請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91656
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 周涵怡 | zh_TW |
dc.contributor.advisor | Han-Yi Elizabeth Chou | en |
dc.contributor.author | 謝宛宜 | zh_TW |
dc.contributor.author | Wan-Yi Shie | en |
dc.date.accessioned | 2024-02-20T16:24:47Z | - |
dc.date.available | 2024-02-21 | - |
dc.date.copyright | 2024-02-20 | - |
dc.date.issued | 2023 | - |
dc.date.submitted | 2023-12-06 | - |
dc.identifier.citation | 1. Fares J, Fares MY, Khachfe HH, Salhab HA and Fares Y: Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 5: 28, 2020.
2. Meyer KA, Kammerling EM and et al.: pH studies of malignant tissues in human beings. Cancer Res 8: 513-518, 1948. 3. Boedtkjer E and Pedersen SF: The Acidic Tumor Microenvironment as a Driver of Cancer. Annu Rev Physiol 82: 103-126, 2020. 4. Li Y, Zhao L and Li XF: Hypoxia and the Tumor Microenvironment. Technol Cancer Res Treat 20: 15330338211036304, 2021. 5. Kartikasari AER, Huertas CS, Mitchell A and Plebanski M: Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis. Front Oncol 11: 692142, 2021. 6. Chen Z, Han F, Du Y, Shi H and Zhou W: Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 8: 70, 2023. 7. Singleton DC, Macann A and Wilson WR: Therapeutic targeting of the hypoxic tumour microenvironment. Nat Rev Clin Oncol 18: 751-772, 2021. 8. Shi Z, Li Q and Mei L: pH-Sensitive nanoscale materials as robust drug delivery systems for cancer therapy. Chinese Chemical Letters 31: 1345-1356, 2020. 9. Anemone A, Consolino L, Arena F, Capozza M and Longo DL: Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH. Cancer Metastasis Rev 38: 25-49, 2019. 10. Kim SH and Baek KH: Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect. Int J Mol Sci 22: 2021. 11. Becker HM: Carbonic anhydrase IX and acid transport in cancer. Br J Cancer 122: 157-167, 2020. 12. Pascale RM, Calvisi DF, Simile MM, Feo CF and Feo F: The Warburg Effect 97 Years after Its Discovery. Cancers (Basel) 12: 2020. 13. Swietach P, Boedtkjer E and Pedersen SF: How protons pave the way to aggressive cancers. Nat Rev Cancer 23: 825-841, 2023. 14. Damaghi M, Tafreshi NK, Lloyd MC, et al: Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane. Nat Commun 6: 8752, 2015. 15. Su T, Huang S, Zhang Y, et al: miR-7/TGF-beta2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis. Acta Pharm Sin B 12: 821-837, 2022. 16. Toft NJ, Axelsen TV, Pedersen HL, et al: Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival. Elife 10: 2021. 17. Anemone A, Consolino L, Conti L, et al: Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential. Br J Cancer 124: 207-216, 2021. 18. Busco G, Cardone RA, Greco MR, et al: NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space. FASEB J 24: 3903-3915, 2010. 19. Ji K, Mayernik L, Moin K and Sloane BF: Acidosis and proteolysis in the tumor microenvironment. Cancer Metastasis Rev 38: 103-112, 2019. 20. Qian X, Zhang Y, Tao J, et al: Acidosis induces synovial fibroblasts to release vascular endothelial growth factor via acid-sensitive ion channel 1a. Lab Invest 101: 280-291, 2021. 21. Peppicelli S, Bianchini F, Contena C, Tombaccini D and Calorini L: Acidic pH via NF-kappaB favours VEGF-C expression in human melanoma cells. Clin Exp Metastasis 30: 957-967, 2013. 22. Yu IF, Yu YH, Chen LY, Fan SK, Chou HY and Yang JT: A portable microfluidic device for the rapid diagnosis of cancer metastatic potential which is programmable for temperature and CO2. Lab Chip 14: 3621-3628, 2014. 23. Niu D, Luo T, Wang H, Xia Y and Xie Z: Lactic acid in tumor invasion. Clin Chim Acta 522: 61-69, 2021. 24. Vlachostergios PJ, Oikonomou KG, Gibilaro E and Apergis G: Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer biomarkers : section A of Disease markers 15: 725-734, 2015. 