Cancer Cell International. Dec/31/2012; 13: 89-89

Published online Sep/2/2013

PMID: 24004445

PMC: 3849184

doi: 10.1186/1475-2867-13-89

Acidic extracellular microenvironment and cancer

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.

Introduction

The extracellular pH (pH_e) of tumor tissues is often acidic [1], 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) [2], the H⁺-lactate co-transporter, monocarboxylate transporters (MCTs), and the H⁺-ATPase (H⁺ pump) are responsible for the secretion of H⁺[3]. 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 [4]. Acidic pH_e 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 [5]. 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 pH_e 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 [1]. High lactate levels indicate metastases, tumor recurrence, and prognosis in some cancer patients [6-9]. 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 [10]. 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 [11]. Lactate inhibits dendritic cell activation during antigen-specific autologous T-cell stimulation [12]. It also enhances the motility of tumor cells and inhibits monocyte migration and cytokine release [13]. It can contribute to angiogenesis through induction of IL-8 via nuclear factor-κB (NF-κB) [14] and induction of vascular endothelial growth factor (VEGF/VEGF-A) via hypoxia-inducible transcription factor (HIF)-1 [15]. Furthermore, lactate production contributes to radio-resistance of tumors due to its antioxidant properties [16].

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 [17]. Quercetin (CYP2C9), which is an inhibitory flavonoid, inhibits lactate transport and acts as a hyperthermic sensitizer of HeLa cells [18].

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 [19]. Since high lactate corresponds to a high proton concentration, an acidic pH_e is a major feature of the solid tumor tissue [1,20-22]. 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 [23,24] and colorectal cancers [25-27].

CO₂ is a major source of acid in glycolytically impaired mice [4]. 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 [28,29] and the proton can be secreted through H⁺-ATPase [30]. Induction of CA II expression itself is also induced by an acidic pH_e[31]. 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 [32] and solid tumor tissue [1,20-22]. 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 [20-22,33]. The acidic microenvironment acts as a trigger for pain in both inflammation [34,35] and in cancer patients [36].

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 [37]. OGR1 (GPR68) stimulates cyclooxygenase-2 expression and prostaglandin (PG) E₂ production in response to acidic pH_e in a human osteoblastic cell line [38]. Because PGE₂ is involved in osteoclastic differentiation of precursor cells [39], inhibition of the OGR1 signaling negatively regulates osteoclastogenesis [40]. Another type of G-protein-coupled receptor, TDAG8 (GPR65), also senses pH_e[41,42].

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 [36]. During this process, patients feel pain through acid-sensing ion channels (ASIC) 1a, 1b and 3 [36,43,44].

An acidic pH_e is also found in the epidermis and plays an important protective role against bacterial infection [45-47]. Using the conditional knockout (KO) mice for focal adhesion kinase (FAK) in keratinocytes, Ilic et al. [47] showed that the stratum corneum pH_e gradient of keratinocytes in these mice had significantly more neutral pH values, and that NHE1 failed to localize to the plasma membrane [47]. Thus, FAK controls pH-dependent epidermal barrier homeostasis by regulating actin-directed NHE1 plasma membrane localization [47].

Lung liquid is acidic [48], which is worse in patients with cystic fibrosis [49], although the airway pH is not known for certain because different detecting methods have been used [50].

CA expression in cancer

CA isoforms are associated with tumor malignancy, including CA I [51], CA II [51,52], CA IX [53,54], CA XII [55], and CA XIII [56]. Among them, CA IX in particular has been well studied in association with hypoxia and tumor survival through regulating intracellular pH [53,57]. In ovarian cancer, high expression of CA IX with a concomitant increase in VEGF-A is associated with overall survival rates positively [58]. Overexpression of CA IX increases tumor cell migration and invasion [59]. CA inhibitor suppresses invasion of renal cancer cells in vitro[60]. Based on the accumulated evidence, a new therapeutic strategy targeting CA has been considered [61-63].

Acidic pH_e activates proteinase activity and induces gene expression

Acidic pH_e activates some proteinases. Although caries is due to some bacterial acidic metabolites, Tjäderhane et al. [64] 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 [65,66]. Activation of proMMP-9 by an acidic pH_e also occurs in a human melanoma model [67].

Lysosomal enzymes have an acidic optimal pH. Some tumor cells have the ability to secrete them, such as cathepsin B and cathepsin L [5]. Cathepsin K plays an important role in osteoclast-mediated bone resorption [68,69]; its inhibition prevents breast cancer-induced osteolysis and skeletal tumor burden [70]. Thus, osteoclast-mediated acidic pH_e leads to mineral dissolution and activation of cathepsins to digest bone matrix, such as type I collagen. Podgorski et al. [71] 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 [72,73].

Also, acidic microenvironments affect the expression of some genes, such as MMP-9 [74,75] and acidic sphingomyelinase in mouse B16 melanoma [74], platelet-derived endothelial cell growth factor (thymidine phosphorylase) in human breast cancer cells [76], the inducible isoform of nitric oxide synthase (iNOS) in macrophages [77], VEGF-A in glioma [78] and glioblastoma [79] cells, and IL-8 expression in human pancreatic adenocarcinoma [80-82] and ovarian carcinoma cells [83].

