. 66.

    Davis GE Identification of an abundant latent 94-kDa gelatin-degrading metalloprotease in human saliva which is activated by acid exposure: implications for a role in digestion of collagenous proteinsArch Biochem Biophys1991 2862551554

    Not in our library10.1016/0003-9861(91)90078-w

  67. 67.

    Martinez-Zaguilan R Seftor EA Seftor RE Chu YW Gillies RJ Hendrix MJ Acidic pH enhances the invasive behavior of human melanoma cellsClin Exp Metastasis1996 142176186

    Not in our library10.1007/bf00121214

  68. 68.

    Karsdal MA Henriksen K Sorensen MG Gram J Schaller S Dziegiel MH Heegaard AM Christophersen P Martin TJ Christiansen C Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorptionAm J Pathol2005 1662467476

    Not in our library10.1016/s0002-9440(10)62269-9

  69. 69.

    Saftig P Hunziker E Wehmeyer O Jones S Boyde A Rommerskirch W Moritz JD Schu P Von Figura K Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient miceProc Natl Acad Sci U S A1998 95231345313458

    Not in our library10.1073/pnas.95.23.13453

  70. 70.

    Le Gall C Bellahcene A Bonnelye E Gasser JA Castronovo V Green J Zimmermann J Clezardin P A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burdenCancer Res2007 672098949902

    Not in our library10.1158/0008-5472.can-06-3940

  71. 71.

    Podgorski I Linebaugh BE Koblinski JE Rudy DL Herroon MK Olive MB Sloane BF Bone marrow-derived cathepsin K cleaves SPARC in bone metastasisAm J Pathol2009 175312551269

    Not in our library10.2353/ajpath.2009.080906

  72. 72.

    Nakajima M Irimura T Di Ferrante D Di Ferrante N Nicolson GL Heparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublinesScience1983 2204597611613

    Not in our library10.1126/science.6220468

  73. 73.

    Nakajima M Irimura T Di Ferrante N Nicolson GL Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidaseJ Biol Chem1984 259422832290

    Not in our library

  74. 74.

    Kato Y Ozawa S Tsukuda M Kubota E Miyazaki K St-Pierre Y Hata R Acidic extracellular pH increases calcium influx-triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase-9 expression in mouse metastatic melanomaFEBS J2007 2741231713183

    Not in our library10.1111/j.1742-4658.2007.05848.x

  75. 75.

    Kato Y Nakayama Y Umeda M Miyazaki K Induction of 103-kDa gelatinase/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell linesJ Biol Chem1992 267161142411430

    Not in our library

  76. 76.

    Griffiths L Dachs GU Bicknell R Harris AL Stratford IJ The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivoCancer Res1997 574570572

    Not in our library

  77. 77.

    Bellocq A Suberville S Philippe C Bertrand F Perez J Fouqueray B Cherqui G Baud L Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages. Evidence for involvement of nuclear factor-κB activationJ Biol Chem1998 273950865092

    Not in our library10.1074/jbc.273.9.5086

  78. 78.

    Fukumura D Xu L Chen Y Gohongi T Seed B Jain RK Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivoCancer Res2001 611660206024

    Not in our library

  79. 79.

    Xu L Fukumura D Jain RK Acidic extracellular pH induces vascular endothelial growth factor (VEGF) in human glioblastoma cells via ERK1/2 MAPK signaling pathway: mechanism of low pH-induced VEGFJ Biol Chem2002 277131136811374

    Not in our library10.1074/jbc.m108347200

  80. 80.

    Shi Q Abbruzzese JL Huang S Fidler IJ Xiong Q Xie K Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastaticClin Cancer Res1999 51137113721

    Not in our library

  81. 81.

    Shi Q Le X Wang B Xiong Q Abbruzzese JL Xie K Regulation of interleukin-8 expression by cellular pH in human pancreatic adenocarcinoma cellsJ Interferon Cytokine Res2000 201110231028

    Not in our library10.1089/10799900050198471

  82. 82.

    Shi Q Xiong Q Le X Xie K Regulation of interleukin-8 expression by tumor-associated stress factorsJ Interferon Cytokine Res2001 218553566

    Not in our library10.1089/10799900152547812

  83. 83.

    Xu L Fidler IJ Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cellsCancer Res2000 601646104616

    Not in our library

  84. 84.

    Shi Q Le X Wang B Abbruzzese JL Xiong Q He Y Xie K Regulation of vascular endothelial growth factor expression by acidosis in human cancer cellsOncogene2001 202837513756

    Not in our library10.1038/sj.onc.1204500

  85. 85.

