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Open Access 01-02-2020 | Metastasis | Research Paper

Adaptation to chronic acidic extracellular pH elicits a sustained increase in lung cancer cell invasion and metastasis

Authors: Shusaku Sutoo, Toyonobu Maeda, Atsuko Suzuki, Yasumasa Kato

Published in: Clinical & Experimental Metastasis | Issue 1/2020

Abstract

Acidic extracellular pH (pH_e) is an important microenvironment for cancer cells. This study assessed whether adaptation to acidic pH_e enhances the metastatic phenotype of tumor cells. The low metastatic variant of Lewis lung carcinoma (LLCm1) cells were subjected to stepwise acidification, establishing acidic pH_e-adapted (LLCm1A) cells growing exponentially at pH 6.2. These LLCm1A cells showed increased production of matrix metalloproteinases (MMPs), including MMP-2, -3, -9, and -13, and pulmonary metastasis following injection into mouse tail veins. Although LLCm1A cells exhibited a fibroblastic shape, keratin-5 expression was increased and α-smooth muscle actin expression was reduced. Despite serial passage of these cells at pH 7.4, high invasive activity through Matrigel^® was sustained for at least 28 generations. Thus, adaptation to acidic pH_e resulted in a more invasive phenotype, which was sustained during passage at pH 7.4, suggesting that an acidic microenvironment at the primary tumor site is important in the acquisition of a metastatic phenotype.

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Kato Y, Maeda T, Suzuki A, Baba Y (2018) Cancer metabolism: new insights into classic characteristics. Jpn Dent Sci Rev 54(1):8–21. https://doi.org/10.1016/j.jdsr.2017.08.003 CrossRefPubMed

Le Floch R, Chiche J, Marchiq I, Naiken T, Ilc K, Murray CM, Critchlow SE, Roux D, Simon MP, Pouyssegur J (2011) CD147 subunit of lactate/H⁺ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci USA 108(40):16663–16668. https://doi.org/10.1073/pnas.1106123108 CrossRefPubMed

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

Lee SH, McIntyre D, Honess D, Hulikova A, Pacheco-Torres J, Cerdan S, Swietach P, Harris AL, Griffiths JR (2018) Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo. Br J Cancer 119(5):622–630. https://doi.org/10.1038/s41416-018-0216-5 CrossRefPubMedPubMedCentral

Auyeung KK, Ko JK (2017) Angiogenesis and oxidative stress in metastatic tumor progression: pathogenesis and novel therapeutic approach of colon cancer. Curr Pharm Des 23(27):3952–3961. https://doi.org/10.2174/1381612823666170228124105 CrossRefPubMed

Xu L, Fukumura D, Jain RK (2002) 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 277(13):11368–11374. https://doi.org/10.1074/jbc.M108347200 CrossRefPubMed

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

Peppicelli S, Bianchini F, Contena C, Tombaccini D, Calorini L (2013) Acidic pH via NF-κB favours VEGF-C expression in human melanoma cells. Clin Exp Metastasis 30(8):957–967. https://doi.org/10.1007/s10585-013-9595-4 CrossRefPubMed

Kato Y, Nakayama Y, Umeda M, Miyazaki K (1992) Induction of 103-kDa gelatinase/type IV collagenase by acidic culture conditions in mouse metastatic melanoma cell lines. J Biol Chem 267(16):11424–11430PubMed

10.

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

11.

Peppicelli S, Bianchini F, Torre E, Calorini L (2014) Contribution of acidic melanoma cells undergoing epithelial-to-mesenchymal transition to aggressiveness of non-acidic melanoma cells. Clin Exp Metastasis 31(4):423–433. https://doi.org/10.1007/s10585-014-9637-6 CrossRefPubMed

12.

Suzuki A, Maeda T, Baba Y, Shimamura K, Kato Y (2014) Acidic extracellular pH promotes epithelial mesenchymal transition in Lewis lung carcinoma model. Cancer Cell Int 14(1):129. https://doi.org/10.1186/s12935-014-0129-1 CrossRefPubMedPubMedCentral

13.