25. Brizel DM, Schroeder T, Scher RL, et al: Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. International journal of radiation oncology, biology, physics 51: 349-353, 2001. 26. Estrella V, Chen T, Lloyd M, et al: Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73: 1524-1535, 2013. 27. Castaneda M, den Hollander P, Kuburich NA, Rosen JM and Mani SA: Mechanisms of cancer metastasis. Semin Cancer Biol 87: 17-31, 2022. 28. Liu M, Yang J, Xu B and Zhang X: Tumor metastasis: Mechanistic insights and therapeutic interventions. MedComm 2: 587-617, 2021. 29. Faubert B, Solmonson A and DeBerardinis RJ: Metabolic reprogramming and cancer progression. Science 368: 2020. 30. Bergers G and Fendt SM: The metabolism of cancer cells during metastasis. Nat Rev Cancer 21: 162-180, 2021. 31. Chen Q, Zou J, He Y, et al: A narrative review of circulating tumor cells clusters: A key morphology of cancer cells in circulation promote hematogenous metastasis. Front Oncol 12: 944487, 2022. 32. Lawrence R, Watters M, Davies CR, Pantel K and Lu YJ: Circulating tumour cells for early detection of clinically relevant cancer. Nat Rev Clin Oncol 20: 487-500, 2023. 33. Jin F, Zhu L, Shao J, et al: Circulating tumour cells in patients with lung cancer universally indicate poor prognosis. Eur Respir Rev 31: 2022. 34. Amintas S, Bedel A, Moreau-Gaudry F, et al: Circulating Tumor Cell Clusters: United We Stand Divided We Fall. Int J Mol Sci 21: 2020. 35. Aceto N, Bardia A, Miyamoto DT, et al: Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158: 1110-1122, 2014. 36. Au SH, Storey BD, Moore JC, et al: Clusters of circulating tumor cells traverse capillary-sized vessels. Proc Natl Acad Sci U S A 113: 4947-4952, 2016. 37. Murlidhar V, Reddy RM, Fouladdel S, et al: Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers. Cancer Res 77: 5194-5206, 2017. 38. Luo XL, Lin L, Hu H, et al: Development and characterization of mammary intraductal (MIND) spontaneous metastasis models for triple-negative breast cancer in syngeneic mice. Sci Rep 10: 4681, 2020. 39. Gomez-Cuadrado L, Tracey N, Ma R, Qian B and Brunton VG: Mouse models of metastasis: progress and prospects. Dis Model Mech 10: 1061-1074, 2017. 40. Giacobbe A and Abate-Shen C: Modeling metastasis in mice: a closer look. Trends Cancer 7: 916-929, 2021. 41. Minn AJ, Gupta GP, Siegel PM, et al: Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524, 2005. 42. Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD and Muller WJ: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A 89: 10578-10582, 1992. 43. Hemler ME, Huang C, Takada Y, Schwarz L, Strominger JL and Clabby ML: Characterization of the cell surface heterodimer VLA-4 and related peptides. Journal of Biological Chemistry 262: 11478-11485, 1987. 44. Pang X, He X, Qiu Z, et al: Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct Target Ther 8: 1, 2023. 45. Kadry YA and Calderwood DA: Chapter 22: Structural and signaling functions of integrins. Biochim Biophys Acta Biomembr 1862: 183206, 2020. 46. Hight-Warburton W and Parsons M: Regulation of cell migration by alpha4 and alpha9 integrins. Biochem J 476: 705-718, 2019. 47. Yang JT, Rayburn H and Hynes RO: Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development (Cambridge, England) 121: 549-560, 1995. 48. Prosper F, Stroncek D, McCarthy JB and Verfaillie CM: Mobilization and homing of peripheral blood progenitors is related to reversible downregulation of alpha4 beta1 integrin expression and function. J Clin Invest 101: 2456-2467, 1998. 