Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression

Boedtkjer, Ebbe

doi:10.1007/112_2021_63

Cited by 12 publications

(15 citation statements)

References 350 publications

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“…47 Because H + and Ca 2+ buffers overlap and pH modifies the activity of many Ca 2+ transporters and channels, changes in pH i have potential to modify the intracellular Ca 2+ concentration. 4 Interestingly, local acid-base conditions may moreover influence macropinocytosis, which is commonly inhibited by amiloride-derivatives that block Na + /H + exchangers. [48][49][50][51] Macropinocytosis is prominent in breast and colon cancer cells, [49][50][51] and could accelerate cellular ATP uptake.…”

Section: Discussionmentioning

confidence: 99%

“…Associated net ATP hydrolysis also liberates H + ; however, under steady‐state conditions, H + consumption during ATP synthesis is expected to balance H + release from ATP hydrolysis avoiding substantial acute changes in intracellular pH (pH i ) 47 . Because H + and Ca 2+ buffers overlap and pH modifies the activity of many Ca 2+ transporters and channels, changes in pH i have potential to modify the intracellular Ca 2+ concentration 4 . Interestingly, local acid‐base conditions may moreover influence macropinocytosis, which is commonly inhibited by amiloride‐derivatives that block Na + /H + exchangers 48‐51 .…”

Section: Discussionmentioning

confidence: 99%

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Amplified Ca²⁺ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation

Henningsen

McWhan

Dam

et al. 2022

Intl Journal of Cancer

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Intracellular Ca2+ dynamics shape malignant behaviors of cancer cells. Whereas previous studies focused on cultured cancer cells, we here used breast organoids and colonic crypts freshly isolated from human and murine surgical biopsies. We performed fluorescence microscopy to evaluate intracellular Ca2+ concentrations in breast and colon cancer tissue with preferential focus on intracellular Ca2+ release in response to purinergic and cholinergic stimuli. Inhibition of the sarco‐/endoplasmic reticulum Ca2+ ATPase with cyclopiazonic acid elicited larger Ca2+ responses in breast cancer tissue, but not in colon cancer tissue, relative to respective normal tissue. The resting intracellular Ca2+ concentration was elevated, and ATP, UTP and acetylcholine induced strongly augmented intracellular Ca2+ responses in breast cancer tissue compared with normal breast tissue. In contrast, resting intracellular Ca2+ levels and acetylcholine‐induced increases in intracellular Ca2+ concentrations were unaffected and ATP‐ and UTP‐induced Ca2+ responses were smaller in colon cancer tissue compared with normal colon tissue. In accordance with the amplified Ca2+ responses, ATP and UTP substantially increased proliferative activity—evaluated by bromodeoxyuridine incorporation—in breast cancer tissue, whereas the effect was minimal in normal breast tissue. ATP caused cell death—identified with ethidium homodimer‐1 staining—in breast cancer tissue only at concentrations above the expected pathophysiological range. We conclude that intracellular Ca2+ responses are amplified in breast cancer tissue, but not in colon cancer tissue, and that nucleotide signaling stimulates breast cancer cell proliferation within the extracellular concentration range typical for solid cancer tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Amplified Ca²⁺ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation

Henningsen

McWhan

Dam

et al. 2022

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

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“…Low pH is another feature of the TME, which results mainly from metabolic materials and a variety of ion effluxes [ 70 ]. Low pH contributes to cancer cell apoptosis resistance, proliferation, and multiple drug resistance (MDR) [ 71 ].…”

Section: The Tumor Microenvironmentmentioning

confidence: 99%

Mesoporous nanodrug delivery system: a powerful tool for a new paradigm of remodeling of the tumor microenvironment

et al. 2023

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Tumor microenvironment (TME) plays an important role in tumor progression, metastasis and therapy resistance. Remodeling the TME has recently been deemed an attractive tumor therapeutic strategy. Due to its complexity and heterogeneity, remodeling the TME still faces great challenges. With the great advantage of drug loading ability, tumor accumulation, multifactor controllability, and persistent guest molecule release ability, mesoporous nanodrug delivery systems (MNDDSs) have been widely used as effective antitumor drug delivery tools as well as remolding TME. This review summarizes the components and characteristics of the TME, as well as the crosstalk between the TME and cancer cells and focuses on the important role of drug delivery strategies based on MNDDSs in targeted remodeling TME metabolic and synergistic anticancer therapy. Graphical Abstract

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“…1 A, lower panel). The magnitude of the local acid load and the mechanisms of acid–base regulation and sensing vary between tumors of different origins, molecular subtypes, and malignancies [ 3 – 6 ]. The acid–base composition of the tumor microenvironment holds considerable promise for prognostic prediction and development of new therapeutic approaches, yet we still lack mechanistic insight to rationally design targeted interventions.…”

Section: Introductionmentioning

confidence: 99%

“…During fermentative glycolysis (Fig. 1 A, lower panel), monocarboxylate transporters (MCTs) also contribute with coupled cellular efflux of H + and lactate [ 6 ]. Interpatient heterogeneity in cytosolic pH, the capacity for Na + ,HCO 3 – -cotransport and Na + /H + -exchange, and the expression of NBCn1 and NHE1 in breast tumors independently predict proliferative activity in primary carcinomas, the occurrence of regional lymph node metastasis, and patient survival [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer

et al. 2023

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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.

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Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression

Cited by 12 publications

References 350 publications

Amplified Ca²⁺ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation

Amplified Ca²⁺ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation

Mesoporous nanodrug delivery system: a powerful tool for a new paradigm of remodeling of the tumor microenvironment

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer

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Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression

Cited by 12 publications

References 350 publications

Amplified Ca2+ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation

Amplified Ca2+ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation

Mesoporous nanodrug delivery system: a powerful tool for a new paradigm of remodeling of the tumor microenvironment

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer

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Amplified Ca²⁺ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation

Amplified Ca²⁺ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation