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New Insights into Tumour pH Regulation

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 62455

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Dr. Alzbeta Hulikova

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Department of Physiology, Anatomy & Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
Interests: cellular pH regulation; nuclear pH; H⁺ and HCO₃⁻ transport; carbonic anhydrases; pH imaging in 2D and 3D cell models

Special Issue Information

Dear colleagues,

Solid cancer tissues are heterogeneous in many aspects, including non-uniformity of extracellular and intracellular pH, one of the hallmarks of malignant tumours.

To understand cancer cell pH regulation, one has to consider the complexity of this process. H⁺ions and acidic metabolites like CO₂ and lactic acid are generated by cell respiration. Protons can either stay free, which determines the actual pH value, or immediately interact with small mobile buffers and proteins. Free H⁺ ions can be transported across plasma membranes by transporters facilitating acid extrusion (e.g., Na⁺/H⁺ exchangers, Na⁺/HCO3⁻ co-transporters) or acid-loading (e.g., anion exchangers). The rate of buffering reactions can be modulated by enzymes like carbonic anhydrases catalyzing the swift equilibration of carbonate buffer. Equally important is the efficiency of venting of acid from cells, where it originates, to the closest functional blood vessel. In this case, alternative routes of acid venting via gap junctional coupling are beneficial for cancer cell survival in acidic areas of the tumour. Finally, we have to consider the feedback of the acidic environment on the pH regulatory system, cell metabolism, and biology. Cells capable of adapting to harsh, acidic conditions can give rise to cell populations with high metastatic potential and poor outcome for patients.

Technological and methodological progress in “in vivo pH measurement” enabled us to map the pH across tumour growths. Discovery of pH sensitive peptides, MRI dyes, and other molecules not only confirmed the presence of acidic areas (pH_e < 7.0) in tumours but is very promising for diagnostics, carcinoma grading and acid-targeted drug delivery.

Dr. Alzbeta Hulikova
Guest Editor

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Keywords

tumour acidosis
pH regulation
active transport
carbonic anhydrase
metastasis
gap junctions
pH imaging

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Published Papers (11 papers)

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Research

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27 pages, 4183 KiB

Open AccessArticle

Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival

by Jiayi Yao, Dominika Czaplinska, Renata Ialchina, Julie Schnipper, Bin Liu, Albin Sandelin and Stine Falsig Pedersen

Cancers 2020, 12(8), 2183; https://doi.org/10.3390/cancers12082183 - 5 Aug 2020

Cited by 23 | Viewed by 4797

Abstract

The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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18 pages, 4007 KiB

Open AccessArticle

Targeting the Acidic Tumor Microenvironment: Unexpected Pro-Neoplastic Effects of Oral NaHCO₃ Therapy in Murine Breast Tissue

by Ninna C. S. Voss, Thomas Dreyer, Mikkel B. Henningsen, Pernille Vahl, Bent Honoré and Ebbe Boedtkjer

Cancers 2020, 12(4), 891; https://doi.org/10.3390/cancers12040891 - 6 Apr 2020

Cited by 22 | Viewed by 4659

Abstract

The acidic tumor microenvironment modifies malignant cell behavior. Here, we study consequences of the microenvironment in breast carcinomas. Beginning at carcinogen-based breast cancer induction, we supply either regular or NaHCO₃-containing drinking water to female C57BL/6j mice. We evaluate urine and blood acid-base status, tumor metabolism (microdialysis sampling), and tumor pH (pH-sensitive microelectrodes) in vivo. Based on freshly isolated epithelial organoids from breast carcinomas and normal breast tissue, we assess protein expression (immunoblotting, mass spectrometry), intracellular pH (fluorescence microscopy), and cell proliferation (bromodeoxyuridine incorporation). Oral NaHCO₃ therapy increases breast tumor pH in vivo from 6.68 ± 0.04 to 7.04 ± 0.09 and intracellular pH in breast epithelial organoids by ~0.15. Breast tumors develop with median latency of 85.5 ± 8.2 days in NaHCO₃-treated mice vs. 82 ± 7.5 days in control mice. Oral NaHCO₃ therapy does not affect tumor growth, histopathology or glycolytic metabolism. The capacity for cellular net acid extrusion is increased in NaHCO₃-treated mice and correlates negatively with breast tumor latency. Oral NaHCO₃ therapy elevates proliferative activity in organoids from breast carcinomas. Changes in protein expression patterns—observed by high-throughput proteomics analyses—between cancer and normal breast tissue and in response to oral NaHCO₃ therapy reveal complex influences on metabolism, cytoskeleton, cell-cell and cell-matrix interaction, and cell signaling pathways. We conclude that oral NaHCO₃ therapy neutralizes the microenvironment of breast carcinomas, elevates the cellular net acid extrusion capacity, and accelerates proliferation without net effect on breast cancer development or tumor growth. We demonstrate unexpected pro-neoplastic consequences of oral NaHCO₃ therapy that in breast tissue cancel out previously reported anti-neoplastic effects. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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21 pages, 4541 KiB

