Top

Published in:

Open Access 01-12-2013 | Review

Acidic extracellular microenvironment and cancer

Authors: Yasumasa Kato, Shigeyuki Ozawa, Chihiro Miyamoto, Yojiro Maehata, Atsuko Suzuki, Toyonobu Maeda, Yuh Baba

Published in: Cancer Cell International | Issue 1/2013

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.

Warburg O, Posener K, Negelein E: Über den Stoffwechsel der Tumoren (On metabolism of tumors). Biochem Z. 1924, 152: 319-344.

Chesler M, Nicholson C: Regulation of intracellular pH in vertebrate central neurons. Brain Res. 1985, 325 (1–2): 313-316.PubMed

Nishisho T, Hata K, Nakanishi M, Morita Y, Sun-Wada GH, Wada Y, Yasui N, Yoneda T: The a 3 isoform vacuolar type H⁺-ATPase promotes distant metastasis in the mouse B16 melanoma cells. Mol Cancer Res. 2011, 9 (7): 845-855. 10.1158/1541-7786.MCR-10-0449.PubMed

Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK: Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res. 2002, 8 (4): 1284-1291.PubMed

Rofstad EK, Mathiesen B, Kindem K, Galappathi K: Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res. 2006, 66 (13): 6699-6707. 10.1158/0008-5472.CAN-06-0983.PubMed

Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W: Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001, 51 (2): 349-353. 10.1016/S0360-3016(01)01630-3.PubMed

Walenta S, Chau TV, Schroeder T, Lehr HA, Kunz-Schughart LA, Fuerst A, Mueller-Klieser W: Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists?. J Cancer Res Clin Oncol. 2003, 129 (6): 321-326. 10.1007/s00432-003-0450-x.PubMed

Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK, Mueller-Klieser W: Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am J Pathol. 1997, 150 (2): 409-415.PubMedCentralPubMed

McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O: Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem. 2008, 283 (33): 22700-22708. 10.1074/jbc.M801765200.PubMedCentralPubMed

10.

Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S: Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007, 109 (9): 3812-3819. 10.1182/blood-2006-07-035972.PubMed

11.

Yabu M, Shime H, Hara H, Saito T, Matsumoto M, Seya T, Akazawa T, Inoue N: IL-23-dependent and -independent enhancement pathways of IL-17A production by lactic acid. Int Immunol. 2011, 23 (1): 29-41. 10.1093/intimm/dxq455.PubMed

12.

Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A, Kreutz M: Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006, 107 (5): 2013-2021. 10.1182/blood-2005-05-1795.PubMed

13.

Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA, Mueller-Klieser W: Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol. 2011, 39 (2): 453-463.PubMed

14.

Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O: Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011, 71 (7): 2550-2560. 10.1158/0008-5472.CAN-10-2828.PubMed

15.

Hunt TK, Aslam RS, Beckert S, Wagner S, Ghani QP, Hussain MZ, Roy S, Sen CK: Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal. 2007, 9 (8): 1115-1124. 10.1089/ars.2007.1674.PubMedCentralPubMed

16.

Sattler UG, Meyer SS, Quennet V, Hoerner C, Knoerzer H, Fabian C, Yaromina A, Zips D, Walenta S, Baumann M: Glycolytic metabolism and tumour response to fractionated irradiation. Radiother Oncol. 2010, 94 (1): 102-109. 10.1016/j.radonc.2009.11.007.PubMed

17.

Sonveaux P, Copetti T, De Saedeleer CJ, Vegran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frerart F: Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One. 2012, 7 (3): e33418-10.1371/journal.pone.0033418.PubMedCentralPubMed

18.

Kim JH, Kim SH, Alfieri AA, Young CW: Quercetin, an inhibitor of lactate transport and a hyperthermic sensitizer of HeLa cells. Cancer Res. 1984, 44 (1): 102-106.PubMed

19.