49. Arroyo AG, Yang JT, Rayburn H and Hynes RO: Alpha4 integrins regulate the proliferation/differentiation balance of multilineage hematopoietic progenitors in vivo. Immunity 11: 555-566, 1999. 50. Young SA, McCabe KE, Bartakova A, et al: Integrin α4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma. PLoS One 10: e0120815, 2015. 51. Tissino E, Pozzo F, Benedetti D, et al: CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression. Blood 135: 1244-1254, 2020. 52. Fang T, Yin X, Wang Y, Wang H, Wang X and Xue Y: Lymph Node Metastasis-Related Gene ITGA4 Promotes the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Regulating Tumor Immune Microenvironment. J Oncol 2022: 1315677, 2022. 53. Sevilla-Movilla S, Arellano-Sanchez N, Martinez-Moreno M, et al: Upregulated expression and function of the alpha4beta1 integrin in multiple myeloma cells resistant to bortezomib. J Pathol 252: 29-40, 2020. 54. Hartmann TN, Burger JA, Glodek A, Fujii N and Burger M: CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene 24: 4462-4471, 2005. 55. Lu TN, Ganganna B, Pham TT, et al: Antitumor effect of the integrin alpha4 signaling inhibitor JK273 in non-small cell lung cancer NCI-H460 cells. Biochem Biophys Res Commun 491: 355-360, 2017. 56. Xie J, Yang P, Lin HP, et al: Integrin alpha4 up-regulation activates the hedgehog pathway to promote arsenic and benzo[alpha]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis. Cancer Lett 493: 143-155, 2020. 57. Spicer AP, Olson JS and McDonald JA: Molecular cloning and characterization of a cDNA encoding the third putative mammalian hyaluronan synthase. J Biol Chem 272: 8957-8961, 1997. 58. Skandalis SS, Karalis T and Heldin P: Intracellular hyaluronan: Importance for cellular functions. Semin Cancer Biol 62: 20-30, 2020. 59. Kobayashi T, Chanmee T and Itano N: Hyaluronan: Metabolism and Function. Biomolecules 10: 2020. 60. Spinelli FM, Vitale DL, Sevic I and Alaniz L: Hyaluronan in the Tumor Microenvironment. Adv Exp Med Biol 1245: 67-83, 2020. 61. Kultti A, Li X, Jiang P, Thompson CB, Frost GI and Shepard HM: Therapeutic targeting of hyaluronan in the tumor stroma. Cancers (Basel) 4: 873-903, 2012. 62. Kuo YZ, Fang WY, Huang CC, et al: Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer. Oncotarget 8: 15563-15583, 2017. 63. Hasegawa K, Saga R, Ohuchi K, et al: 4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression. Cells 11: 2022. 64. Lee WJ, Tu SH, Cheng TC, et al: Type-3 Hyaluronan Synthase Attenuates Tumor Cells Invasion in Human Mammary Parenchymal Tissues. Molecules 26: 2021. 65. Cheng XB, Wang S, Yang H, et al: Negative regulation between the expression levels of receptor for hyaluronic acid-mediated motility and hyaluronan leads to cell migration in pancreatic cancer. Oncol Lett 20: 199, 2020. 66. Czyrnik ED, Wiesehofer M, Dankert JT and Wennemuth G: The regulation of HAS3 by miR-10b and miR-29a in neuroendocrine transdifferentiated LNCaP prostate cancer cells. Biochem Biophys Res Commun 523: 713-718, 2020. 67. Xie Y, Su N, Yang J, et al: FGF/FGFR signaling in health and disease. Signal Transduct Target Ther 5: 181, 2020. 68. Zhan X, Culpepper A, Reddy M, Loveless J and Goldfarb M: Human oncogenes detected by a defined medium culture assay. Oncogene 1: 369-376, 1987. 69. Higgins CA, Petukhova L, Harel S, et al: FGF5 is a crucial regulator of hair length in humans. Proc Natl Acad Sci U S A 111: 10648-10653, 2014. 70. Reed SA and Johnson SE: Expression of scleraxis and tenascin C in equine adipose and umbilical cord blood derived stem cells is dependent upon substrata and FGF supplementation. Cytotechnology 66: 27-35, 2014. 71. Park GC, Song JS, Park HY, et al: Role of Fibroblast Growth Factor-5 on the Proliferation of Human Tonsil-Derived Mesenchymal Stem Cells. Stem Cells Dev 25: 1149-1160, 2016. 