    Bischoff DS Zhu JH Makhijani NS Yamaguchi DT Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (interleukin-8), in human adult mesenchymal stem cells via the extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and NF-κB pathwaysJ Cell Biochem2008 104413781392

    Not in our library10.1002/jcb.21714

  86. 86.

    Kato Y Ozono S Shuin T Miyazaki K Slow induction of gelatinase B mRNA by acidic culture conditions in mouse metastatic melanoma cellsCell Biol Int1996 205375377

    Not in our library10.1006/cbir.1996.0044

  87. 87.

    Kato Y Lambert CA Colige AC Mineur P Noël A Frankenne F Foidart JM Baba M Hata RI Miyazaki K Acidic extracellular pH induces matrix metalloproteinase-9 expression in mouse metastatic melanoma cells through the phospholipase D-mitogen-activated protein kinase signalingJ Biol Chem2005 280121093810944

    Not in our library10.1074/jbc.m411313200

  88. 88.

    Itatsu K Sasaki M Harada K Yamaguchi J Ikeda H Sato Y Ohta T Sato H Nagino M Nimura Y Phosphorylation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and nuclear translocation of nuclear factor-κB are involved in upregulation of matrix metalloproteinase-9 by tumour necrosis factor-αLiver Int2009 292291298

    Not in our library10.1111/j.1478-3231.2008.01858.x

  89. 89.

    Hirata S Fukamachi T Sakano H Tarora A Saito H Kobayashi H Extracellular acidic environments induce phosphorylation of ZAP-70 in Jurkat T cellsImmunol Lett2008 1152105109

    Not in our library10.1016/j.imlet.2007.10.006

  90. 90.

    Tomura H Wang JQ Komachi M Damirin A Mogi C Tobo M Kon J Misawa N Sato K Okajima F Prostaglandin l2 production and cAMP accumulation in response to acidic extracellular pH through OGR1 in human aortic smooth muscle cellsJ Biol Chem2005 280413445834464

    Not in our library10.1074/jbc.m505287200

  91. 91.

    Torigoe T Izumi H Yoshida Y Ishiguchi H Okamoto T Itoh H Kohno K Low pH enhances Sp1 DNA binding activity and interaction with TBPNucleic Acids Res2003 311545234530

    Not in our library10.1093/nar/gkg487

  92. 92.

    Chen Y Chen CH Tung PY Huang SH Wang SM An acidic extracellular pH disrupts adherens junctions in HepG2 cells by Src kinases-dependent modification of E-cadherinJ Cell Biochem2009 1084851859

    Not in our library10.1002/jcb.22313

  93. 93.

    Chen Y Kung HN Chen CH Huang SH Chen KH Wang SM Acidic extracellular pH induces p120-catenin-mediated disruption of adherens junctions via the Src kinase-PKCδ pathwayFEBS Lett2011 5854705710

    Not in our library10.1016/j.febslet.2011.01.022

  94. 94.

    Bourguignon LY Singleton PA Diedrich F Stern R Gilad E CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasionJ Biol Chem2004 279262699127007

    Not in our library10.1074/jbc.m311838200

  95. 95.

    Mori H Tomari T Koshikawa N Kajita M Itoh Y Sato H Tojo H Yana I Seiki M CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domainEMBO J2002 211539493959

    Not in our library10.1093/emboj/cdf411

  96. 96.

    Suenaga N Mori H Itoh Y Seiki M CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinaseOncogene2005 245859868

    Not in our library10.1038/sj.onc.1208258

  97. 97.

    Lin Y Chang G Wang J Jin W Wang L Li H Ma L Li Q Pang T NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMPExp Cell Res2011 3171420312040

    Not in our library10.1016/j.yexcr.2011.05.026

  98. 98.

    Lin Y Wang J Jin W Wang L Li H Ma L Li Q Pang T NHE1 mediates migration and invasion of HeLa cells via regulating the expression and localization of MT1-MMPCell Biochem Funct2012 14146

    Not in our library10.1002/cbf.1815

  99. 99.

    Robey IF Baggett BK Kirkpatrick ND Roe DJ Dosescu J Sloane BF Hashim AI Morse DL Raghunand N Gatenby RA Bicarbonate increases tumor pH and inhibits spontaneous metastasesCancer Res2009 69622602268

    Not in our library10.1158/0008-5472.can-07-5575

  100. 100.

    Lora-Michiels M Yu D Sanders L Poulson JM Azuma C Case B Vujaskovic Z Thrall DE Charles HC Dewhirst MW Extracellular pH and P-31 magnetic resonance spectroscopic variables are related to outcome in canine soft tissue sarcomas treated with thermoradiotherapyClin Cancer Res2006 121957335740

    Not in our library10.1158/1078-0432.ccr-05-2669

  101. 101.