Open AccessArticle

Effects of Andrographolide on Intracellular pH Regulation, Cellular Migration, and Apoptosis in Human Cervical Cancer Cells (Running Tittle: Effects of Andrographolide on pH Regulators and Apoptosis in Cervical Cancer)

by Shih-Hurng Loh, Yi-Ting Tsai, Shu-Fu Huang, Tien-Chieh Yu, Pei-Chun Kuo, Shih-Chi Chao, Mei-Fang Chou, Chien-Sung Tsai and Shiao-Pieng Lee

Cancers 2020, 12(2), 387; https://doi.org/10.3390/cancers12020387 - 7 Feb 2020

Cited by 13 | Viewed by 3775

Abstract

Cancer cells have been characterized with alkaline intracellular pH (pH_i) values (≥7.2) to enable cancer proliferation, migration, and progression. The aim of the present study was to explore the concentration-dependent effects of Andrographolide, an active diterpenoid compound of herb Andrographis paniculata, on Na⁺/H⁺ exchanger isoform 1 (NHE1), cellular migration and apoptosis in human cervical cancer cells (HeLa). The pH_i was detected by microspectrofluorometry method, and intracellular acidification was induced by NH₄Cl prepulse technique. Viability and protein expression were determined by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and Western blot, respectively. Human normal endocervical cells (End1), ectocervical cells (Ect1), and HeLa were bought commercially. The resting pH_i value of HeLa (≈7.47) was significantly higher than that of End1 and Ect1 (≈7.30), and shifted from alkaline to acidic following acid/base impacts. In HEPES (4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid | N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) -buffered superfusate, NHE1 and V-ATPase co-existed functionally for acid extrusion in HeLa, while only NHE1 existed functionally in End/Ect1. Andrographolide (3–1000 μM) concentration-dependently inhibited NHE1 activity. Cell-migration and expressions of NHE1, V-ATPase, PARP (poly-ADP-ribose-polymerase), pro-Caspase-3, and Bcl-2 were significantly reduced by pretreating with Andrographolide (≥100 μM) for 24–48 h in HeLa. Andrographolide inhibited cell viability of End1-cells/Ect1 and HeLa (≥100 and ≥30 μM, respectively). The present findings implicate the promising clinical applications of Andrographolide on cervical cancer treatment. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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Review

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19 pages, 3045 KiB

Open AccessReview

Cancer and pH Dynamics: Transcriptional Regulation, Proteostasis, and the Need for New Molecular Tools

by Brandon J. Czowski, Ricardo Romero-Moreno, Keelan J. Trull and Katharine A. White

Cancers 2020, 12(10), 2760; https://doi.org/10.3390/cancers12102760 - 25 Sep 2020

Cited by 21 | Viewed by 5046

Abstract

An emerging hallmark of cancer cells is dysregulated pH dynamics. Recent work has suggested that dysregulated intracellular pH (pHi) dynamics enable diverse cancer cellular behaviors at the population level, including cell proliferation, cell migration and metastasis, evasion of apoptosis, and metabolic adaptation. However, the molecular mechanisms driving pH-dependent cancer-associated cell behaviors are largely unknown. In this review article, we explore recent literature suggesting pHi dynamics may play a causative role in regulating or reinforcing tumorigenic transcriptional and proteostatic changes at the molecular level, and discuss outcomes on tumorigenesis and tumor heterogeneity. Most of the data we discuss are population-level analyses; lack of single-cell data is driven by a lack of tools to experimentally change pHi with spatiotemporal control. Data is also sparse on how pHi dynamics play out in complex in vivo microenvironments. To address this need, at the end of this review, we cover recent advances for live-cell pHi measurement at single-cell resolution. We also discuss the essential role for tool development in revealing mechanisms by which pHi dynamics drive tumor initiation, progression, and metastasis. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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37 pages, 1005 KiB