Feng S, Zheng Z, Feng L, Yang L, Chen Z, Lin Y, Gao Y, Chen Y (2016) Proton pump inhibitor pantoprazole inhibits the proliferation, selfrenewal and chemoresistance of gastric cancer stem cells via the EMT/betacatenin pathways. Oncol Rep 36(6):3207–3214. https://doi.org/10.3892/or.2016.5154 CrossRefPubMed

14.

Kato Y, Ozawa S, Tsukuda M, Kubota E, Miyazaki K, St-Pierre Y, Hata R (2007) 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 274(12):3171–3183. https://doi.org/10.1111/j.1742-4658.2007.05848.x CrossRefPubMed

15.

Riemann A, Schneider B, Ihling A, Nowak M, Sauvant C, Thews O, Gekle M (2011) Acidic environment leads to ROS-induced MAPK signaling in cancer cells. PLoS ONE 6(7):e22445. https://doi.org/10.1371/journal.pone.0022445 CrossRefPubMedPubMedCentral

16.

Gao L, Fang YQ, Zhang TY, Ge B, Tang RJ, Huang JF, Jiang LM, Tan N (2015) Acidic extracellular microenvironment promotes the invasion and cathepsin B secretion of PC-3 cells. Int J Clin Exp Med 8(5):7367–7373PubMedPubMedCentral

17.

Menard JA, Christianson HC, Kucharzewska P, Bourseau-Guilmain E, Svensson KJ, Lindqvist E, Indira Chandran V, Kjellen L, Welinder C, Bengzon J, Johansson MC, Belting M (2016) Metastasis stimulation by hypoxia and acidosis-induced extracellular lipid uptake is mediated by proteoglycan-dependent endocytosis. Cancer Res 76(16):4828–4840. https://doi.org/10.1158/0008-5472.CAN-15-2831 CrossRefPubMed

18.

Kondo A, Yamamoto S, Nakaki R, Shimamura T, Hamakubo T, Sakai J, Kodama T, Yoshida T, Aburatani H, Osawa T (2017) Extracellular acidic pH activates the sterol regulatory element-binding protein 2 to promote tumor progression. Cell Rep 18(9):2228–2242. https://doi.org/10.1016/j.celrep.2017.02.006 CrossRefPubMed

19.

Mitachi T, Mezaki M, Yamashita K, Itagaki H (2018) Acidic conditions induce the suppression of CD86 and CD54 expression in THP-1 cells. J Toxicol Sci 43(5):299–309. https://doi.org/10.2131/jts.43.299 CrossRefPubMed

20.

Delli Castelli D, Ferrauto G, Cutrin JC, Terreno E, Aime S (2014) In vivo maps of extracellular pH in murine melanoma by CEST-MRI. Magn Reson Med 71(1):326–332. https://doi.org/10.1002/mrm.24664 CrossRefPubMed

21.

Mendoza EE, Pocceschi MG, Kong X, Leeper DB, Caro J, Limesand KH, Burd R (2012) Control of glycolytic flux by AMP-activated protein kinase in tumor cells adapted to low pH. Transl Oncol 5(3):208–216CrossRef

22.

Damaghi M, Tafreshi NK, Lloyd MC, Sprung R, Estrella V, Wojtkowiak JW, Morse DL, Koomen JM, Bui MM, Gatenby RA, Gillies RJ (2015) Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane. Nat Commun 6:8752. https://doi.org/10.1038/ncomms9752 CrossRefPubMedPubMedCentral

23.

Andreucci E, Peppicelli S, Carta F, Brisotto G, Biscontin E, Ruzzolini J, Bianchini F, Biagioni A, Supuran CT, Calorini L (2017) Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. J Mol Med (Berlin) 95(12):1341–1353. https://doi.org/10.1007/s00109-017-1590-9 CrossRef

24.

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8(6):e1000412. https://doi.org/10.1371/journal.pbio.1000412 CrossRefPubMedPubMedCentral

25.