    Berdiev BK Xia J McLean LA Markert JM Gillespie GY Mapstone TB Naren AP Jovov B Bubien JK Ji HL Acid-sensing ion channels in malignant gliomasJ Biol Chem2003 278171502315034

    Not in our library10.1074/jbc.m300991200

  102. 102.

    Ohta T Imagawa T Ito S Novel gating and sensitizing mechanism of capsaicin receptor (TRPV1): tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1J Biol Chem2008 2831493779387

    Not in our library10.1074/jbc.m709377200

  103. 103.

    Nakaya K Harbidge DG Wangemann P Schultz BD Green ED Wall SM Marcus DC Lack of pendrin HCO3- transport elevates vestibular endolymphatic [Ca2+] by inhibition of acid-sensitive TRPV5 and TRPV6 channelsAm J Physiol Renal Physiol2007 2925F1314F1321

    Not in our library10.1152/ajprenal.00432.2006

  104. 104.

    Chen Y Willcockson HH Valtschanoff JG Vanilloid receptor TRPV1-mediated phosphorylation of ERK in murine adjuvant arthritisOsteoarthritis Cartilage2009 172244251

    Not in our library10.1016/j.joca.2008.06.015

  105. 105.

    Chen Y Williams SH McNulty AL Hong JH Lee SH Rothfusz NE Parekh PK Moore C Gereau RW Taylor AB Temporomandibular joint pain: A critical role for Trpv4 in the trigeminal ganglionPain2013 154812951304

    Not in our library10.1016/j.pain.2013.04.004

  106. 106.

    Wang G Su J Li L Feng J Shi L He W Liu Y Edaravone alleviates hypoxia-acidosis/reoxygenation-induced neuronal injury by activating ERK1/2Neurosci Lett2013 5437277

    Not in our library10.1016/j.neulet.2013.02.067

  107. 107.

    Numata T Okada Y Proton conductivity through the human TRPM7 channel and its molecular determinantsJ Biol Chem2008 283221509715103

    Not in our library10.1074/jbc.m709261200

  108. 108.

    Davis FM Azimi I Faville RA Peters AA Jalink K Putney JW Jr Goodhill GJ Thompson EW Roberts-Thomson SJ Monteith GR Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependentOncogene2013 in press

    Not in our library10.1038/onc.2013.187

  109. 109.

    Stüwe L Müller M Fabian A Waning J Mally S Noël J Schwab A Stock C pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solutionJ Physiol2007 585Pt 2351360

    Not in our library10.1113/jphysiol.2007.145185

  110. 110.

    Tominaga T Barber DL Na-H exchange acts downstream of RhoA to regulate integrin-induced cell adhesion and spreadingMol Biol Cell1998 9822872303

    Not in our library10.1091/mbc.9.8.2287

  111. 111.

    Denker SP Barber DL Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1J Cell Biol2002 159610871096

    Not in our library10.1083/jcb.200208050

  112. 112.

    Stock C Gassner B Hauck CR Arnold H Mally S Eble JA Dieterich P Schwab A Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchangeJ Physiol2005 567Pt 1225238

    Not in our library10.1113/jphysiol.2005.088344

  113. 113.

    Krahling H Mally S Eble JA Noel J Schwab A Stock C The glycocalyx maintains a cell surface pH nanoenvironment crucial for integrin-mediated migration of human melanoma cellsPflugers Arch2009 458610691083

    Not in our library10.1007/s00424-009-0694-7

  114. 114.

    Cardone RA Casavola V Reshkin SJ The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasisNat Rev Cancer2005 510786795

    Not in our library10.1038/nrc1713

  115. 115.

    Montcourrier P Silver I Farnoud R Bird I Rochefort H Breast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanismClin Exp Metastasis1997 154382392

    Not in our library10.1023/a:1018446104071

  116. 116.

    Chi SL Pizzo SV Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthaseCancer Res2006 662875882

    Not in our library10.1158/0008-5472.can-05-2806

  117. 117.
    Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy · 2010
    Not checked
  118. 118.

    De Milito A Canese R Marino ML Borghi M Iero M Villa A Venturi G Lozupone F Iessi E Logozzi M pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidityInt J Cancer2010 1271207219

    Not in our library10.1002/ijc.25009

  119. 119.

    Wiedmann RM Von Schwarzenberg K Palamidessi A Schreiner L Kubisch R Liebl J Schempp C Trauner D Vereb G Zahler S The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1Cancer Res2012 722259765987

    Not in our library10.1158/0008-5472.can-12-1772

  120. 120.