Acidic pH_e signal transduction pathway

Thus, although acidic pH_e 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 pH_e-induced expression of VEGF-A [78,84] and IL-8 [80-83,85]. p38 mitogen-activated protein kinase (MAPK) is involved in acidic pH_e signaling that induces IL-8 [85].

We also found involvement of phospholipase D (PLD) in the acidic pH_e-intracellular signaling to induce MMP-9 production [75,86]. Acidic pH_e-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 pH_e-induced MMP-9 expression [87]. Acidic pH_e 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 pH_e-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 pH_e-induced MMP-9 promoter activity, and NF-κB activity was induced by acidic pH_e. Pharmacological inhibitors specific for MEK1/2 (PD098059) and p38 (SB203580) attenuated acidic pH_e-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 pH_e 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 [88]. This suggests that acidic pH_e signaling is, at least in part, the signaling pathway for TNF-α. However, it has been reported that acidic pH_e activates p38, but not ERK1/2, in T-cell receptor signaling in Jurkat cells [89]. This may be cell-type specific. In a further contribution dealing with the intracellular substances of acidic pH_e, we have found that calcium influx triggers acidic pH_e-induced PLD activation and that acidic sphingomyelinase mediates acidic pH_e signaling to activate NF-κB independently of the PLD-MAPK pathway [74].

OGR1 stimulates cyclooxygenase-2 expression and PGE₂ production in response to an acidic pH_e in a human osteoblastic cell line through G(q/11)/phospholipase C/protein kinase C pathway [38] and in human aortic smooth muscle cells through the phospholipase C/cyclooxygenase/PGI₂ pathway [90].

Acidic pH directly affects transcription factor activity; DNA binding activity of the transcription factor, SP1, is enhanced by intracellular acidic pH [91]. Intracellular pH is maintained a constitutively neutral state but known to become transiently acidic when pH_e decreases to acidic. Therefore an acidic pH can activate SP1.

Acidic pH_e 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 [92,93]. Acidic pH_e also induces motility of tumor cells, and inhibits monocyte migration and cytokine release [13].

Acidic pH_e stimulates metastatic potential

Brockton et al. [54] 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 pH_e stimulates invasion through a type-IV collagen barrier [75,86]. In human melanoma models, an acidic pH_e increases both migration and invasiveness in vitro, accompanied by MMP-9 activation [67]. 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 [94]. Because HA directs membrane-type 1 matrix metalloproteinase (MT1-MMP) to the invasion front (invadopodia) [95,96], NHE1 might interact with MT1-MMP through CD44 at an acidic pH_e[97,98].

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 [5]; elevation of pH by one unit following injection of sodium bicarbonate prevents spontaneous metastases [99]. Furthermore, using P-31 magnetic resonance spectroscopic evaluation, it was found that acidic pH_e in spontaneous soft tissue sarcomas predicts metastasis in dogs [100].

Acidic pH_e sensing systems

ASICs are voltage-independent and proton-activated channels found in tumor cells and associated tumor malignancy [101]. Transient receptor potential (TRP) V isoforms, TRPV1, TRPV5 and TRPV6, also act as acid-sensitive channels [102,103]. ERK1/2 plays as a downstream target of ASICs and TRPVs [104-106]. Another subfamily of TRP, TRPM7 has proton conductivity [107]. TRPM7 regulates EGF signaling to induce STAT3 activation and vimentin expression during epithelial-mesenchymal transition [108]. OGR1 also acts as a proton-sensing receptor, stimulating inositol phosphate formation [37].

pH_e gradient formation by H⁺ pumps and exchangers

NHE1 accumulates at the leading edge to make a pH_e gradient associated with cell migration [109]. The Rho-ROCK pathway contributes to NHE1 activation and focal adhesions [110,111]. Protons stabilize the collagen–α2β1 integrin bond, but alkalosis, a lack of protons or an inhibited NHE activity, prevents adhesion [112]. Furthermore, the cell forms an individual pH_e gradient to facilitate movement: i.e. at leading edge or invadopodia, cells preferentially attach to the substrate due to the acidic pH_e induced by NHE1, while cell-matrix interaction at the rear end is weak due to a mid-alkaline pH_e[113]. Mutation studies clearly showed that downregulation of NHE1 function suppresses cell polarity, migration, and invasion through matrigel™ [111]. Inhibition of NHE1 activity by HOE642 (cariporide) reduced migration and adhesion activities [109].

To secrete acidic metabolites, NHE1 and the H⁺-lactate co-transporter are involved [114]. H⁺-ATPase (the H⁺ pump) and cell surface ATP synthase also play a role in extracellular acidification [115,116], thereby contributing to tumor metastasis [3]. Therefore, inhibition of the H⁺ pump can be a new strategy for cancer treatment [117-119]. Angiostatin has anti-tumor efficacy by inhibiting cell surface ATP synthase activity through binding its β subunit [116]. In particular, treatment of the cells with angiostatin proved more cytotoxicity at an acidic pH_e than a neutral pH_e.