Hata R, Izukuri K, Kato Y, Sasaki S, Mukaida N, Maehata Y, Miyamoto C, Akasaka T, Yang X, Nagashima Y, Takeda K, Kiyono T, Taniguchi M (2015) Suppressed rate of carcinogenesis and decreases in tumour volume and lung metastasis in CXCL14/BRAK transgenic mice. Sci Rep 5:9083. https://doi.org/10.1038/srep09083 CrossRefPubMedPubMedCentral

26.

Maeda T, Suzuki A, Koga K, Miyamoto C, Maehata Y, Ozawa S, Hata RI, Nagashima Y, Nabeshima K, Miyazaki K, Kato Y (2017) TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells. Oncotarget 8(45):78312–78326. https://doi.org/10.18632/oncotarget.20826 CrossRefPubMedPubMedCentral

27.

Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C_T method. Nat Protoc 3(6):1101–1108CrossRef

28.

Chan AO, Jim MH, Lam KF, Morris JS, Siu DC, Tong T, Ng FH, Wong SY, Hui WM, Chan CK, Lai KC, Cheung TK, Chan P, Wong G, Yuen MF, Lau YK, Lee S, Szeto ML, Wong BC, Lam SK (2007) Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease. JAMA 298(12):1412–1419. https://doi.org/10.1001/jama.298.12.1412 CrossRefPubMed

29.

Longo DL, Bartoli A, Consolino L, Bardini P, Arena F, Schwaiger M, Aime S (2016) In vivo imaging of tumor metabolism and acidosis by combining PET and MRI-CEST pH imaging. Cancer Res 76(22):6463–6470. https://doi.org/10.1158/0008-5472.CAN-16-0825 CrossRefPubMed

30.

Hong CS, Graham NA, Gu W, Espindola Camacho C, Mah V, Maresh EL, Alavi M, Bagryanova L, Krotee PAL, Gardner BK, Behbahan IS, Horvath S, Chia D, Mellinghoff IK, Hurvitz SA, Dubinett SM, Critchlow SE, Kurdistani SK, Goodglick L, Braas D, Graeber TG, Christofk HR (2016) MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4. Cell Rep 14(7):1590–1601. https://doi.org/10.1016/j.celrep.2016.01.057 CrossRefPubMedPubMedCentral

31.

Kato Y, Lambert CA, Colige AC, Mineur P, Noël A, Frankenne F, Foidart JM, Baba M, Hata R, Miyazaki K, Tsukuda M (2005) 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 280(12):10938–10944. https://doi.org/10.1074/jbc.M411313200 CrossRefPubMed

32.

Maeda T, Yuzawa S, Suzuki A, Baba Y, Nishimura Y, Kato Y (2016) RhoA mediates the expression of acidic extracellular pH-induced matrix metalloproteinase-9 mRNA through phospholipase D1 in mouse metastatic B16-BL6 melanoma cells. Int J Oncol 48:1251–1257. https://doi.org/10.3892/ijo.2016.3322 CrossRefPubMed

33.

Riemann A, Schneider B, Gundel D, Stock C, Thews O, Gekle M (2014) Acidic priming enhances metastatic potential of cancer cells. Pflügers Arch 466(11):2127–2138. https://doi.org/10.1007/s00424-014-1458-6 CrossRefPubMed

34.

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

35.

Yu C, Liu Y, Qin Z (2018) Metadherin contributes to epithelial-mesenchymal transition and paclitaxel resistance induced by acidic extracellular pH in nasopharyngeal carcinoma. Oncol Lett 15(3):3858–3863. https://doi.org/10.3892/ol.2018.7760 CrossRefPubMedPubMedCentral

36.

Gunasinghe NP, Wells A, Thompson EW, Hugo HJ (2012) Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev 31(3–4):469–478. https://doi.org/10.1007/s10555-012-9377-5 CrossRefPubMed

37.

Lamonte G, Tang X, Chen JL, Wu J, Ding CK, Keenan MM, Sangokoya C, Kung HN, Ilkayeva O, Boros LG, Newgard CB, Chi JT (2013) Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress. Cancer Metab 1(1):23. https://doi.org/10.1186/2049-3002-1-23 CrossRefPubMedPubMedCentral

38.

