肿瘤酸性微环境的形成机制及其对肿瘤进展的影响
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摘要
肿瘤微环境在肿瘤形成和发展中具有重要的作用,偏酸性是肿瘤微环境的显著特征之一。由于异常的血管结构以及肿瘤细胞的过度增殖,肿瘤组织通常处于缺氧状态,导致其代谢过程发生改变。相对于正常组织以有氧代谢为主的代谢过程,肿瘤组织的代谢则更多地依赖于无氧糖酵解,其代谢产物乳酸与呼吸作用产生的CO2共同造成了肿瘤微环境的酸化,并对肿瘤发生和发展的诸多方面产生影响。本文总结了肿瘤酸性微环境的形成机制,并从肿瘤免疫、侵袭转移、自噬和抗肿瘤治疗等方面阐述了偏酸性肿瘤微环境对肿瘤进展的影响和调控。
Tumor microenvironment plays an important role in the formation and development of tumors, and the acidity is one of the remarkable features of tumor microenvironment. Due to excessive proliferation of tumor cells and abnormal structure of tumor blood vessels, the tumor tissues are usually in a hypoxia state, leading to changes in the metabolic processes of tumor cells. Compared with the normal tissues which mainly rely on aerobic oxidation to obtain energy, the metabolism of tumor cells dominatingly depends on the anaerobic glycolysis. Therefore, the lactate acid produced by glycolysis and the carbon dioxide produced by respiration together result in the acidification of tumor microenvironment(TME), and affects many aspects of tumorigenesis and development. This review focuses on the formation mechanism of tumor acidic microenvironment and its impacts on tumor progression, including tumor immunity, invasion,autophagy and resistance to anti-cancer treatment.
Tumor microenvironment plays an important role in the formation and development of tumors, and the acidity is one of the remarkable features of tumor microenvironment. Due to excessive proliferation of tumor cells and abnormal structure of tumor blood vessels, the tumor tissues are usually in a hypoxia state, leading to changes in the metabolic processes of tumor cells. Compared with the normal tissues which mainly rely on aerobic oxidation to obtain energy, the metabolism of tumor cells dominatingly depends on the anaerobic glycolysis. Therefore, the lactate acid produced by glycolysis and the carbon dioxide produced by respiration together result in the acidification of tumor microenvironment(TME), and affects many aspects of tumorigenesis and development. This review focuses on the formation mechanism of tumor acidic microenvironment and its impacts on tumor progression, including tumor immunity, invasion,autophagy and resistance to anti-cancer treatment.
引文
[1]SEMENZA GL.The hypoxic tumor microenvironment:A driving force for breast cancer progression[J].Biochim Biophys Acta,2016,1863(3):382-391.
[2]BISSELL MJ,RADISKY DC,RIZKI A,et al.The organizing principle:Microenvironmental influences in the normal and malignan t breast[J].Differentiation,2002,70(9/10):537-546.
[3]BHOME R,BULLOCK MD,Al SAIHATI HA,et al.A top-down view of the tumor microenvironment:Structure,cells and signaling[J].Front Cell Dev Biol,2015,3:33.
[4]NERI D,SUPURAN CT.Interfering with ph regulation in tumours as a therapeutic strategy[J].Nat Rev Drug Discov,2011,10(10):767-777.
[5]PEPPICELLI S,BIANCHINI F,CALORINI L.Extracellular acidity,a“reappreciated”trait of tumor environment driving malignancy:Perspectives in diagnosis and therapy[J].Cancer Metastasis Rev,2014,33(2/3):823-832.
[6]PILON-THOMAS S,KODUMUDI KN,[]EL-KENAWI AE,et al.Neutralization of tumor acidity improves antitumor responses to immunotherapy[J].Cancer Res,2016,76(6):1381-1390.
[7]VAUPEL P.Tumor microenvironmental physiology and its implications for radiation oncology[J].Semin Radiat Oncol,2004,14(3):198-206.
[8]CORBET C,FERON O.Tumour acidosis:From the passenger to the driver’s seat[J].Nat Rev Cancer,2017,17(10):577-593.
[9]HASHIM A I,ZHANG X,WOJTKOWIAK JW,et al.Imaging ph and metastasis[J].NMR Biomed,2011,24(6):582-591.
[10]MICHIELS C,TELLIER C,FERON O.Cycling hypoxia:A key feature of the tumor microenvironment[J].Biochim Biophys Acta,2016,1866(1):76-86.
[11]PEPPICELLI S,ANDREUCCI E,RUZZOLINI J,et al.The acidic microenvironment as a possible niche of dormant tumor cells[J].Cell Mol Life Sci,2017,74(15):2761-2771.
[12]NAKAZAWA MS,KEITH B,SIMON MC.Oxygen availability and metabolic adaptations[J].NatRev Cancer,2016,16(10):663-673.
[13]NEWELL K,FRANCHI A,POUYSSEGUR J,et al.Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity[J].Proc Natl Acad Sci USA,1993,90(3):1127-1131.
[14]CORBET C,FERON O.Cancer cell metabolism and mitochondr i a:Nutrient plasticity for tca cycle fueling[J].Biochim Biophys Acta Rev Cancer,2017,1868(1):7-15.
[15]IHNATKOh R,KUBES M,TAKACOVA M,et al.Extracellular acidosis elevates carbonic anhydraseⅨin human glioblastoma cells via transcriptional modulation that does not depend on hypoxia[J].Int J Oncol,2006,29(4):1025-1033.
[16]MOOKERJEE SA,GONCALVESRLS,GERENCSER AA,et al.The contributions of respiration and glycolysis to extracellular acid production[J].Biochim Biophys Acta,2015,1847(2):171-181.
[17]FOULDS L.The experimental study of tumor progression:A review[J].Cancer Res,1954,14(5):327-339.
[18]CALORINI L,PEPPICELLI S,BIANCHINI F.Extracellular acidity as favouring factor of tumor progression and metastatic dissemination[J].Exp Oncol,2012,34(2):79-84.
[19]BRAND A,S I NGE R K,KOE H LGUDRUN E,et al.Ldha-associated lactic acid production blunts tumor immunosurveillance by Tand NK cells[J].Cell Metab,2016,24(5):657-671.
[20]GOTTFRIED E,KUNZ-SCHUGHART LA,EBNER S,et al.Tumor-derived lactic acid modulates dendritic cell activation and antigen expression[J].Blood,2006,107(5):2013-2021.
[21]SEVERIN T,MULLER B,GIESE G,et al.Ph-dependent lak cell cytotoxicity[J].Tumour Biol,1994,15(5):304-310.
[22]LOEFFLER DA,HEPPNER GH,JUNEAU PL.Natural killer-cell activity under conditions reflective of tumor microenvironment[J].Int J Cancer,1991,48(6):895-899.
[23]FRIEDL P,WOLF K.Tumour-cell invasion and migration:Diversity and escape mechanisms[J].Nat Rev Cancer,2003,3(5):362-74.
[24]ESTRELLA V,CHEN T,LLOYD M,et al.Acidity generated by the tumor microenvironment drives local invasion[J].Cancer Res,2013,73(5):1524-1535.
[25]ROZHIN J,SAMENI M,ZIEGLER G,et al.Pericellular ph affects distribution and secretion of cathepsin B in malignant cells[J].Cancer Res,1994,54(24):6517-6525.
[26]MOELLERING RE,BLACK KC,KRISHNAMURTY C,et al.Acid treatment of melanoma cells selects for invasive phenotypes[J].Clin Exp Metastasis,2008,25(4):411-425.
[27]MASON SD,JOYCE JA.Proteolytic networks in cancer[J].Trends Cell Biol,2011,21(4):228-237.
[28]GORETZKI L,SCHMITT M,MANN K,et al.Effective activation of the proenzyme form of the urokinase-type plasminogen activator(pro-upa)by the cysteine protease cathepsin L[J].FEBS Lett,1992,297(1/2):112-118.
[29]VIHINEN P,KAHARI VM.Matrix metalloproteinases in cancer:Prognostic markers and therapeutic targets[J].Int J Cancer,2002,99(2):157-166.
[30]KI VM,SAARIALHO-KERE U.Matrix metalloproteinases and their inhibitors in tumour growth and invasion[J].Ann Med,1999,31(1):34-45.
[31]KATO Y,NAKAYAMA Y,UMEDA M,et al.Induction of 103-kda gelatinase/typeⅣcollagenase by acidic culture conditions in mouse metastatic melanoma cell lines[J].J Biol Chem,1992,267(16):11424-11430.
[32]MARINO ML,PELLEGRINI P,DI LERNIA G,et a l.Autophagy i s a protective mechani sm for human melanoma cells under acidic stress[J].J Biol Chem,2012,287(36):30664-30676.
[33]WOJTKOWIAK JW,ROTHBERG JM,KUMAR V,et al.Chronic autophagy is a cellular adaptation to tumor acidic ph microenvironments[J].Cancer Res,2012,72(16):3938-3947.
[34]FRAZIER DP,WILSON A,GRAHAM RM,et al.Acidosis regulates the stability,hydrophobicity,and activity of the bh3-only protein bnip3[J].Antioxi d Redox Signal,2006,8(9-10):1625-1634.
[35]XU T,SU H,GANAPATHY S,et al.Modulation of autophagic activity by extracellular ph[J].Autophagy,2011,7(11):1316-1322.
[36]DE MILITO A,FAIS S.Tumor acidity,chemoresistance and proton pump inhibitors[J].Future Oncol,2005,1(6):779-786.
[37]COWAN DS,TANNOCK IF.Factors that influence the penetration of methotrexate through solid tissue[J].Int J Cancer,2001,91(1):120-125.
[38]THEWS O,GASSNER B,KELLEHER DK,et al.Impact of extracellular acidity on the activity of p-glycoprotein and the cytotoxicity of chemotherapeutic drugs[J].Neoplasia,2006,8(2):143-152.
[39]HUNTER A,HENDRIKSE A,RENAN M,et al.Does the tumor microenvironment influencer adiation-induced apoptosis?[J].Apoptosis,2006,11(10):1727-1735.
[40]LEE HS,PARK HJ,LYONS JC,et al.Radiation-induced apoptosis in different ph environments in vitro[J].Int J Radiat Oncol Biol Phys,1997,38(5):1079-1087.
[41]PARK H,LYONS JC,GRIFFIN RJ,et al.Apoptosis and cell cycle progression in an acidic environment after irradiation[J].Radiat Res,2000,153(3):295-304.
[42]PARK HJ,LYONS JC,OHTSUBO T,et al.Cell cycle progression and apoptosis after irradiation in an acidic environment[J].Cell Death Differ,2000,7(8):729-738.
[43]FREEMAN ML,SIERRA E.An acidic extracellular environment reduces the fixation of radiation damage[J].Radiat Res,1984,97(1):154-161.
[44]TAYLOR S,SPUGNINI EP,ASSARAF YG,et al.Microenvironment acidity as a major determinant of tumor chemoresistance:Proton pump inhibitors(ppis)as a novel therapeutic approach[J].Drug Resist Updat,2015,23:69-78.
[45]PETRUL HM,SCHATZ CA,KOPITZ CC,et al.Therapeutic mechanism and efficacy of the antibody-drug conjugate bay79-4620 targeting human carbonic anhydrase 9[J].Mol Cancer Ther,2012,11(2):340-349.
[46]BOLA BM,CHADWICK AL,MICHOPOULOS F,et al.Inhibition of monocarboxylate transporter-1(mct1)by azd3965 enhances radiosensitivity by reducing lactate transport[J].Mol Cancer Ther,2014,13(12):2805-2816.
[47]PARKS SK,CORMERAIS Y,DURIVAULT J,et al.Genetic disruption of the ph(i)-regulating proteins Na+/H+exchanger1(slc9a1)and carbonic anhydrase9 severely reduces growth of colon cancer cells[J].Oncotarget,2017,8(6):10225-10237.
[48]FERRARI S,PERUT F,FAGIOLI F,et al.Proton pump inhibitor chemosensitization in human osteosarcoma:from the bench to the patients’bed[J].J Transl Med,2013,11:268.
[49]WANG BY,ZHANG J,WANG JL,et al.Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer[J].J Exp Clin Cancer Res,2015,34:85.
[2]BISSELL MJ,RADISKY DC,RIZKI A,et al.The organizing principle:Microenvironmental influences in the normal and malignan t breast[J].Differentiation,2002,70(9/10):537-546.
[3]BHOME R,BULLOCK MD,Al SAIHATI HA,et al.A top-down view of the tumor microenvironment:Structure,cells and signaling[J].Front Cell Dev Biol,2015,3:33.
[4]NERI D,SUPURAN CT.Interfering with ph regulation in tumours as a therapeutic strategy[J].Nat Rev Drug Discov,2011,10(10):767-777.
[5]PEPPICELLI S,BIANCHINI F,CALORINI L.Extracellular acidity,a“reappreciated”trait of tumor environment driving malignancy:Perspectives in diagnosis and therapy[J].Cancer Metastasis Rev,2014,33(2/3):823-832.