72. Tian R, Yao C, Yang C, et al: Fibroblast growth factor-5 promotes spermatogonial stem cell proliferation via ERK and AKT activation. Stem Cell Res Ther 10: 40, 2019. 73. Allerstorfer S, Sonvilla G, Fischer H, et al: FGF5 as an oncogenic factor in human glioblastoma multiforme: autocrine and paracrine activities. Oncogene 27: 4180-4190, 2008. 74. Huang Y, Wang H and Yang Y: Expression of Fibroblast Growth Factor 5 (FGF5) and Its Influence on Survival of Breast Cancer Patients. Med Sci Monit 24: 3524-3530, 2018. 75. Fang F, Chang RM, Yu L, et al: MicroRNA-188-5p suppresses tumor cell proliferation and metastasis by directly targeting FGF5 in hepatocellular carcinoma. J Hepatol 63: 874-885, 2015. 76. Zhu Z, Wu Q, Zhang M, Tong J, Zhong B and Yuan K: Hsa_circ_0016760 exacerbates the malignant development of non‑small cell lung cancer by sponging miR‑145‑5p/FGF5. Oncol Rep 45: 501-512, 2021. 77. Zhao T, Qian K and Zhang Y: High Expression of FGF5 Is an Independent Prognostic Factor for Poor Overall Survival and Relapse-Free Survival in Lung Adenocarcinoma. J Comput Biol 27: 948-957, 2020. 78. Xie X, Wang Z, Chen F, et al: Roles of FGFR in oral carcinogenesis. Cell Prolif 49: 261-269, 2016. 79. Chen WJ, Ho CC, Chang YL, et al: Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun 5: 3472, 2014. 80. Peppicelli S, Bianchini F, Torre E and Calorini L: Contribution of acidic melanoma cells undergoing epithelial-to-mesenchymal transition to aggressiveness of non-acidic melanoma cells. Clin Exp Metastasis 31: 423-433, 2014. 81. Chen S, Zhou Y, Chen Y and Gu J: fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34: i884-i890, 2018. 82. Liao Y, Smyth GK and Shi W: featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30: 923-930, 2014. 83. Love MI, Huber W and Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15: 550, 2014. 84. Robinson MD, McCarthy DJ and Smyth GK: edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26: 139-140, 2010. 85. Bolger AM, Lohse M and Usadel B: Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30: 2114-2120, 2014. 86. Kim D, Paggi JM, Park C, Bennett C and Salzberg SL: Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol 37: 907-915, 2019. 87. Bu D, Luo H, Huo P, et al: KOBAS-i: intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis. Nucleic acids research 49: W317-W325, 2021. 88. Ruzzolini J, Peppicelli S, Andreucci E, et al: Everolimus selectively targets vemurafenib resistant BRAF(V600E) melanoma cells adapted to low pH. Cancer Lett 408: 43-54, 2017. 89. Edgar R, Domrachev M and Lash AE: Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic acids research 30: 207-210, 2002. 90. Hynes RO: Integrins: bidirectional, allosteric signaling machines. Cell 110: 673-687, 2002. 91. Tammi MI, Oikari S, Pasonen-Seppanen S, Rilla K, Auvinen P and Tammi RH: Activated hyaluronan metabolism in the tumor matrix - Causes and consequences. Matrix Biol 78-79: 147-164, 2019. 92. Bulian P, Shanafelt TD, Fegan C, et al: CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia. J Clin Oncol 32: 897-904, 2014. 93. Pulkka OP, Mpindi JP, Tynninen O, et al: Clinical relevance of integrin alpha 4 in gastrointestinal stromal tumours. Journal of Cellular and Molecular Medicine 22: 2220-2230, 2018. 94. Bao X, Ran J, Kong C, et al: Pan-cancer analysis reveals the potential of hyaluronate synthase as therapeutic targets in human tumors. Heliyon 9: e19112, 2023. 95. Chen Q, Peng Q, Cai J, et al: Super Enhancer Driven Hyaluronan Synthase 3 Promotes Malignant Progression of Nasopharyngeal Carcinoma. J Cancer 14: 1751-1762, 2023. 96. Wang J, Jordan AR, Zhu H, et al: Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma. Cancer Cell Int 22: 421, 2022. 