Corbet C, Pinto A, Martherus R, Santiago de Jesus JP, Polet F, Feron O (2016) Acidosis drives the reprogramming of fatty acid metabolism in cancer cells through changes in mitochondrial and histone acetylation. Cell Metab 24(2):311–323. https://doi.org/10.1016/j.cmet.2016.07.003 CrossRefPubMed

39.

Chano T, Avnet S, Kusuzaki K, Bonuccelli G, Sonveaux P, Rotili D, Mai A, Baldini N (2016) Tumour-specific metabolic adaptation to acidosis is coupled to epigenetic stability in osteosarcoma cells. Am J Cancer Res 6(4):859–875PubMedPubMedCentral

40.

Alison MR, Lin WR, Lim SM, Nicholson LJ (2012) Cancer stem cells: in the line of fire. Cancer Treat Rev 38(6):589–598. https://doi.org/10.1016/j.ctrv.2012.03.003 CrossRefPubMed

41.

Filatova A, Seidel S, Bogurcu N, Graf S, Garvalov BK, Acker T (2016) Acidosis acts through HSP90 in a PHD/VHL-independent manner to promote HIF function and stem cell maintenance in glioma. Cancer Res 76(19):5845–5856. https://doi.org/10.1158/0008-5472.CAN-15-2630 CrossRefPubMed

42.

Iqbal W, Alkarim S, AlHejin A, Mukhtar H, Saini KS (2016) Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis. Oncotarget 7(46):76337–76353. https://doi.org/10.18632/oncotarget.10942 CrossRefPubMedPubMedCentral

43.

Welch DR, Neri A, Nicolson GL (1983) Comparison of ‘spontaneous’ and ‘experimental’ metastasis using rat 13762 mammary adenocarcinoma metastatic cell clones. Invasion Metastasis 3(2):65–80PubMed

44.

Sato N, Maehara N, Mizumoto K, Nagai E, Yasoshima T, Hirata K, Tanaka M (2001) Telomerase activity of cultured human pancreatic carcinoma cell lines correlates with their potential for migration and invasion. Cancer 91(3):496–504CrossRef

45.

Sundareshan P, Hendrix MJ (1992) Growth, morphologic, and invasive characteristics of early and late passages of a human endometrial carcinoma cell line (RL95-2). In Vitro Cell Dev Biol 28A(7–8):544–552CrossRef

46.

Fishman DA, Bafetti LM, Banionis S, Kearns AS, Chilukuri K, Stack MS (1997) Production of extracellular matrix-degrading proteinases by primary cultures of human epithelial ovarian carcinoma cells. Cancer 80(8):1457–1463. https://doi.org/10.1002/(SICI)1097-0142(19971015)80:8%3c1457:AID-CNCR46%3e3.0.CO;2-4 CrossRefPubMed

47.

Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H (2007) NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26(5):711–724. https://doi.org/10.1038/sj.onc.1209808 CrossRefPubMed

48.

Fatimah SS, Tan GC, Chua K, Fariha MM, Tan AE, Hayati AR (2013) Stemness and angiogenic gene expression changes of serial-passage human amnion mesenchymal cells. Microvasc Res 86:21–29. https://doi.org/10.1016/j.mvr.2012.12.004 CrossRefPubMed

49.

van Lamsweerde AL, Henry N, Vaes G (1983) Metastatic heterogeneity of cells from Lewis lung carcinoma. Cancer Res 43(11):5314–5320PubMed

Title: Adaptation to chronic acidic extracellular pH elicits a sustained increase in lung cancer cell invasion and metastasis
Authors: Shusaku Sutoo
Toyonobu Maeda
Atsuko Suzuki
Yasumasa Kato
Publication date: 01-02-2020
Publisher: Springer Netherlands
Keywords: Metastasis
Lung Cancer
Lung Cancer
Lung Cancer
Published in: Clinical & Experimental Metastasis / Issue 1/2020
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-019-09990-1

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