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Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment

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Title: Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment
Authors: Annan, Dorcas A. Browse this author →KAKEN DB
Maishi, Nako Browse this author →KAKEN DB
Soga, Tomoyoshi Browse this author
Dawood, Randa Browse this author
Li, Cong Browse this author
Kikuchi, Hiroshi Browse this author
Hojo, Takayuki Browse this author →KAKEN DB
Morimoto, Masahiro Browse this author
Kitamura, Tetsuya Browse this author →KAKEN DB
Alam, Mohammad Towfik Browse this author →KAKEN DB
Minowa, Kazuyuki Browse this author →KAKEN DB
Shinohara, Nobuo Browse this author →KAKEN DB
Nam, Jin-Min Browse this author →KAKEN DB
Hida, Yasuhiro Browse this author →KAKEN DB
Hida, Kyoko Browse this author →KAKEN DB
Keywords: Lactic acidosis
Tumor endothelial cells
Carbonic anhydrase 2 (CAII)
pH regulation
Angiogenesis
Issue Date: 17-Dec-2019
Publisher: BioMed Central
Journal Title: Cell communication and signaling
Volume: 17
Issue: 1
Start Page: 169
Publisher DOI: 10.1186/s12964-019-0478-4
Abstract: Background Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood. Methodology The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia. Results The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis. Conclusion These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy.
Rights: https://creativecommons.org/licenses/by/4.0/
Type: article
URI: http://hdl.handle.net/2115/77025
Appears in Collections:歯学院・歯学研究院 (Graduate School of Dental Medicine / Faculty of Dental Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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