Drug efficacy and acidic pH_e

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 pH_e, which provides a rationale for selectivity because many solid tumors, while creating an acidic extracellular environment, maintain a normal intracellular pH [120]. An acidic pH_e inhibits cellular uptake of mitoxantrone and topotecan, so that elevation of pH_e in tumor tissue enhances those drugs’ efficacy [120,121]. Because the buffer action is weaker in tumor tissue than normal tissue, NaHCO₃ has much potential to raise pH_e relatively specifically in tumor tissue [122,123]. Acidic pH_e also plays a role in the resistance of tumor cells to drugs by increasing the expression of p-glycoprotein, thereby increasing drug efflux [124,125]. Recently, an acidic pH_e-specific drug-releasing system has been developed [126,127]. 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 [127]. To measure pH_e, a magnetic resonance image technique has been developed using acidic pH_e specific probes [128,129]. Thus, clinicians should pay attention to tumor pH_e 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 [130]. Although the reduction in tumor growth by those drugs also reduces the oxygen supply, it reduces pH_e. In patients given vasodilating drugs, anti-tumor drugs with weak acidic pK_a value, such as 5-fluorouracil (5FU) and cyclophosphamide, may have increased efficacy at an acidic pH_e. In contrast, the anti-tumor drugs with weak base pK_a values, such as doxorubicin, mitoxantrone and daunorubicin, may not be fully functioned because acidic pH_e reduces their cytotoxicity [121,131]. In early-stage breast cancer, high CAIX is a predictive marker of doxorubicin resistance [132].

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 [133,134]. 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 pH_e

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 [135]. Melanoma cells growing at low pH are sensitized to hyperthermia because of the altered intracellular pH threshold for the heat sensitization in vitro[136,137].

Conclusion

Acidic pH_e is toxic to many cells, including tumors [138]. 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 pH_e 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.

Acknowledgements

We thank Profs. Masaichi-Chang-Il Lee, Eiro Kubota, Kaoru Miyazaki, and Ryu-Ichiro Hata for their critical comments.