Hatanaka M, Hanafusa H: Analysis of a functional change in membrane in the process of cell transformation by Rous sarcoma virus; alteration in the characteristics of sugar transport. Virology. 1970, 41 (4): 647-652. 10.1016/0042-6822(70)90429-0.PubMed

20.

Kallinowski F, Vaupel P: Concurrent measurements of O₂ partial pressures and pH values in human mammary carcinoma xenotransplants. Adv Exp Med Biol. 1986, 200: 609-621. 10.1007/978-1-4684-5188-7_74.PubMed

21.

Martin GR, Jain RK: Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res. 1994, 54 (21): 5670-5674.PubMed

22.

Helmlinger G, Yuan F, Dellian M, Jain RK: Interstitial pH and pO₂ gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997, 3 (2): 177-182. 10.1038/nm0297-177.PubMed

23.

Kayser G, Kassem A, Sienel W, Schulte-Uentrop L, Mattern D, Aumann K, Stickeler E, Werner M, Passlick B, Zur Hausen A: Lactate-dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1. Diagn Pathol. 2010, 5: 22-10.1186/1746-1596-5-22.PubMedCentralPubMed

24.

Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, Harris AL: Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer. 2003, 89 (5): 877-885. 10.1038/sj.bjc.6601205.PubMedCentralPubMed

25.

Koukourakis MI, Giatromanolaki A, Simopoulos C, Polychronidis A, Sivridis E: Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis. 2005, 22 (1): 25-30. 10.1007/s10585-005-2343-7.PubMed

26.

Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL: Lactate 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 Group. J Clin Oncol. 2006, 24 (26): 4301-4308. 10.1200/JCO.2006.05.9501.PubMed

27.

Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Trarbach T, Folprecht G, Shi MM, Lebwohl D, Jalava T, Laurent D: Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapy. Clin Cancer Res. 2011, 17 (14): 4892-4900. 10.1158/1078-0432.CCR-10-2918.PubMedCentralPubMed

28.

Baron R, Neff L, Louvard D, Courtoy PJ: Cell-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 border. J Cell Biol. 1985, 101 (6): 2210-2222. 10.1083/jcb.101.6.2210.PubMed

29.

Lehenkari P, Hentunen TA, Laitala-Leinonen T, Tuukkanen J, Vaananen HK: Carbonic anhydrase II plays a major role in osteoclast differentiation and bone resorption by effecting the steady state intracellular pH and Ca²⁺. Exp Cell Res. 1998, 242 (1): 128-137. 10.1006/excr.1998.4071.PubMed

30.

Mobasheri A, Golding S, Pagakis SN, Corkey K, Pocock AE, Fermor B, O’Brien MJ, Wilkins RJ, Ellory JC, Francis MJ: Expression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblasts. Cell Biol Int. 1998, 22 (7–8): 551-562.PubMed

31.

Biskobing DM, Fan D: Acid pH increases carbonic anhydrase II and calcitonin receptor mRNA expression in mature osteoclasts. Calcif Tissue Int. 2000, 67 (2): 178-183. 10.1007/s00223001107.PubMed

32.

Häbler C: Über den K- und Ca-Gehalt von eiter und Exsudaten und seine Beziehungen zum Entzündungsschmerz. Klin Wochenschrift. 1929, 8: 1569-1572. 10.1007/BF01849103.

33.

Dellian M, Helmlinger G, Yuan F, Jain RK: Fluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradients. Br J Cancer. 1996, 74 (8): 1206-1215. 10.1038/bjc.1996.518.PubMedCentralPubMed

34.

Rocha-Gonzalez HI, Herrejon-Abreu EB, Lopez-Santillan FJ, Garcia-Lopez BE, Murbartian J, Granados-Soto V: Acid increases inflammatory pain in rats: Effect of local peripheral ASICs inhibitors. Eur J Pharmacol. 2009, 603 (1–3): 56-61.PubMed

35.