97. Lee PJ, Ho CC, Ho H, et al: Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts. Theranostics 11: 9667-9686, 2021. 98. Andreucci E, Peppicelli S, Ruzzolini J, et al: The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells. J Mol Med (Berl) 98: 1431-1446, 2020. 99. Choodetwattana P, Proungvitaya S, Jearanaikoon P and Limpaiboon T: The Upregulation of OCT4 in Acidic Extracellular pH is Associated with Gemcitabine Resistance in Cholangiocarcinoma Cell Lines. Asian Pac J Cancer Prev 20: 2745-2748, 2019. 100. Li H, Yin H and Yan Y: Circ_0041732 regulates tumor properties of triple-negative breast cancer cells by the miR-149-5p/FGF5 pathway. Int J Biol Markers 37: 178-190, 2022. 101. Cannon-Albright LA, Teerlink CC, Stevens J, et al: A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer. Int J Cancer 153: 364-372, 2023. 102. Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F and Polyak K: Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514: 54-58, 2014. 103. Michl J, Wang Y, Monterisi S, et al: CRISPR-Cas9 screen identifies oxidative phosphorylation as essential for cancer cell survival at low extracellular pH. Cell Rep 38: 110493, 2022. 104. Munoz R, Man S, Shaked Y, et al: Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy. Cancer Res 66: 3386-3391, 2006. 105. Sabatier L, Chen D, Fagotto-Kaufmann C, et al: Fibrillin assembly requires fibronectin. Mol Biol Cell 20: 846-858, 2009. 106. Schlesinger M and Bendas G: Contribution of very late antigen-4 (VLA-4) integrin to cancer progression and metastasis. Cancer Metastasis Rev 34: 575-591, 2015. 107. Schmaus A, Bauer J and Sleeman JP: Sugars in the microenvironment: the sticky problem of HA turnover in tumors. Cancer Metastasis Rev 33: 1059-1079, 2014. 108. Clift R, Souratha J, Garrovillo SA, Zimmerman S and Blouw B: Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti-Programmed Death-Ligand 1 Immunotherapy. Cancer Res 79: 4149-4159, 2019. 109. Kultti A, Pasonen-Seppanen S, Jauhiainen M, et al: 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res 315: 1914-1923, 2009. 110. Saha D, Mitra D, Alam N, et al: Lupeol and Paclitaxel cooperate in hindering hypoxia induced vasculogenic mimicry via suppression of HIF-1alpha-EphA2-Laminin-5gamma2 network in human oral cancer. J Cell Commun Signal 17: 591-608, 2023. 111. Fu R, Du W, Ding Z, et al: HIF-1alpha promoted vasculogenic mimicry formation in lung adenocarcinoma through NRP1 upregulation in the hypoxic tumor microenvironment. Cell Death Dis 12: 394, 2021. 112. Chen J, Chen S, Zhuo L, Zhu Y and Zheng H: Regulation of cancer stem cell properties, angiogenesis, and vasculogenic mimicry by miR-450a-5p/SOX2 axis in colorectal cancer. Cell Death Dis 11: 173, 2020. 113. Zhao B, Wu M, Hu Z, et al: Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation. Signal Transduct Target Ther 5: 117, 2020. 114. He X, You J, Ding H, et al: Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status. BMC Cancer 21: 132, 2021. 115. Liang Z, Liu H, Zhang Y, et al: Cyr61 from adipose-derived stem cells promotes colorectal cancer metastasis and vasculogenic mimicry formation via integrin alpha(V) beta(5). Mol Oncol 15: 3447-3467, 2021. 116. Franco P, Camerino I, Merlino F, et al: alphaV-Integrin-Dependent Inhibition of Glioblastoma Cell Migration, Invasion and Vasculogenic Mimicry by the uPAcyclin Decapeptide. Cancers (Basel) 15: 2023. 117. Becelli R, Renzi G, Morello R and Altieri F: Intracellular and extracellular tumor pH measurement in a series of patients with oral cancer. The Journal of craniofacial surgery 18: 1051-1054, 2007. 118. de Bem Prunes B, Nunes JS, da Silva VP, et al: The role of tumor acidification in aggressiveness, cell dissemination and treatment resistance of oral squamous cell carcinoma. Life Sci 288: 120163, 2022. 119. Persi E, Duran-Frigola M, Damaghi M, et al: Systems analysis of intracellular pH vulnerabilities for cancer therapy. Nat Commun 9: 2997, 2018. 120. Moellering RE, Black KC, Krishnamurty C, et al: Acid treatment of melanoma cells selects for invasive phenotypes. Clin Exp Metastasis 25: 411-425, 2008. 121. Amano R, Namekata M, Horiuchi M, et al: Specific inhibition of FGF5-induced cell proliferation by RNA aptamers. Sci Rep 11: 2976, 2021. 122. Damaghi M, West J, Robertson-Tessi M, et al: The harsh microenvironment in early breast cancer selects for a Warburg phenotype. Proc Natl Acad Sci U S A 118: 2021. 123. Lora-Michiels M, Yu D, Sanders L, et al: Extracellular pH and P-31 magnetic resonance spectroscopic variables are related to outcome in canine soft tissue sarcomas treated with thermoradiotherapy. Clin Cancer Res 12: 5733-5740, 2006. 124. Morishima H, Washio J, Kitamura J, Shinohara Y, Takahashi T and Takahashi N: Real-time monitoring system for evaluating the acid-producing activity of oral squamous cell carcinoma cells at different environmental pH. Sci Rep 7: 10092, 2017. 125. Iwabu J, Yamashita S, Takeshima H, et al: FGF5 methylation is a sensitivity marker of esophageal squamous cell carcinoma to definitive chemoradiotherapy. Sci Rep 9: 13347, 2019. 126. Derynck R, Jarrett JA, Chen EY, et al: Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature 316: 701-705, 1985. 127. Franzén P, ten Dijke P, Ichijo H, et al: Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor. Cell 75: 681-692, 1993. 128. Tzavlaki K and Moustakas A: TGF-beta Signaling. Biomolecules 10: 2020. 129. Rastogi S, Mishra SS, Arora MK, et al: Lactate acidosis and simultaneous recruitment of TGF-beta leads to alter plasticity of hypoxic cancer cells in tumor microenvironment. Pharmacol Ther 250: 108519, 2023. 130. Trempolec N, Degavre C, Doix B, Brusa D, Corbet C and Feron O: Acidosis-Induced TGF-beta2 Production Promotes Lipid Droplet Formation in Dendritic Cells and Alters Their Potential to Support Anti-Mesothelioma T Cell Response. Cancers (Basel) 12: 2020. 131. Corbet C, Bastien E, Santiago de Jesus JP, et al: TGFbeta2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells. Nat Commun 11: 454, 2020. 132. Yamahana H, Terashima M, Takatsuka R, et al: TGF-beta1 facilitates MT1-MMP-mediated proMMP-9 activation and invasion in oral squamous cell carcinoma cells. Biochem Biophys Rep 27: 101072, 2021. 133. Shen H, Sun B, Yang Y, et al: MIR4435-2HG regulates cancer cell behaviors in oral squamous cell carcinoma cell growth by upregulating TGF-beta1. Odontology 108: 553-559, 2020. 134. Lv S, Luo T, Yang Y, et al: Naa10p and IKKalpha interaction regulates EMT in oral squamous cell carcinoma via TGF-beta1/Smad pathway. J Cell Mol Med 25: 6760-6772, 2021. 135. Takahashi K, Podyma-Inoue KA, Saito M, et al: TGF-beta generates a population of cancer cells residing in G1 phase with high motility and metastatic potential via KRTAP2-3. Cell Rep 40: 111411, 2022. | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91656 | - |
dc.description.abstract | 腫瘤微環境酸化是瓦式效應所帶來的影響,原因是糖解作用提高,乳酸和氫離子產生,腫瘤活化乳酸質子雙向轉運蛋白的活性,維持腫瘤細胞內pH值來適應酸性環境。此外,酸化導致細胞外基質重塑,刺激血管或是淋巴管生成,有利於腫瘤擴散,這些都是轉移的先決條件。轉移是腫瘤從原位腫瘤脫離並進入血管或淋巴管,循環腫瘤細胞在循環系統存活,最後在新環境殖民生長。目前常見轉移動物模組,有自發性轉移模型、實驗性轉移模型、基因工程小鼠轉移模型三種。但腫瘤如何殖民,一直沒有異種移植可以了解,腫瘤殖民模型是需要被建立。另外需要提及的是,酸化造成的影響是特定癌症才有?還是廣泛對各種癌症有影響?因此,我們建立多種長期酸化細胞株,以及可觀察腫瘤殖民的模型,了解其中影響,有機會透過治療阻止腫瘤轉移。在本研究中,我們利用長期肺癌酸化細胞株,成功建立腫瘤殖民模型。轉錄組定序揭露出酸化主要影響細胞外基質路徑。在臨床組織切片中,ITGA4和HAS3在有轉移潛力的原位癌高度表現以及影響肺癌進程。此外,體內以及體外實驗中,酸化增加擬態血管數目,讓腫瘤有效率在新環境中殖民。這些結果指出我們能觀察腫瘤殖民過程,酸化誘導腫瘤重組細胞外基質,增加轉移潛力、提升發生率,並穩定擬態血管能力以及有害代謝物的清除,在新環境中殖民生長。另外,我們也建立長期酸化口腔鱗狀細胞癌來驗證酸化並不是腫瘤特異性。同時,轉錄組定序揭露出酸化在口腔鱗狀細胞癌主要影響細胞和細胞之間訊息路徑。我們也找出SAS和CLS1細胞共同酸化基因 FGF5,在異種移植實驗中,酸化造成FGF5高表現量。酸化誘導 FGF5 在細胞的表達和重新分佈。在臨床組織切片中,FGF5在有轉移潛力的原位癌高度表現並且有差存活率。最後,FGF5表現可能與吸菸危險因子有相關。綜合以上的結果,我們建立的轉移殖民模型,結合酸化研究,能了解腫瘤殖民過程,提供新的腫瘤治療觀點,阻止腫瘤轉移殖民。 | zh_TW |
dc.description.abstract | The acidosis of the tumor microenvironment is caused by the Warburg effect. The reason is that glycolysis increases, resulting in the production of lactic acid and hydrogen ions. Tumors activate the activity of the lactate proton bidirectional transporter to maintain the pH value in tumor cells and adapt to the acidic environment. In addition, acidosis leads to the remodeling of the extracellular matrix, stimulates the formation of blood vessels or lymphatic vessels, and facilitates the spread of tumors, all of which are necessary for metastasis. Metastasis occurs when a tumor detaches from the primary tumor and invades either blood vessels or lymphatic vessels. Circulating tumor cells survive in the circulatory system and eventually colonize and grow in a new environment. Currently, there are three common animal models for studying metastasis: the spontaneous metastasis model, the experimental metastasis model, and the genetically engineered mouse metastasis model. However, there is a lack of a suitable model to understand how tumors colonize. A novel animal metastatic model should be established to assess the colonization of circulating tumor cells after extravasation. Another thing that needs to be mentioned is, does the impact of acidification only affect specific cancers? Or does it affect a wide range of cancers? Therefore, we have established a variety of long-term acidified cell lines and models that can observe tumor colonization. This allows us to understand the effects and provides an opportunity to prevent tumor metastasis through treatment.
In this study, we successfully established a tumor colonization model using long-term acidosis lung cancer cell lines. Long-term acidosis increased the incidence of tumors. RNA-Seq revealed that acidosis induced extracellular matrix (ECM) reorganization. Identify the acidosis-responsive genes ITGA4 and HAS3, which exhibited high expression at both the RNA and protein levels. In clinical tissue sections, ITGA4 and HAS3 were upregulation expression in primary tumors with metastatic potential. In addition, long-term acidosis increases vasculogenic mimicry, which provides nutrition and enables tumors to efficiently colonize new environments. These results indicated that Long-term acidosis reprograms the transcriptome of lung cancer cells, characterized by extensive changes in extracellular matrix (ECM) composition. The upregulation of ITGA4 and HAS3 is associated with the stability of the simulated vascular structure and the elimination of toxic metabolites, thereby facilitating the formation of new metastatic colonies following CTC extravasation. In addition, we also established long-term acidosis oral squamous cell carcinoma (OSCC) cell lines to verify that acidosis is not specific to cancer. Acidosis mainly affects the cell-cell signaling pathway in OSCC, as revealed by RNA-Seq, which was found the common acidosis-responsive gene FGF5 in OSCC and CLS1 cells. In vivo, acidosis increased the high expression of FGF5 in tumors, and it also induced the expression and redistribution of FGF5 in cells. In clinical tissue sections, the presence of primary tumors with metastatic potential and high FGF5 expression was associated with poor survival. Finally, the expression of FGF5 was found to be related with cigarette consumption. Based on the above results, we believe that the establish of metastatic colonization model, combined with acidosis study, can help us to understand the mechanism of tumor colonization and provide new perspectives on tumor treatment. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-02-20T16:24:47Z No. of bitstreams: 0 | en |
dc.description.provenance | Made available in DSpace on 2024-02-20T16:24:47Z (GMT). No. of bitstreams: 0 | en |
dc.description.tableofcontents | 誌謝 I
中文摘要 II ABSTRACT III CONTENTS VI LIST OF FIGURES X LIST OF SUPPLEMENTARY DATA XIV LIST OF TABLES XV Chapter 1 Introduction 1 1.1 Acidosis of the tumor microenvironment 1 1.2 The effect of acidosis on tumors 2 1.3 Tumor metastasis 4 1.4 Circulating tumor cells (CTCs) 6 1.5 Mouse metastasis model 7 1.6 Integrin Subunit Alpha 4 (ITGA4) 9 1.7 Hyaluronan synthase 3 (HAS3) 10 1.8 Fibroblast growth factor 5 (FGF5) 11 1.9 Study dilemmas and Approach 13 Chapter 2 Aims 15 Chapter 3 Materials and methods 16 3.1 Cell lines and cell culture 16 3.2 Acidic treatment 16 3.3 Time lapse microscopy 17 3.4 Trypan blue exclusion assay 17 3.5 MTT assay 17 3.6 Side population analysis 18 3.7 Western Blot Analysis 18 3.8 Metastatic colonization model 19 3.9 Transcriptome sequencing and analyses 20 3.10 Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein-protein interaction (PPI) analysis 22 3.11 Histological and immunohistochemistry staining 23 3.12 Vasculogenic mimicry assay 24 3.13 OSCC patients and tissue array samples 25 3.14 Xenograft model 26 3.15 Immunofluorescence staining 27 3.16 Statistical analysis 28 Chapter 4 Results 30 4.1 Establishment of long-term acidosis cell model 30 4.2 Acidosis results in re-organization of the extracellular matrix 31 4.3 Acidosis promotes metastatic incidence and growth 32 4.4 Enhanced protein expression of ITGA4 in the metastatic tumors 34 4.5 Expression of ITGA4 is upregulated in primary tumors that display metastatic potential, before migration 36 4.6 ITGA4 upregulation is related with adjacent normal tissues 37 4.7 HAS3 overexpression correlates with tumor metastatic potential and tumor stage 38 4.8 HAS3 did not response to adjacent normal tissues 39 4.9 Long-term acidosis enhances vasculogenic mimicry 40 4.10 Long-term acidosis OSCC cell model and transcriptome sequencing analysis of acidosis expression response 42 4.11 Identification of acidosis-responsive genes for cell-cell interactions 43 4.12 Redistribution of FGF5 expression can be induced by acidosis 44 4.13 FGF5 protein is enhanced in the acidotic xenografts 45 4.14 The expression of the FGF5 protein is related to tumor metastatic potential and survival 46 4.15 FGF5 level is associated with cigarette consumption 47 Chapter 5 Discussion 49 Chapter 6 Conclusion 62 Chapter 7 Future studies 64 References 67 Figures and Legend 86 Supplementary data 132 Tables 138 Appendix 141 | - |
dc.language.iso | en | - |
dc.title | 探討微環境酸化對腫瘤進程之影響 | zh_TW |
dc.title | The Effect of Acidosis Microenvironment on Tumor Progression | en |
dc.type | Thesis | - |
dc.date.schoolyear | 112-1 | - |
dc.description.degree | 博士 | - |
dc.contributor.oralexamcommittee | 郭彥彬;章浩宏;李財坤;沈湯龍 | zh_TW |
dc.contributor.oralexamcommittee | Mark Yen-Ping Kuo;Hao-Hueng Chang;Tsai-Kun Li;Tang-Long Shen | en |
dc.subject.keyword | 酸化,轉移,殖民,細胞外基質,擬態血管,ITGA4,HAS3,FGF5, | zh_TW |
dc.subject.keyword | acidosis,metastasis,colonization,ECM,vasculogenic mimicry,ITGA4,HAS3,FGF5, | en |
dc.relation.page | 172 | - |
dc.identifier.doi | 10.6342/NTU202304480 | - |
dc.rights.note | 未授權 | - |
dc.date.accepted | 2023-12-07 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 口腔生物科學研究所 | - |
顯示於系所單位: | 口腔生物科學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-112-1.pdf 目前未授權公開取用 | 133.88 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。