References

1. WarburgOPosenerKNegeleinEÜber den Stoffwechsel der Tumoren (On metabolism of tumors)Biochem Z1924152319344[Google Scholar]
2. CheslerMNicholsonCRegulation of intracellular pH in vertebrate central neuronsBrain Res19853251–2313316[PubMed][Google Scholar]
3. NishishoTHataKNakanishiMMoritaYSun-WadaGHWadaYYasuiNYonedaTThe a3 isoform vacuolar type H⁺-ATPase promotes distant metastasis in the mouse B16 melanoma cellsMol Cancer Res201197845855[PubMed][Google Scholar]
4. HelmlingerGSckellADellianMForbesNSJainRKAcid production in glycolysis-impaired tumors provides new insights into tumor metabolismClin Cancer Res20028412841291[PubMed][Google Scholar]
5. RofstadEKMathiesenBKindemKGalappathiKAcidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude miceCancer Res2006661366996707[PubMed][Google Scholar]
6. BrizelDMSchroederTScherRLWalentaSCloughRWDewhirstMWMueller-KlieserWElevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancerInt J Radiat Oncol Biol Phys2001512349353[PubMed][Google Scholar]
7. WalentaSChauTVSchroederTLehrHAKunz-SchughartLAFuerstAMueller-KlieserWMetabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists?J Cancer Res Clin Oncol20031296321326[PubMed][Google Scholar]
8. WalentaSSalamehALyngHEvensenJFMitzeMRofstadEKMueller-KlieserWCorrelation of high lactate levels in head and neck tumors with incidence of metastasisAm J Pathol19971502409415[PubMed][Google Scholar]
9. McFateTMohyeldinALuHThakarJHenriquesJHalimNDWuHSchellMJTsangTMTeahanOPyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cellsJ Biol Chem2008283332270022708[PubMed][Google Scholar]
10. FischerKHoffmannPVoelklSMeidenbauerNAmmerJEdingerMGottfriedESchwarzSRotheGHovesSInhibitory effect of tumor cell-derived lactic acid on human T cellsBlood2007109938123819[PubMed][Google Scholar]
11. YabuMShimeHHaraHSaitoTMatsumotoMSeyaTAkazawaTInoueNIL-23-dependent and -independent enhancement pathways of IL-17A production by lactic acidInt Immunol20112312941[PubMed][Google Scholar]
12. GottfriedEKunz-SchughartLAEbnerSMueller-KlieserWHovesSAndreesenRMackensenAKreutzMTumor-derived lactic acid modulates dendritic cell activation and antigen expressionBlood2006107520132021[PubMed][Google Scholar]
13. GoetzeKWalentaSKsiazkiewiczMKunz-SchughartLAMueller-KlieserWLactate enhances motility of tumor cells and inhibits monocyte migration and cytokine releaseInt J Oncol2011392453463[PubMed][Google Scholar]
14. VegranFBoidotRMichielsCSonveauxPFeronOLactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesisCancer Res201171725502560[PubMed][Google Scholar]
15. HuntTKAslamRSBeckertSWagnerSGhaniQPHussainMZRoySSenCKAerobically derived lactate stimulates revascularization and tissue repair via redox mechanismsAntioxid Redox Signal20079811151124[PubMed][Google Scholar]
16. SattlerUGMeyerSSQuennetVHoernerCKnoerzerHFabianCYarominaAZipsDWalentaSBaumannMGlycolytic metabolism and tumour response to fractionated irradiationRadiother Oncol2010941102109[PubMed][Google Scholar]
17. SonveauxPCopettiTDe SaedeleerCJVegranFVerraxJKennedyKMMoonEJDhupSDanhierPFrerartFTargeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesisPLoS One201273e33418[PubMed][Google Scholar]
18. KimJHKimSHAlfieriAAYoungCWQuercetin, an inhibitor of lactate transport and a hyperthermic sensitizer of HeLa cellsCancer Res1984441102106[PubMed][Google Scholar]
19. HatanakaMHanafusaHAnalysis of a functional change in membrane in the process of cell transformation by Rous sarcoma virus; alteration in the characteristics of sugar transportVirology1970414647652[PubMed][Google Scholar]
20. KallinowskiFVaupelPConcurrent measurements of O₂ partial pressures and pH values in human mammary carcinoma xenotransplantsAdv Exp Med Biol1986200609621[PubMed][Google Scholar]
21. MartinGRJainRKNoninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopyCancer Res1994542156705674[PubMed][Google Scholar]
22. HelmlingerGYuanFDellianMJainRKInterstitial pH and pO₂ gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlationNat Med199732177182[PubMed][Google Scholar]
23. KayserGKassemASienelWSchulte-UentropLMatternDAumannKStickelerEWernerMPasslickBZur HausenALactate-dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1Diagn Pathol2010522[PubMed][Google Scholar]
24. KoukourakisMIGiatromanolakiASivridisEBougioukasGDidilisVGatterKCHarrisALLactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosisBr J Cancer2003895877885[PubMed][Google Scholar]
25. KoukourakisMIGiatromanolakiASimopoulosCPolychronidisASivridisELactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancerClin Exp Metastasis20052212530[PubMed][Google Scholar]
26. KoukourakisMIGiatromanolakiASivridisEGatterKCHarrisALLactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway–a report of the Tumour Angiogenesis Research GroupJ Clin Oncol2006242643014308[PubMed][Google Scholar]
27. KoukourakisMIGiatromanolakiASivridisEGatterKCTrarbachTFolprechtGShiMMLebwohlDJalavaTLaurentDPrognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapyClin Cancer Res2011171448924900[PubMed][Google Scholar]
28. BaronRNeffLLouvardDCourtoyPJCell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled borderJ Cell Biol1985101622102222[PubMed][Google Scholar]
29. LehenkariPHentunenTALaitala-LeinonenTTuukkanenJVaananenHKCarbonic anhydrase II plays a major role in osteoclast differentiation and bone resorption by effecting the steady state intracellular pH and Ca²⁺Exp Cell Res19982421128137[PubMed][Google Scholar]
30. MobasheriAGoldingSPagakisSNCorkeyKPocockAEFermorBO’BrienMJWilkinsRJElloryJCFrancisMJExpression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblastsCell Biol Int1998227–8551562[PubMed][Google Scholar]
31. BiskobingDMFanDAcid pH increases carbonic anhydrase II and calcitonin receptor mRNA expression in mature osteoclastsCalcif Tissue Int2000672178183[PubMed][Google Scholar]
32. HäblerCÜber den K- und Ca-Gehalt von eiter und Exsudaten und seine Beziehungen zum EntzündungsschmerzKlin Wochenschrift1929815691572[PubMed][Google Scholar]
33. DellianMHelmlingerGYuanFJainRKFluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradientsBr J Cancer199674812061215[PubMed][Google Scholar]
34. Rocha-GonzalezHIHerrejon-AbreuEBLopez-SantillanFJGarcia-LopezBEMurbartianJGranados-SotoVAcid increases inflammatory pain in rats: Effect of local peripheral ASICs inhibitorsEur J Pharmacol20096031–35661[PubMed][Google Scholar]
35. SteenKHIssbernerUReehPWPain due to experimental acidosis in human skin: evidence for non-adapting nociceptor excitationNeurosci Lett199519912932[PubMed][Google Scholar]
36. NagaeMHiragaTYonedaTAcidic microenvironment created by osteoclasts causes bone pain associated with tumor colonizationJ Bone Miner Metab200725299104[PubMed][Google Scholar]
37. LudwigMGVanekMGueriniDGasserJAJonesCEJunkerUHofstetterHWolfRMSeuwenKProton-sensing G-protein-coupled receptorsNature200342569539398[PubMed][Google Scholar]
38. TomuraHWangJQLiuJPKomachiMDamirinAMogiCToboMNochiHTamotoKImDSCyclooxygenase-2 expression and prostaglandin E₂ production in response to acidic pH through OGR1 in a human osteoblastic cell lineJ Bone Miner Res200823711291139[PubMed][Google Scholar]
39. KobayashiYMizoguchiTTakeIKuriharaSUdagawaNTakahashiNProstaglandin E₂ enhances osteoclastic differentiation of precursor cells through protein kinase A-dependent phosphorylation of TAK1J Biol Chem2005280121139511403[PubMed][Google Scholar]
40. IwaiKKoikeMOhshimaSMiyatakeKUchiyamaYSaekiYIshiiMRGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathwayJ Bone Miner Res2007221016121620[PubMed][Google Scholar]
41. IharaYKiharaYHamanoFYanagidaKMorishitaYKunitaAYamoriTFukayamaMAburataniHShimizuTThe G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensorProc Natl Acad Sci U S A2010107401730917314[PubMed][Google Scholar]
42. HeXDToboMMogiCNakakuraTKomachiMMurataNTakanoMTomuraHSatoKOkajimaFInvolvement of proton-sensing receptor TDAG8 in the anti-inflammatory actions of dexamethasone in peritoneal macrophagesBiochem Biophys Res Commun20114154627631[PubMed][Google Scholar]
43. NagaeMHiragaTWakabayashiHWangLIwataKYonedaTOsteoclasts play a part in pain due to the inflammation adjacent to boneBone200639511071115[PubMed][Google Scholar]
44. JastiJFurukawaHGonzalesEBGouauxEStructure of acid-sensing ion channel 1 at 1.9 A resolution and low pHNature20074497160316323[PubMed][Google Scholar]
45. MarplesMJThe ecology of human skin1965Springfield, IL: Charles C. Thomas
46. BehneMJBarryNPHansonKMAronchikICleggRWGrattonEFeingoldKHolleranWMEliasPMMauroTMNeonatal development of the stratum corneum pH gradient: localization and mechanisms leading to emergence of optimal barrier functionJ Invest Dermatol200312069981006[PubMed][Google Scholar]
47. IlicDMao-QiangMCrumrineDDolganovGLarocqueNXuPDemerjianMBrownBELimSTOssovskayaVFocal adhesion kinase controls pH-dependent epidermal barrier homeostasis by regulating actin-directed Na⁺/H⁺ exchanger 1 plasma membrane localizationAm J Pathol2007170620552067[PubMed][Google Scholar]
48. AdamsonTMBoydRDPlattHSStrangLBComposition of alveolar liquid in the foetal lambJ Physiol19692041159168[PubMed][Google Scholar]
49. TateSMacGregorGDavisMInnesJAGreeningAPAirways in cystic fibrosis are acidified: detection by exhaled breath condensateThorax20025711926929[PubMed][Google Scholar]
50. RicciardoloFLGastonBHuntJAcid stress in the pathology of asthmaJ Allergy Clin Immunol20041134610619[PubMed][Google Scholar]
51. BekkuSMochizukiHYamamotoTUenoHTakayamaETadakumaTExpression of carbonic anhydrase I or II and correlation to clinical aspects of colorectal cancerHepatogastroenterology200047349981001[PubMed][Google Scholar]
52. LeppilampiMKoistinenPSavolainenERHannukselaJParkkilaAKNiemelaOPastorekovaSPastorekJWaheedASlyWSThe expression of carbonic anhydrase II in hematological malignanciesClin Cancer Res20028722402245[PubMed][Google Scholar]
53. ChicheJIlcKLaferriereJTrottierEDayanFMazureNMBrahimi-HornMCPouyssegurJHypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pHCancer Res2009691358368[PubMed][Google Scholar]
54. BrocktonNTKlimowiczACBosePPetrilloSKKonnoMRudmikLDeanMNakoneshnySCMatthewsTWChandaranaSHigh stromal carbonic anhydrase IX expression is associated with nodal metastasis and decreased survival in patients with surgically-treated oral cavity squamous cell carcinomaOral Oncol2012487615622[PubMed][Google Scholar]
55. ParkkilaSParkkilaAKSaarnioJKivelaJKarttunenTJKaunistoKWaheedASlyWSTureciOVirtanenIExpression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumorsJ Histochem Cytochem2000481216011608[PubMed][Google Scholar]