Steen KH, Issberner U, Reeh PW: Pain due to experimental acidosis in human skin: evidence for non-adapting nociceptor excitation. Neurosci Lett. 1995, 199 (1): 29-32. 10.1016/0304-3940(95)12002-L.PubMed

36.

Nagae M, Hiraga T, Yoneda T: Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization. J Bone Miner Metab. 2007, 25 (2): 99-104. 10.1007/s00774-006-0734-8.PubMed

37.

Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K: Proton-sensing G-protein-coupled receptors. Nature. 2003, 425 (6953): 93-98. 10.1038/nature01905.PubMed

38.

Tomura H, Wang JQ, Liu JP, Komachi M, Damirin A, Mogi C, Tobo M, Nochi H, Tamoto K, Im DS: Cyclooxygenase-2 expression and prostaglandin E₂ production in response to acidic pH through OGR1 in a human osteoblastic cell line. J Bone Miner Res. 2008, 23 (7): 1129-1139. 10.1359/jbmr.080236.PubMed

39.

Kobayashi Y, Mizoguchi T, Take I, Kurihara S, Udagawa N, Takahashi N: Prostaglandin E₂ enhances osteoclastic differentiation of precursor cells through protein kinase A-dependent phosphorylation of TAK1. J Biol Chem. 2005, 280 (12): 11395-11403. 10.1074/jbc.M411189200.PubMed

40.

Iwai K, Koike M, Ohshima S, Miyatake K, Uchiyama Y, Saeki Y, Ishii M: RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway. J Bone Miner Res. 2007, 22 (10): 1612-1620. 10.1359/jbmr.070612.PubMed

41.

Ihara Y, Kihara Y, Hamano F, Yanagida K, Morishita Y, Kunita A, Yamori T, Fukayama M, Aburatani H, Shimizu T: The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor. Proc Natl Acad Sci U S A. 2010, 107 (40): 17309-17314. 10.1073/pnas.1001165107.PubMedCentralPubMed

42.

He XD, Tobo M, Mogi C, Nakakura T, Komachi M, Murata N, Takano M, Tomura H, Sato K, Okajima F: Involvement of proton-sensing receptor TDAG8 in the anti-inflammatory actions of dexamethasone in peritoneal macrophages. Biochem Biophys Res Commun. 2011, 415 (4): 627-631. 10.1016/j.bbrc.2011.10.122.PubMed

43.

Nagae M, Hiraga T, Wakabayashi H, Wang L, Iwata K, Yoneda T: Osteoclasts play a part in pain due to the inflammation adjacent to bone. Bone. 2006, 39 (5): 1107-1115. 10.1016/j.bone.2006.04.033.PubMed

44.

Jasti J, Furukawa H, Gonzales EB, Gouaux E: Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature. 2007, 449 (7160): 316-323. 10.1038/nature06163.PubMed

45.

Marples MJ: The ecology of human skin. 1965, Springfield, IL: Charles C. Thomas

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 function. J Invest Dermatol. 2003, 120 (6): 998-1006. 10.1038/jid.2003.11.PubMed

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 localization. Am J Pathol. 2007, 170 (6): 2055-2067. 10.2353/ajpath.2007.061277.PubMedCentralPubMed

48.

Adamson TM, Boyd RD, Platt HS, Strang LB: Composition of alveolar liquid in the foetal lamb. J Physiol. 1969, 204 (1): 159-168.PubMedCentralPubMed

49.

Tate S, MacGregor G, Davis M, Innes JA, Greening AP: Airways in cystic fibrosis are acidified: detection by exhaled breath condensate. Thorax. 2002, 57 (11): 926-929. 10.1136/thorax.57.11.926.PubMedCentralPubMed

50.