    Adams DJ Dewhirst MW Flowers JL Gamcsik MP Colvin OM Manikumar G Wani MC Wall ME Camptothecin analogues with enhanced antitumor activity at acidic pHCancer Chemother Pharmacol2000 464263271

    Not in our library10.1007/s002800000157

  121. 121.

    Vukovic V Tannock IF Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecanBr J Cancer1997 75811671172

    Not in our library10.1038/bjc.1997.201

  122. 122.
    Enhancement of chemotherapy by manipulation of tumour pH · 1999
    No notice
  123. 123.

    Raghunand N Mahoney B Van Sluis R Baggett B Gillies RJ Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantroneNeoplasia2001 33227235

    Not in our library10.1038/sj.neo.7900151

  124. 124.

    Lotz C Kelleher DK Gassner B Gekle M Vaupel P Thews O Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cellsOncol Rep2007 171239244

    Not in our library

  125. 125.

    Thews O Dillenburg W Rosch F Fellner M PET imaging of the impact of extracellular pH and MAP kinases on the p-glycoprotein (Pgp) activityAdv Exp Med Biol2013 765279286

    Not in our library10.1007/978-1-4614-4989-8_39

  126. 126.

    Ko J Park K Kim YS Kim MS Han JK Kim K Park RW Kim IS Song HK Lee DS Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapyJ Control Release2007 1232109115

    Not in our library10.1016/j.jconrel.2007.07.012

  127. 127.

    Lee ES Gao Z Kim D Park K Kwon IC Bae YH Super pH-sensitive multifunctional polymeric micelle for tumor pHe specific TAT exposure and multidrug resistanceJ Control Release2008 1293228236

    Not in our library10.1016/j.jconrel.2008.04.024

  128. 128.

    Garcia-Martin ML Martinez GV Raghunand N Sherry AD Zhang S Gillies RJ High resolution pHe imaging of rat glioma using pH-dependent relaxivityMagn Reson Med2006 552309315

    Not in our library10.1002/mrm.20773

  129. 129.

    Van Sluis R Bhujwalla ZM Raghunand N Ballesteros P Alvarez J Cerdan S Galons JP Gillies RJ In vivo imaging of extracellular pH using 1H MRSIMagn Reson Med1999 414743750

    Not in our library10.1002/(sici)1522-2594(199904)41:4<743::aid-mrm13>3.0.co;2-z

  130. 130.

    Adachi E Tannock IF The effects of vasodilating drugs on pH in tumorsOncol Res1999 114179185

    Not in our library

  131. 131.

    Raghunand N Mahoney BP Gillies RJ Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agentsBiochem Pharmacol2003 66712191229

    Not in our library10.1016/s0006-2952(03)00468-4

  132. 132.

    Betof AS Rabbani ZN Hardee ME Kim SJ Broadwater G Bentley RC Snyder SA Vujaskovic Z Oosterwijk E Harris LN Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplificationBr J Cancer2012 1065916922

    Not in our library10.1038/bjc.2012.32

  133. 133.

    Teh BG Kobayashi W Narita K Fukui R Kimura H Superselective docetaxel-nedaplatin combined infusion concurrent with radiation thrapy in advanced oral cancersOral Oncol EXTRA2004 40126131

    Not in our library10.1016/j.ooe.2004.08.002

  134. 134.

    Shiga K Yokoyama J Hashimoto S Saijo S Tateda M Ogawa T Watanabe M Kobayashi T Combined therapy after superselective arterial cisplatin infusion to treat maxillary squamous cell carcinomaOtolaryngol Head Neck Surg2007 136610031009

    Not in our library10.1016/j.otohns.2006.12.018

  135. 135.

    Overgaard J Bichel P The influence of hypoxia and acidity on the hyperthermic response of malignant cells in vitroRadiology1977 1232511514

    Not in our library10.1148/123.2.511

  136. 136.

    Coss RA Storck CW Daskalakis C Berd D Wahl ML Intracellular acidification abrogates the heat shock response and compromises survival of human melanoma cellsMol Cancer Ther2003 24383388

    Not in our library

  137. 137.

    Coss RA Storck CW Wachsberger PR Reilly J Leeper DB Berd D Wahl ML Acute extracellular acidification reduces intracellular pH, 42°C-induction of heat shock proteins and clonal survival of human melanoma cells grown at pH 6.7Int J Hyperthermia2004 20193106

    Not in our library10.1080/02656730310001605519

  138. 138.

    Lan A Lagadic-Gossmann D Lemaire C Brenner C Jan G Acidic extracellular pH shifts colorectal cancer cell death from apoptosis to necrosis upon exposure to propionate and acetate, major end-products of the human probiotic propionibacteriaApoptosis2007 123573591

    Not in our library10.1007/s10495-006-0010-3

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