| 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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