Open AccessReview

pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology

by Zoltán Pethő, Karolina Najder, Tiago Carvalho, Roisin McMorrow, Luca Matteo Todesca, Micol Rugi, Etmar Bulk, Alan Chan, Clemens W. G. M. Löwik, Stephan J. Reshkin and Albrecht Schwab

Cancers 2020, 12(9), 2484; https://doi.org/10.3390/cancers12092484 - 2 Sep 2020

Cited by 38 | Viewed by 6856

Abstract

Tissue acidosis plays a pivotal role in tumor progression: in particular, interstitial acidosis promotes tumor cell invasion, and is a major contributor to the dysregulation of tumor immunity and tumor stromal cells. The cell membrane and integral membrane proteins commonly act as important sensors and transducers of altered pH. Cell adhesion molecules and cation channels are prominent membrane proteins, the majority of which is regulated by protons. The pathophysiological consequences of proton-sensitive ion channel function in cancer, however, are scarcely considered in the literature. Thus, the main focus of this review is to highlight possible events in tumor progression and tumor immunity where the pH sensitivity of cation channels could be of great importance. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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39 pages, 4383 KiB

Open AccessReview

Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions

by Sabina Strapcova, Martina Takacova, Lucia Csaderova, Paola Martinelli, Lubomira Lukacikova, Viliam Gal, Juraj Kopacek and Eliska Svastova

Cancers 2020, 12(8), 2005; https://doi.org/10.3390/cancers12082005 - 22 Jul 2020

Cited by 18 | Viewed by 4419

Abstract

Hypoxia is a common phenomenon that occurs in most solid tumors. Regardless of tumor origin, the evolution of a hypoxia-adapted phenotype is critical for invasive cancer development. Pancreatic ductal adenocarcinoma is also characterized by hypoxia, desmoplasia, and the presence of necrosis, predicting poor outcome. Carbonic anhydrase IX (CAIX) is one of the most strict hypoxia regulated genes which plays a key role in the adaptation of cancer cells to hypoxia and acidosis. Here, we summarize clinical data showing that CAIX expression is associated with tumor necrosis, vascularization, expression of Frizzled-1, mucins, or proteins involved in glycolysis, and inevitably, poor prognosis of pancreatic cancer patients. We also describe the transcriptional regulation of CAIX in relation to signaling pathways activated in pancreatic cancers. A large part deals with the preclinical evidence supporting the relevance of CAIX in processes leading to the aggressive behavior of pancreatic tumors. Furthermore, we focus on CAIX occurrence in pre-cancerous lesions, and for the first time, we describe CAIX expression within intraductal papillary mucinous neoplasia. Our review concludes with a detailed account of clinical trials implicating that treatment consisting of conventionally used therapies combined with CAIX targeting could result in an improved anti-cancer response in pancreatic cancer patients. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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20 pages, 1967 KiB

Open AccessReview

The Expression of Carbonic Anhydrases II, IX and XII in Brain Tumors

by Joonas Haapasalo, Kristiina Nordfors, Hannu Haapasalo and Seppo Parkkila

Cancers 2020, 12(7), 1723; https://doi.org/10.3390/cancers12071723 - 29 Jun 2020

Cited by 34 | Viewed by 5205

Abstract

Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that participate in the regulation of pH homeostasis in addition to many other important physiological functions. Importantly, CAs have been associated with neoplastic processes and cancer. Brain tumors represent a heterogeneous group of diseases with a frequently dismal prognosis, and new treatment options are urgently needed. In this review article, we summarize the previously published literature about CAs in brain tumors, especially on CA II and hypoxia-inducible CA IX and CA XII. We review here their role in tumorigenesis and potential value in predicting prognosis of brain tumors, including astrocytomas, oligodendrogliomas, ependymomas, medulloblastomas, meningiomas, and craniopharyngiomas. We also introduce both already completed and ongoing studies focusing on CA inhibition as a potential anti-cancer strategy. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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23 pages, 1602 KiB