56. KummolaLHamalainenJMKivelaJKivelaAJSaarnioJKarttunenTParkkilaSExpression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosaBMC cancer2005541[PubMed][Google Scholar]
57. SwietachPWigfieldSCobdenPSupuranCTHarrisALVaughan-JonesRDTumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growthsJ Biol Chem2008283292047320483[PubMed][Google Scholar]
58. WilliamsEMartinSMossRDurrantLDeenSCo-expression of VEGF and CA9 in ovarian high-grade serous carcinoma and relationship to survivalVirchows Arch201246113339[PubMed][Google Scholar]
59. ShinHJRhoSBJungDCHanIOOhESKimJYCarbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasionJ Cell Sci2011124Pt 710771087[PubMed][Google Scholar]
60. ParkkilaSRajaniemiHParkkilaAKKivelaJWaheedAPastorekovaSPastorekJSlyWSCarbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitroProc Natl Acad Sci U S A200097522202224[PubMed][Google Scholar]
61. ZatovicovaMJelenskaLHulikovaACsaderovaLDitteZDittePGoliasovaTPastorekJPastorekovaSCarbonic anhydrase IX as an anticancer therapy target: preclinical evaluation of internalizing monoclonal antibody directed to catalytic domainCurr Pharm Des2010162932553263[PubMed][Google Scholar]
62. MuselaersSMuldersPOosterwijkEOyenWBoermanOMolecular imaging and carbonic anhydrase IX-targeted radioimmunotherapy in clear cell renal cell carcinomaImmunotherapy201355489495[PubMed][Google Scholar]
63. Oosterwijk-WakkaJCBoermanOCMuldersPFOosterwijkEApplication of Monoclonal Antibody G250 Recognizing Carbonic Anhydrase IX in Renal Cell CarcinomaInt J Mol Sci20131461140211423[PubMed][Google Scholar]
64. TjäderhaneLLarjavaHSorsaTUittoVJLarmasMSaloTThe activation and function of host matrix metalloproteinases in dentin matrix breakdown in caries lesionsJ Dent Res199877816221629[PubMed][Google Scholar]
65. DavisGEMartinBMA latent M_r 94,000 gelatin-degrading metalloprotease induced during differentiation of HL-60 promyelocytic leukemia cells: a member of the collagenase family of enzymesCancer Res199050411131120[PubMed][Google Scholar]
66. DavisGEIdentification 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 Biophys19912862551554[PubMed][Google Scholar]
67. Martinez-ZaguilanRSeftorEASeftorREChuYWGilliesRJHendrixMJAcidic pH enhances the invasive behavior of human melanoma cellsClin Exp Metastasis1996142176186[PubMed][Google Scholar]
68. KarsdalMAHenriksenKSorensenMGGramJSchallerSDziegielMHHeegaardAMChristophersenPMartinTJChristiansenCAcidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorptionAm J Pathol20051662467476[PubMed][Google Scholar]
69. SaftigPHunzikerEWehmeyerOJonesSBoydeARommerskirchWMoritzJDSchuPVon FiguraKImpaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient miceProc Natl Acad Sci U S A199895231345313458[PubMed][Google Scholar]
70. Le GallCBellahceneABonnelyeEGasserJACastronovoVGreenJZimmermannJClezardinPA cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burdenCancer Res2007672098949902[PubMed][Google Scholar]
71. PodgorskiILinebaughBEKoblinskiJERudyDLHerroonMKOliveMBSloaneBFBone marrow-derived cathepsin K cleaves SPARC in bone metastasisAm J Pathol2009175312551269[PubMed][Google Scholar]
72. NakajimaMIrimuraTDi FerranteDDi FerranteNNicolsonGLHeparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublinesScience19832204597611613[PubMed][Google Scholar]
73. NakajimaMIrimuraTDi FerranteNNicolsonGLMetastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidaseJ Biol Chem1984259422832290[PubMed][Google Scholar]
74. KatoYOzawaSTsukudaMKubotaEMiyazakiKSt-PierreYHataRAcidic extracellular pH increases calcium influx-triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase-9 expression in mouse metastatic melanomaFEBS J20072741231713183[PubMed][Google Scholar]
75. KatoYNakayamaYUmedaMMiyazakiKInduction of 103-kDa gelatinase/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell linesJ Biol Chem1992267161142411430[PubMed][Google Scholar]
76. GriffithsLDachsGUBicknellRHarrisALStratfordIJThe 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 Res1997574570572[PubMed][Google Scholar]
77. BellocqASubervilleSPhilippeCBertrandFPerezJFouquerayBCherquiGBaudLLow environmental pH is responsible for the induction of nitric-oxide synthase in macrophages. Evidence for involvement of nuclear factor-κB activationJ Biol Chem1998273950865092[PubMed][Google Scholar]
78. FukumuraDXuLChenYGohongiTSeedBJainRKHypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivoCancer Res2001611660206024[PubMed][Google Scholar]
79. XuLFukumuraDJainRKAcidic 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 Chem2002277131136811374[PubMed][Google Scholar]
80. ShiQAbbruzzeseJLHuangSFidlerIJXiongQXieKConstitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastaticClin Cancer Res199951137113721[PubMed][Google Scholar]
81. ShiQLeXWangBXiongQAbbruzzeseJLXieKRegulation of interleukin-8 expression by cellular pH in human pancreatic adenocarcinoma cellsJ Interferon Cytokine Res2000201110231028[PubMed][Google Scholar]
82. ShiQXiongQLeXXieKRegulation of interleukin-8 expression by tumor-associated stress factorsJ Interferon Cytokine Res2001218553566[PubMed][Google Scholar]
83. XuLFidlerIJAcidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cellsCancer Res2000601646104616[PubMed][Google Scholar]
84. ShiQLeXWangBAbbruzzeseJLXiongQHeYXieKRegulation of vascular endothelial growth factor expression by acidosis in human cancer cellsOncogene2001202837513756[PubMed][Google Scholar]
85. BischoffDSZhuJHMakhijaniNSYamaguchiDTAcidic 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 Biochem2008104413781392[PubMed][Google Scholar]
86. KatoYOzonoSShuinTMiyazakiKSlow induction of gelatinase B mRNA by acidic culture conditions in mouse metastatic melanoma cellsCell Biol Int1996205375377[PubMed][Google Scholar]
87. KatoYLambertCAColigeACMineurPNoëlAFrankenneFFoidartJMBabaMHataRIMiyazakiKAcidic extracellular pH induces matrix metalloproteinase-9 expression in mouse metastatic melanoma cells through the phospholipase D-mitogen-activated protein kinase signalingJ Biol Chem2005280121093810944[PubMed][Google Scholar]
88. ItatsuKSasakiMHaradaKYamaguchiJIkedaHSatoYOhtaTSatoHNaginoMNimuraYPhosphorylation 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 Int2009292291298[PubMed][Google Scholar]
89. HirataSFukamachiTSakanoHTaroraASaitoHKobayashiHExtracellular acidic environments induce phosphorylation of ZAP-70 in Jurkat T cellsImmunol Lett20081152105109[PubMed][Google Scholar]
90. TomuraHWangJQKomachiMDamirinAMogiCToboMKonJMisawaNSatoKOkajimaFProstaglandin l₂ production and cAMP accumulation in response to acidic extracellular pH through OGR1 in human aortic smooth muscle cellsJ Biol Chem2005280413445834464[PubMed][Google Scholar]
91. TorigoeTIzumiHYoshidaYIshiguchiHOkamotoTItohHKohnoKLow pH enhances Sp1 DNA binding activity and interaction with TBPNucleic Acids Res2003311545234530[PubMed][Google Scholar]
92. ChenYChenCHTungPYHuangSHWangSMAn acidic extracellular pH disrupts adherens junctions in HepG2 cells by Src kinases-dependent modification of E-cadherinJ Cell Biochem20091084851859[PubMed][Google Scholar]
93. ChenYKungHNChenCHHuangSHChenKHWangSMAcidic extracellular pH induces p120-catenin-mediated disruption of adherens junctions via the Src kinase-PKCδ pathwayFEBS Lett20115854705710[PubMed][Google Scholar]
94. BourguignonLYSingletonPADiedrichFSternRGiladECD44 interaction with Na⁺-H⁺ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasionJ Biol Chem2004279262699127007[PubMed][Google Scholar]
95. MoriHTomariTKoshikawaNKajitaMItohYSatoHTojoHYanaISeikiMCD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domainEMBO J2002211539493959[PubMed][Google Scholar]
96. SuenagaNMoriHItohYSeikiMCD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinaseOncogene2005245859868[PubMed][Google Scholar]
97. LinYChangGWangJJinWWangLLiHMaLLiQPangTNHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMPExp Cell Res20113171420312040[PubMed][Google Scholar]
98. LinYWangJJinWWangLLiHMaLLiQPangTNHE1 mediates migration and invasion of HeLa cells via regulating the expression and localization of MT1-MMPCell Biochem Funct201214146[Google Scholar]
99. RobeyIFBaggettBKKirkpatrickNDRoeDJDosescuJSloaneBFHashimAIMorseDLRaghunandNGatenbyRABicarbonate increases tumor pH and inhibits spontaneous metastasesCancer Res200969622602268[PubMed][Google Scholar]
100. Lora-MichielsMYuDSandersLPoulsonJMAzumaCCaseBVujaskovicZThrallDECharlesHCDewhirstMWExtracellular pH and P-31 magnetic resonance spectroscopic variables are related to outcome in canine soft tissue sarcomas treated with thermoradiotherapyClin Cancer Res2006121957335740[PubMed][Google Scholar]
101. BerdievBKXiaJMcLeanLAMarkertJMGillespieGYMapstoneTBNarenAPJovovBBubienJKJiHLAcid-sensing ion channels in malignant gliomasJ Biol Chem2003278171502315034[PubMed][Google Scholar]
102. OhtaTImagawaTItoSNovel gating and sensitizing mechanism of capsaicin receptor (TRPV1): tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1J Biol Chem20082831493779387[PubMed][Google Scholar]
103. NakayaKHarbidgeDGWangemannPSchultzBDGreenEDWallSMMarcusDCLack of pendrin HCO₃^- transport elevates vestibular endolymphatic [Ca²⁺] by inhibition of acid-sensitive TRPV5 and TRPV6 channelsAm J Physiol Renal Physiol20072925F1314F1321[PubMed][Google Scholar]
104. ChenYWillcocksonHHValtschanoffJGVanilloid receptor TRPV1-mediated phosphorylation of ERK in murine adjuvant arthritisOsteoarthritis Cartilage2009172244251[PubMed][Google Scholar]
105. ChenYWilliamsSHMcNultyALHongJHLeeSHRothfuszNEParekhPKMooreCGereauRWTaylorABTemporomandibular joint pain: A critical role for Trpv4 in the trigeminal ganglionPain2013154812951304[PubMed][Google Scholar]
106. WangGSuJLiLFengJShiLHeWLiuYEdaravone alleviates hypoxia-acidosis/reoxygenation-induced neuronal injury by activating ERK1/2Neurosci Lett20135437277[PubMed][Google Scholar]
107. NumataTOkadaYProton conductivity through the human TRPM7 channel and its molecular determinantsJ Biol Chem2008283221509715103[PubMed][Google Scholar]
108. DavisFMAzimiIFavilleRAPetersAAJalinkKPutneyJWJrGoodhillGJThompsonEWRoberts-ThomsonSJMonteithGRInduction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependentOncogene2013in press[Google Scholar]
109. StüweLMüllerMFabianAWaningJMallySNoëlJSchwabAStockCpH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solutionJ Physiol2007585Pt 2351360[PubMed][Google Scholar]