Ricciardolo FL, Gaston B, Hunt J: Acid stress in the pathology of asthma. J Allergy Clin Immunol. 2004, 113 (4): 610-619. 10.1016/j.jaci.2003.12.034.PubMed

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 cancer. Hepatogastroenterology. 2000, 47 (34): 998-1001.PubMed

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 malignancies. Clin Cancer Res. 2002, 8 (7): 2240-2245.PubMed

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 pH. Cancer Res. 2009, 69 (1): 358-368. 10.1158/0008-5472.CAN-08-2470.PubMed

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 carcinoma. Oral Oncol. 2012, 48 (7): 615-622. 10.1016/j.oraloncology.2012.01.018.PubMed

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 tumors. J Histochem Cytochem. 2000, 48 (12): 1601-1608. 10.1177/002215540004801203.PubMed

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 mucosa. BMC cancer. 2005, 5: 41-10.1186/1471-2407-5-41.PubMedCentralPubMed

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 growths. J Biol Chem. 2008, 283 (29): 20473-20483. 10.1074/jbc.M801330200.PubMed

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 survival. Virchows Arch. 2012, 461 (1): 33-39. 10.1007/s00428-012-1252-9.PubMed

59.

Shin HJ, Rho SB, Jung DC, Han IO, Oh ES, Kim JY: Carbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasion. J Cell Sci. 2011, 124 (Pt 7): 1077-1087.PubMed

60.

Parkkila S, Rajaniemi H, Parkkila AK, Kivela J, Waheed A, Pastorekova S, Pastorek J, Sly WS: Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci U S A. 2000, 97 (5): 2220-2224. 10.1073/pnas.040554897.PubMedCentralPubMed

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 domain. Curr Pharm Des. 2010, 16 (29): 3255-3263. 10.2174/138161210793429832.PubMed

62.

Muselaers S, Mulders P, Oosterwijk E, Oyen W, Boerman O: Molecular imaging and carbonic anhydrase IX-targeted radioimmunotherapy in clear cell renal cell carcinoma. Immunotherapy. 2013, 5 (5): 489-495. 10.2217/imt.13.36.PubMed

63.

Oosterwijk-Wakka JC, Boerman OC, Mulders PF, Oosterwijk E: Application of Monoclonal Antibody G250 Recognizing Carbonic Anhydrase IX in Renal Cell Carcinoma. Int J Mol Sci. 2013, 14 (6): 11402-11423. 10.3390/ijms140611402.PubMedCentralPubMed

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 lesions. J Dent Res. 1998, 77 (8): 1622-1629. 10.1177/00220345980770081001.PubMed

65.

Davis GE, Martin BM: A latent M_r 94,000 gelatin-degrading metalloprotease induced during differentiation of HL-60 promyelocytic leukemia cells: a member of the collagenase family of enzymes. Cancer Res. 1990, 50 (4): 1113-1120.PubMed

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 proteins. Arch Biochem Biophys. 1991, 286 (2): 551-554. 10.1016/0003-9861(91)90078-W.PubMed

67.

Martinez-Zaguilan R, Seftor EA, Seftor RE, Chu YW, Gillies RJ, Hendrix MJ: Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis. 1996, 14 (2): 176-186. 10.1007/BF00121214.PubMed

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 resorption. Am J Pathol. 2005, 166 (2): 467-476. 10.1016/S0002-9440(10)62269-9.PubMedCentralPubMed

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 mice. Proc Natl Acad Sci U S A. 1998, 95 (23): 13453-13458. 10.1073/pnas.95.23.13453.PubMedCentralPubMed

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 burden. Cancer Res. 2007, 67 (20): 9894-9902. 10.1158/0008-5472.CAN-06-3940.PubMed

71.

Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, Sloane BF: Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Am J Pathol. 2009, 175 (3): 1255-1269. 10.2353/ajpath.2009.080906.PubMedCentralPubMed

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 sublines. Science. 1983, 220 (4597): 611-613. 10.1126/science.6220468.PubMed

73.

Nakajima M, Irimura T, Di Ferrante N, Nicolson GL: Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase. J Biol Chem. 1984, 259 (4): 2283-2290.PubMed

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 melanoma. FEBS J. 2007, 274 (12): 3171-3183. 10.1111/j.1742-4658.2007.05848.x.PubMed

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 lines. J Biol Chem. 1992, 267 (16): 11424-11430.PubMed

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 vivo. Cancer Res. 1997, 57 (4): 570-572.PubMed

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 activation. J Biol Chem. 1998, 273 (9): 5086-5092. 10.1074/jbc.273.9.5086.PubMed

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 vivo. Cancer Res. 2001, 61 (16): 6020-6024.PubMed

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 VEGF. J Biol Chem. 2002, 277 (13): 11368-11374. 10.1074/jbc.M108347200.PubMed

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 metastatic. Clin Cancer Res. 1999, 5 (11): 3711-3721.PubMed

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 cells. J Interferon Cytokine Res. 2000, 20 (11): 1023-1028. 10.1089/10799900050198471.PubMed

82.

Shi Q, Xiong Q, Le X, Xie K: Regulation of interleukin-8 expression by tumor-associated stress factors. J Interferon Cytokine Res. 2001, 21 (8): 553-566. 10.1089/10799900152547812.PubMed

83.

Xu L, Fidler IJ: Acidic pH-induced elevation in interleukin 8 expression by human ovarian carcinoma cells. Cancer Res. 2000, 60 (16): 4610-4616.PubMed

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 cells. Oncogene. 2001, 20 (28): 3751-3756. 10.1038/sj.onc.1204500.PubMed

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 pathways. J Cell Biochem. 2008, 104 (4): 1378-1392. 10.1002/jcb.21714.PubMed

86.

Kato Y, Ozono S, Shuin T, Miyazaki K: Slow induction of gelatinase B mRNA by acidic culture conditions in mouse metastatic melanoma cells. Cell Biol Int. 1996, 20 (5): 375-377. 10.1006/cbir.1996.0044.PubMed

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 signaling. J Biol Chem. 2005, 280 (12): 10938-10944. 10.1074/jbc.M411313200.PubMed

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-α. Liver Int. 2009, 29 (2): 291-298. 10.1111/j.1478-3231.2008.01858.x.PubMed

89.

Hirata S, Fukamachi T, Sakano H, Tarora A, Saito H, Kobayashi H: Extracellular acidic environments induce phosphorylation of ZAP-70 in Jurkat T cells. Immunol Lett. 2008, 115 (2): 105-109. 10.1016/j.imlet.2007.10.006.PubMed

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 cells. J Biol Chem. 2005, 280 (41): 34458-34464. 10.1074/jbc.M505287200.PubMed

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 TBP. Nucleic Acids Res. 2003, 31 (15): 4523-4530. 10.1093/nar/gkg487.PubMedCentralPubMed

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-cadherin. J Cell Biochem. 2009, 108 (4): 851-859. 10.1002/jcb.22313.PubMed

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 pathway. FEBS Lett. 2011, 585 (4): 705-710. 10.1016/j.febslet.2011.01.022.PubMed

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 invasion. J Biol Chem. 2004, 279 (26): 26991-27007. 10.1074/jbc.M311838200.PubMed

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 domain. EMBO J. 2002, 21 (15): 3949-3959. 10.1093/emboj/cdf411.PubMedCentralPubMed

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 metalloproteinase. Oncogene. 2005, 24 (5): 859-868. 10.1038/sj.onc.1208258.PubMed

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-MMP. Exp Cell Res. 2011, 317 (14): 2031-2040. 10.1016/j.yexcr.2011.05.026.PubMed

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-MMP. Cell Biochem Funct. 2012, 1: 41-46.

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 metastases. Cancer Res. 2009, 69 (6): 2260-2268. 10.1158/0008-5472.CAN-07-5575.PubMedCentralPubMed

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 thermoradiotherapy. Clin Cancer Res. 2006, 12 (19): 5733-5740. 10.1158/1078-0432.CCR-05-2669.PubMed

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 gliomas. J Biol Chem. 2003, 278 (17): 15023-15034. 10.1074/jbc.M300991200.PubMed

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 TRPV1. J Biol Chem. 2008, 283 (14): 9377-9387. 10.1074/jbc.M709377200.PubMed

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 channels. Am J Physiol Renal Physiol. 2007, 292 (5): F1314-F1321. 10.1152/ajprenal.00432.2006.PubMedCentralPubMed

104.

Chen Y, Willcockson HH, Valtschanoff JG: Vanilloid receptor TRPV1-mediated phosphorylation of ERK in murine adjuvant arthritis. Osteoarthritis Cartilage. 2009, 17 (2): 244-251. 10.1016/j.joca.2008.06.015.PubMedCentralPubMed

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 ganglion. Pain. 2013, 154 (8): 1295-1304. 10.1016/j.pain.2013.04.004.PubMedCentralPubMed

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 ERK1/2. Neurosci Lett. 2013, 543: 72-77.PubMed

107.

Numata T, Okada Y: Proton conductivity through the human TRPM7 channel and its molecular determinants. J Biol Chem. 2008, 283 (22): 15097-15103. 10.1074/jbc.M709261200.PubMedCentralPubMed

108.

Davis FM, Azimi I, Faville RA, Peters AA, Jalink K, Putney JW, Goodhill GJ, Thompson EW, Roberts-Thomson SJ, Monteith GR: Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Oncogene. 2013, in press

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 solution. J Physiol. 2007, 585 (Pt 2): 351-360.PubMedCentralPubMed

110.

Tominaga T, Barber DL: Na-H exchange acts downstream of RhoA to regulate integrin-induced cell adhesion and spreading. Mol Biol Cell. 1998, 9 (8): 2287-2303. 10.1091/mbc.9.8.2287.PubMedCentralPubMed

111.

Denker SP, Barber DL: Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol. 2002, 159 (6): 1087-1096. 10.1083/jcb.200208050.PubMedCentralPubMed

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⁺ exchange. J Physiol. 2005, 567 (Pt 1): 225-238.PubMedCentralPubMed

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 cells. Pflugers Arch. 2009, 458 (6): 1069-1083. 10.1007/s00424-009-0694-7.PubMed

114.

Cardone RA, Casavola V, Reshkin SJ: The role of disturbed pH dynamics and the Na⁺/H⁺ exchanger in metastasis. Nat Rev Cancer. 2005, 5 (10): 786-795. 10.1038/nrc1713.PubMed

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 mechanism. Clin Exp Metastasis. 1997, 15 (4): 382-392. 10.1023/A:1018446104071.PubMed

116.

Chi SL, Pizzo SV: Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase. Cancer Res. 2006, 66 (2): 875-882. 10.1158/0008-5472.CAN-05-2806.PubMed

117.

Spugnini EP, Citro G, Fais S: Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. J Exp Clin Cancer Res. 2010, 29: 44-10.1186/1756-9966-29-44.PubMedCentralPubMed

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 acidity. Int J Cancer. 2010, 127 (1): 207-219. 10.1002/ijc.25009.PubMed

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 Rac1. Cancer Res. 2012, 72 (22): 5976-5987. 10.1158/0008-5472.CAN-12-1772.PubMed

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 pH. Cancer Chemother Pharmacol. 2000, 46 (4): 263-271. 10.1007/s002800000157.PubMed

121.

Vukovic V, Tannock IF: Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan. Br J Cancer. 1997, 75 (8): 1167-1172. 10.1038/bjc.1997.201.PubMedCentralPubMed

122.

Raghunand N, He X, Van Sluis R, Mahoney B, Baggett B, Taylor CW, Paine-Murrieta G, Roe D, Bhujwalla ZM, Gillies RJ: Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer. 1999, 80 (7): 1005-1011. 10.1038/sj.bjc.6690455.PubMedCentralPubMed

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 mitoxantrone. Neoplasia. 2001, 3 (3): 227-235. 10.1038/sj.neo.7900151.PubMedCentralPubMed

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 cells. Oncol Rep. 2007, 17 (1): 239-244.PubMed

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) activity. Adv Exp Med Biol. 2013, 765: 279-286. 10.1007/978-1-4614-4989-8_39.PubMed

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 therapy. J Control Release. 2007, 123 (2): 109-115. 10.1016/j.jconrel.2007.07.012.PubMed

127.

Lee ES, Gao Z, Kim D, Park K, Kwon IC, Bae YH: Super pH-sensitive multifunctional polymeric micelle for tumor pH_e specific TAT exposure and multidrug resistance. J Control Release. 2008, 129 (3): 228-236. 10.1016/j.jconrel.2008.04.024.PubMedCentralPubMed

128.

Garcia-Martin ML, Martinez GV, Raghunand N, Sherry AD, Zhang S, Gillies RJ: High resolution pH_e imaging of rat glioma using pH-dependent relaxivity. Magn Reson Med. 2006, 55 (2): 309-315. 10.1002/mrm.20773.PubMed

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 MRSI. Magn Reson Med. 1999, 41 (4): 743-750. 10.1002/(SICI)1522-2594(199904)41:4<743::AID-MRM13>3.0.CO;2-Z.PubMed

130.

Adachi E, Tannock IF: The effects of vasodilating drugs on pH in tumors. Oncol Res. 1999, 11 (4): 179-185.PubMed

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 agents. Biochem Pharmacol. 2003, 66 (7): 1219-1229. 10.1016/S0006-2952(03)00468-4.PubMed

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 amplification. Br J Cancer. 2012, 106 (5): 916-922. 10.1038/bjc.2012.32.PubMedCentralPubMed

133.

Teh BG, Kobayashi W, Narita K, Fukui R, Kimura H: Superselective docetaxel-nedaplatin combined infusion concurrent with radiation thrapy in advanced oral cancers. Oral Oncol EXTRA. 2004, 40: 126-131. 10.1016/j.ooe.2004.08.002.

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 carcinoma. Otolaryngol Head Neck Surg. 2007, 136 (6): 1003-1009. 10.1016/j.otohns.2006.12.018.PubMed

135.

Overgaard J, Bichel P: The influence of hypoxia and acidity on the hyperthermic response of malignant cells in vitro. Radiology. 1977, 123 (2): 511-514.PubMed

136.

Coss RA, Storck CW, Daskalakis C, Berd D, Wahl ML: Intracellular acidification abrogates the heat shock response and compromises survival of human melanoma cells. Mol Cancer Ther. 2003, 2 (4): 383-388.PubMed

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 6.7. Int J Hyperthermia. 2004, 20 (1): 93-106. 10.1080/02656730310001605519.PubMed

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 propionibacteria. Apoptosis. 2007, 12 (3): 573-591. 10.1007/s10495-006-0010-3.PubMed

Title: Acidic extracellular microenvironment and cancer
Authors: Yasumasa Kato
Shigeyuki Ozawa
Chihiro Miyamoto
Yojiro Maehata
Atsuko Suzuki
Toyonobu Maeda
Yuh Baba
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Cancer Cell International / Issue 1/2013
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/1475-2867-13-89

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2013

RNAi silencing of c-Myc inhibits cell migration, invasion, and proliferation in HepG2 human hepatocellular carcinoma cell line: c-Myc silencing in hepatocellular carcinoma cell

Wilms’ tumour suppressor gene 1 (WT1) is involved in the carcinogenesis of Lung cancer through interaction with PI3K/Akt pathway

Localization of BRCA1 protein in breast cancer tissue and cell lines with mutations

Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells

Promoter methylation status of the tumor suppressor gene SOX11 is associated with cell growth and invasion in nasopharyngeal carcinoma

Src-mediated morphology transition of lung cancer cells in three-dimensional organotypic culture

Keynote webinar | Spotlight on antibody–drug conjugates in cancer