Open AccessReview

How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH

by Shen-Han Lee and John R. Griffiths

Cancers 2020, 12(6), 1616; https://doi.org/10.3390/cancers12061616 - 18 Jun 2020

Cited by 99 | Viewed by 9242

Abstract

The acidic tumour microenvironment is now recognized as a tumour phenotype that drives cancer somatic evolution and disease progression, causing cancer cells to become more invasive and to metastasise. This property of solid tumours reflects a complex interplay between cellular carbon metabolism and acid removal that is mediated by cell membrane carbonic anhydrases and various transport proteins, interstitial fluid buffering, and abnormal tumour-associated vessels. In the past two decades, a convergence of advances in the experimental and mathematical modelling of human cancers, as well as non-invasive pH-imaging techniques, has yielded new insights into the physiological mechanisms that govern tumour extracellular pH (pH_e). In this review, we examine the mechanisms by which solid tumours maintain a low pH_e, with a focus on carbonic anhydrase IX (CAIX), a cancer-associated cell surface enzyme. We also review the accumulating evidence that suggest a role for CAIX as a biological pH-stat by which solid tumours stabilize their pH_e. Finally, we highlight the prospects for the clinical translation of CAIX-targeted therapies in oncology. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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18 pages, 2086 KiB

Open AccessReview

Transport Metabolons and Acid/Base Balance in Tumor Cells

by Holger M. Becker and Joachim W. Deitmer

Cancers 2020, 12(4), 899; https://doi.org/10.3390/cancers12040899 - 7 Apr 2020

Cited by 29 | Viewed by 4675

Abstract

Solid tumors are metabolically highly active tissues, which produce large amounts of acid. The acid/base balance in tumor cells is regulated by the concerted interplay between a variety of membrane transporters and carbonic anhydrases (CAs), which cooperate to produce an alkaline intracellular, and an acidic extracellular, environment, in which cancer cells can outcompete their adjacent host cells. Many acid/base transporters form a structural and functional complex with CAs, coined “transport metabolon”. Transport metabolons with bicarbonate transporters require the binding of CA to the transporter and CA enzymatic activity. In cancer cells, these bicarbonate transport metabolons have been attributed a role in pH regulation and cell migration. Another type of transport metabolon is formed between CAs and monocarboxylate transporters, which mediate proton-coupled lactate transport across the cell membrane. In this complex, CAs function as “proton antenna” for the transporter, which mediate the rapid exchange of protons between the transporter and the surroundings. These transport metabolons do not require CA catalytic activity, and support the rapid efflux of lactate and protons from hypoxic cancer cells to allow sustained glycolytic activity and cell proliferation. Due to their prominent role in tumor acid/base regulation and metabolism, transport metabolons might be promising drug targets for new approaches in cancer therapy. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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22 pages, 317 KiB

Open AccessReview

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

by Khalid O. Alfarouk, Samrein B. M. Ahmed, Ahmed Ahmed, Robert L. Elliott, Muntaser E. Ibrahim, Heyam S. Ali, Christian C. Wales, Ibrahim Nourwali, Ahmed N. Aljarbou, Adil H. H. Bashir, Sari T. S. Alhoufie, Saad Saeed Alqahtani, Rosa A. Cardone, Stefano Fais, Salvador Harguindey and Stephan J. Reshkin

Cancers 2020, 12(4), 898; https://doi.org/10.3390/cancers12040898 - 7 Apr 2020

Cited by 32 | Viewed by 7829

Abstract

Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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12 pages, 2225 KiB

Open AccessPerspective

Lysosome as a Central Hub for Rewiring PH Homeostasis in Tumors

by Ran Chen, Marja Jäättelä and Bin Liu

Cancers 2020, 12(9), 2437; https://doi.org/10.3390/cancers12092437 - 27 Aug 2020

Cited by 51 | Viewed by 5273

Abstract

Cancer cells generate large quantities of cytoplasmic protons as byproducts of aberrantly activated aerobic glycolysis and lactate fermentation. To avoid potentially detrimental acidification of the intracellular milieu, cancer cells activate multiple acid-removal pathways that promote cytosolic alkalization and extracellular acidification. Accumulating evidence suggests that in addition to the well-characterized ion pumps and exchangers in the plasma membrane, cancer cell lysosomes are also reprogrammed for this purpose. On the one hand, the increased expression and activity of the vacuolar-type H⁺−ATPase (V-ATPase) on the lysosomal limiting membrane combined with the larger volume of the lysosomal compartment increases the lysosomal proton storage capacity substantially. On the other hand, enhanced lysosome exocytosis enables the efficient release of lysosomal protons to the extracellular space. Together, these two steps dynamically drive proton flow from the cytosol to extracellular space. In this perspective, we provide mechanistic insight into how lysosomes contribute to the rewiring of pH homeostasis in cancer cells. Full article

(This article belongs to the Special Issue New Insights into Tumour pH Regulation)

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