[6]PILON-THOMAS S,KODUMUDI KN,[]EL-KENAWI AE,et al.Neutralization of tumor acidity improves antitumor responses to immunotherapy[J].Cancer Res,2016,76(6):1381-1390.
[7]VAUPEL P.Tumor microenvironmental physiology and its implications for radiation oncology[J].Semin Radiat Oncol,2004,14(3):198-206.
[8]CORBET C,FERON O.Tumour acidosis:From the passenger to the driver’s seat[J].Nat Rev Cancer,2017,17(10):577-593.
[9]HASHIM A I,ZHANG X,WOJTKOWIAK JW,et al.Imaging ph and metastasis[J].NMR Biomed,2011,24(6):582-591.
[10]MICHIELS C,TELLIER C,FERON O.Cycling hypoxia:A key feature of the tumor microenvironment[J].Biochim Biophys Acta,2016,1866(1):76-86.
[11]PEPPICELLI S,ANDREUCCI E,RUZZOLINI J,et al.The acidic microenvironment as a possible niche of dormant tumor cells[J].Cell Mol Life Sci,2017,74(15):2761-2771.
[12]NAKAZAWA MS,KEITH B,SIMON MC.Oxygen availability and metabolic adaptations[J].NatRev Cancer,2016,16(10):663-673.
[13]NEWELL K,FRANCHI A,POUYSSEGUR J,et al.Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity[J].Proc Natl Acad Sci USA,1993,90(3):1127-1131.
[14]CORBET C,FERON O.Cancer cell metabolism and mitochondr i a:Nutrient plasticity for tca cycle fueling[J].Biochim Biophys Acta Rev Cancer,2017,1868(1):7-15.
[15]IHNATKOh R,KUBES M,TAKACOVA M,et al.Extracellular acidosis elevates carbonic anhydraseⅨin human glioblastoma cells via transcriptional modulation that does not depend on hypoxia[J].Int J Oncol,2006,29(4):1025-1033.
[16]MOOKERJEE SA,GONCALVESRLS,GERENCSER AA,et al.The contributions of respiration and glycolysis to extracellular acid production[J].Biochim Biophys Acta,2015,1847(2):171-181.
[17]FOULDS L.The experimental study of tumor progression:A review[J].Cancer Res,1954,14(5):327-339.
[18]CALORINI L,PEPPICELLI S,BIANCHINI F.Extracellular acidity as favouring factor of tumor progression and metastatic dissemination[J].Exp Oncol,2012,34(2):79-84.
[19]BRAND A,S I NGE R K,KOE H LGUDRUN E,et al.Ldha-associated lactic acid production blunts tumor immunosurveillance by Tand NK cells[J].Cell Metab,2016,24(5):657-671.
[20]GOTTFRIED E,KUNZ-SCHUGHART LA,EBNER S,et al.Tumor-derived lactic acid modulates dendritic cell activation and antigen expression[J].Blood,2006,107(5):2013-2021.
[21]SEVERIN T,MULLER B,GIESE G,et al.Ph-dependent lak cell cytotoxicity[J].Tumour Biol,1994,15(5):304-310.
[22]LOEFFLER DA,HEPPNER GH,JUNEAU PL.Natural killer-cell activity under conditions reflective of tumor microenvironment[J].Int J Cancer,1991,48(6):895-899.
[23]FRIEDL P,WOLF K.Tumour-cell invasion and migration:Diversity and escape mechanisms[J].Nat Rev Cancer,2003,3(5):362-74.
[24]ESTRELLA V,CHEN T,LLOYD M,et al.Acidity generated by the tumor microenvironment drives local invasion[J].Cancer Res,2013,73(5):1524-1535.
[25]ROZHIN J,SAMENI M,ZIEGLER G,et al.Pericellular ph affects distribution and secretion of cathepsin B in malignant cells[J].Cancer Res,1994,54(24):6517-6525.
[26]MOELLERING RE,BLACK KC,KRISHNAMURTY C,et al.Acid treatment of melanoma cells selects for invasive phenotypes[J].Clin Exp Metastasis,2008,25(4):411-425.
[27]MASON SD,JOYCE JA.Proteolytic networks in cancer[J].Trends Cell Biol,2011,21(4):228-237.
[28]GORETZKI L,SCHMITT M,MANN K,et al.Effective activation of the proenzyme form of the urokinase-type plasminogen activator(pro-upa)by the cysteine protease cathepsin L[J].FEBS Lett,1992,297(1/2):112-118.