110. TominagaTBarberDLNa-H exchange acts downstream of RhoA to regulate integrin-induced cell adhesion and spreadingMol Biol Cell19989822872303[PubMed][Google Scholar]
111. DenkerSPBarberDLCell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1J Cell Biol2002159610871096[PubMed][Google Scholar]
112. StockCGassnerBHauckCRArnoldHMallySEbleJADieterichPSchwabAMigration of human melanoma cells depends on extracellular pH and Na⁺/H⁺ exchangeJ Physiol2005567Pt 1225238[PubMed][Google Scholar]
113. KrahlingHMallySEbleJANoelJSchwabAStockCThe glycocalyx maintains a cell surface pH nanoenvironment crucial for integrin-mediated migration of human melanoma cellsPflugers Arch2009458610691083[PubMed][Google Scholar]
114. CardoneRACasavolaVReshkinSJThe role of disturbed pH dynamics and the Na⁺/H⁺ exchanger in metastasisNat Rev Cancer2005510786795[PubMed][Google Scholar]
115. MontcourrierPSilverIFarnoudRBirdIRochefortHBreast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanismClin Exp Metastasis1997154382392[PubMed][Google Scholar]
116. ChiSLPizzoSVAngiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthaseCancer Res2006662875882[PubMed][Google Scholar]
117. SpugniniEPCitroGFaisSProton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategyJ Exp Clin Cancer Res20102944[PubMed][Google Scholar]
118. De MilitoACaneseRMarinoMLBorghiMIeroMVillaAVenturiGLozuponeFIessiELogozziMpH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidityInt J Cancer20101271207219[PubMed][Google Scholar]
119. WiedmannRMVon SchwarzenbergKPalamidessiASchreinerLKubischRLieblJSchemppCTraunerDVerebGZahlerSThe V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1Cancer Res2012722259765987[PubMed][Google Scholar]
120. AdamsDJDewhirstMWFlowersJLGamcsikMPColvinOMManikumarGWaniMCWallMECamptothecin analogues with enhanced antitumor activity at acidic pHCancer Chemother Pharmacol2000464263271[PubMed][Google Scholar]
121. VukovicVTannockIFInfluence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecanBr J Cancer199775811671172[PubMed][Google Scholar]
122. RaghunandNHeXVan SluisRMahoneyBBaggettBTaylorCWPaine-MurrietaGRoeDBhujwallaZMGilliesRJEnhancement of chemotherapy by manipulation of tumour pHBr J Cancer199980710051011[PubMed][Google Scholar]
123. RaghunandNMahoneyBVan SluisRBaggettBGilliesRJAcute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantroneNeoplasia200133227235[PubMed][Google Scholar]
124. LotzCKelleherDKGassnerBGekleMVaupelPThewsORole of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cellsOncol Rep2007171239244[PubMed][Google Scholar]
125. ThewsODillenburgWRoschFFellnerMPET imaging of the impact of extracellular pH and MAP kinases on the p-glycoprotein (Pgp) activityAdv Exp Med Biol2013765279286[PubMed][Google Scholar]
126. KoJParkKKimYSKimMSHanJKKimKParkRWKimISSongHKLeeDSTumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapyJ Control Release20071232109115[PubMed][Google Scholar]
127. LeeESGaoZKimDParkKKwonICBaeYHSuper pH-sensitive multifunctional polymeric micelle for tumor pH_e specific TAT exposure and multidrug resistanceJ Control Release20081293228236[PubMed][Google Scholar]
128. Garcia-MartinMLMartinezGVRaghunandNSherryADZhangSGilliesRJHigh resolution pH_e imaging of rat glioma using pH-dependent relaxivityMagn Reson Med2006552309315[PubMed][Google Scholar]
129. Van SluisRBhujwallaZMRaghunandNBallesterosPAlvarezJCerdanSGalonsJPGilliesRJIn vivo imaging of extracellular pH using ¹H MRSIMagn Reson Med1999414743750[PubMed][Google Scholar]
130. AdachiETannockIFThe effects of vasodilating drugs on pH in tumorsOncol Res1999114179185[PubMed][Google Scholar]
131. RaghunandNMahoneyBPGilliesRJTumor acidity, ion trapping and chemotherapeutics. II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agentsBiochem Pharmacol200366712191229[PubMed][Google Scholar]
132. BetofASRabbaniZNHardeeMEKimSJBroadwaterGBentleyRCSnyderSAVujaskovicZOosterwijkEHarrisLNCarbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplificationBr J Cancer20121065916922[PubMed][Google Scholar]
133. TehBGKobayashiWNaritaKFukuiRKimuraHSuperselective docetaxel-nedaplatin combined infusion concurrent with radiation thrapy in advanced oral cancersOral Oncol EXTRA200440126131[PubMed][Google Scholar]
134. ShigaKYokoyamaJHashimotoSSaijoSTatedaMOgawaTWatanabeMKobayashiTCombined therapy after superselective arterial cisplatin infusion to treat maxillary squamous cell carcinomaOtolaryngol Head Neck Surg2007136610031009[PubMed][Google Scholar]
135. OvergaardJBichelPThe influence of hypoxia and acidity on the hyperthermic response of malignant cells in vitroRadiology19771232511514[PubMed][Google Scholar]
136. CossRAStorckCWDaskalakisCBerdDWahlMLIntracellular acidification abrogates the heat shock response and compromises survival of human melanoma cellsMol Cancer Ther200324383388[PubMed][Google Scholar]
137. CossRAStorckCWWachsbergerPRReillyJLeeperDBBerdDWahlMLAcute 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 Hyperthermia200420193106[PubMed][Google Scholar]
138. LanALagadic-GossmannDLemaireCBrennerCJanGAcidic extracellular pH shifts colorectal cancer cell death from apoptosis to necrosis upon exposure to propionate and acetate, major end-products of the human probiotic propionibacteriaApoptosis2007123573591[PubMed][Google Scholar]