Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer
Abstract Background Carbonic anhydrases catalyze CO2/HCO3 – buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid–base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient progno...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-023-01644-1 |
| _version_ | 1797836142038482944 |
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| author | Soojung Lee Nicolai J. Toft Trine V. Axelsen Maria Sofia Espejo Tina M. Pedersen Marco Mele Helene L. Pedersen Eva Balling Tonje Johansen Mark Burton Mads Thomassen Pernille Vahl Peer Christiansen Ebbe Boedtkjer |
| author_facet | Soojung Lee Nicolai J. Toft Trine V. Axelsen Maria Sofia Espejo Tina M. Pedersen Marco Mele Helene L. Pedersen Eva Balling Tonje Johansen Mark Burton Mads Thomassen Pernille Vahl Peer Christiansen Ebbe Boedtkjer |
| author_sort | Soojung Lee |
| collection | DOAJ |
| description | Abstract Background Carbonic anhydrases catalyze CO2/HCO3 – buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid–base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear. Methods We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas. Results Carbonic anhydrases—particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14—undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis. Conclusions We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival. |
| first_indexed | 2024-04-09T15:05:00Z |
| format | Article |
| id | doaj.art-43eb9c61abb047289a64eb505c8ecf73 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-04-09T15:05:00Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-43eb9c61abb047289a64eb505c8ecf732023-04-30T11:32:16ZengBMCBreast Cancer Research1465-542X2023-04-0125112710.1186/s13058-023-01644-1Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancerSoojung Lee0Nicolai J. Toft1Trine V. Axelsen2Maria Sofia Espejo3Tina M. Pedersen4Marco Mele5Helene L. Pedersen6Eva Balling7Tonje Johansen8Mark Burton9Mads Thomassen10Pernille Vahl11Peer Christiansen12Ebbe Boedtkjer13Department of Biomedicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Biomedicine, Aarhus UniversityDepartment of Surgery, Randers Regional HospitalDepartment of Pathology, Randers Regional HospitalDepartment of Surgery, Randers Regional HospitalDepartment of Pathology, Randers Regional HospitalDepartment of Clinical Genetics, University of Southern DenmarkDepartment of Clinical Genetics, University of Southern DenmarkDepartment of Pathology, Aarhus University HospitalDepartment of Surgery, Randers Regional HospitalDepartment of Biomedicine, Aarhus UniversityAbstract Background Carbonic anhydrases catalyze CO2/HCO3 – buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid–base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear. Methods We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas. Results Carbonic anhydrases—particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14—undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis. Conclusions We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.https://doi.org/10.1186/s13058-023-01644-1AcetazolamideAcidosisBreast cancerCarbonic anhydrasesErbB2HER2 |
| spellingShingle | Soojung Lee Nicolai J. Toft Trine V. Axelsen Maria Sofia Espejo Tina M. Pedersen Marco Mele Helene L. Pedersen Eva Balling Tonje Johansen Mark Burton Mads Thomassen Pernille Vahl Peer Christiansen Ebbe Boedtkjer Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer Breast Cancer Research Acetazolamide Acidosis Breast cancer Carbonic anhydrases ErbB2 HER2 |
| title | Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer |
| title_full | Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer |
| title_fullStr | Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer |
| title_full_unstemmed | Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer |
| title_short | Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer |
| title_sort | carbonic anhydrases reduce the acidity of the tumor microenvironment promote immune infiltration decelerate tumor growth and improve survival in erbb2 her2 enriched breast cancer |
| topic | Acetazolamide Acidosis Breast cancer Carbonic anhydrases ErbB2 HER2 |
| url | https://doi.org/10.1186/s13058-023-01644-1 |
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