[29]VIHINEN P,KAHARI VM.Matrix metalloproteinases in cancer:Prognostic markers and therapeutic targets[J].Int J Cancer,2002,99(2):157-166.
[30]KI VM,SAARIALHO-KERE U.Matrix metalloproteinases and their inhibitors in tumour growth and invasion[J].Ann Med,1999,31(1):34-45.
[31]KATO Y,NAKAYAMA Y,UMEDA M,et al.Induction of 103-kda gelatinase/typeⅣcollagenase by acidic culture conditions in mouse metastatic melanoma cell lines[J].J Biol Chem,1992,267(16):11424-11430.
[32]MARINO ML,PELLEGRINI P,DI LERNIA G,et a l.Autophagy i s a protective mechani sm for human melanoma cells under acidic stress[J].J Biol Chem,2012,287(36):30664-30676.
[33]WOJTKOWIAK JW,ROTHBERG JM,KUMAR V,et al.Chronic autophagy is a cellular adaptation to tumor acidic ph microenvironments[J].Cancer Res,2012,72(16):3938-3947.
[34]FRAZIER DP,WILSON A,GRAHAM RM,et al.Acidosis regulates the stability,hydrophobicity,and activity of the bh3-only protein bnip3[J].Antioxi d Redox Signal,2006,8(9-10):1625-1634.
[35]XU T,SU H,GANAPATHY S,et al.Modulation of autophagic activity by extracellular ph[J].Autophagy,2011,7(11):1316-1322.
[36]DE MILITO A,FAIS S.Tumor acidity,chemoresistance and proton pump inhibitors[J].Future Oncol,2005,1(6):779-786.
[37]COWAN DS,TANNOCK IF.Factors that influence the penetration of methotrexate through solid tissue[J].Int J Cancer,2001,91(1):120-125.
[38]THEWS O,GASSNER B,KELLEHER DK,et al.Impact of extracellular acidity on the activity of p-glycoprotein and the cytotoxicity of chemotherapeutic drugs[J].Neoplasia,2006,8(2):143-152.
[39]HUNTER A,HENDRIKSE A,RENAN M,et al.Does the tumor microenvironment influencer adiation-induced apoptosis?[J].Apoptosis,2006,11(10):1727-1735.
[40]LEE HS,PARK HJ,LYONS JC,et al.Radiation-induced apoptosis in different ph environments in vitro[J].Int J Radiat Oncol Biol Phys,1997,38(5):1079-1087.
[41]PARK H,LYONS JC,GRIFFIN RJ,et al.Apoptosis and cell cycle progression in an acidic environment after irradiation[J].Radiat Res,2000,153(3):295-304.
[42]PARK HJ,LYONS JC,OHTSUBO T,et al.Cell cycle progression and apoptosis after irradiation in an acidic environment[J].Cell Death Differ,2000,7(8):729-738.
[43]FREEMAN ML,SIERRA E.An acidic extracellular environment reduces the fixation of radiation damage[J].Radiat Res,1984,97(1):154-161.
[44]TAYLOR S,SPUGNINI EP,ASSARAF YG,et al.Microenvironment acidity as a major determinant of tumor chemoresistance:Proton pump inhibitors(ppis)as a novel therapeutic approach[J].Drug Resist Updat,2015,23:69-78.
[45]PETRUL HM,SCHATZ CA,KOPITZ CC,et al.Therapeutic mechanism and efficacy of the antibody-drug conjugate bay79-4620 targeting human carbonic anhydrase 9[J].Mol Cancer Ther,2012,11(2):340-349.
[46]BOLA BM,CHADWICK AL,MICHOPOULOS F,et al.Inhibition of monocarboxylate transporter-1(mct1)by azd3965 enhances radiosensitivity by reducing lactate transport[J].Mol Cancer Ther,2014,13(12):2805-2816.
[47]PARKS SK,CORMERAIS Y,DURIVAULT J,et al.Genetic disruption of the ph(i)-regulating proteins Na+/H+exchanger1(slc9a1)and carbonic anhydrase9 severely reduces growth of colon cancer cells[J].Oncotarget,2017,8(6):10225-10237.
[48]FERRARI S,PERUT F,FAGIOLI F,et al.Proton pump inhibitor chemosensitization in human osteosarcoma:from the bench to the patients’bed[J].J Transl Med,2013,11:268.
[49]WANG BY,ZHANG J,WANG JL,et al.Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer[J].J Exp Clin Cancer Res,2015,34:85.
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