Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo

Lee, Shen-Han; McIntyre, Dominick J.O.; Honess, Davina J.; Hulı́ková, Alžbeta; Pacheco-Torres, Jesús; Cerdán, Sebastián; Swietach, Pawel; Harris, Adrian L.; Griffiths, John R.

doi:10.1038/s41416-018-0216-5

Cited by 99 publications

(94 citation statements)

References 44 publications

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“…Similarly, a voxel by voxel comparison showed a different spatial distribution of acidity and lactate in gliomas, suggesting that intra-and extracellular flow of protons might influence acidosis at distant sites from lactate accumulation. More recently, ISUCA was exploited to monitor the activity of the isoenzyme carbonic anhydrase IX (see Pastorikova this volume) that produces H + and HCO 3 − in the extracellular environment from the hydration of CO 2 , and is associated with the most aggressive forms of cancer [35]. This mechanism of acidification has been validated in vivo on colorectal tumor xenografts with different expression levels of CAIX.…”

Section: Mrs-1 Hmentioning

confidence: 99%

Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH

Anemone

Consolino

Arena

et al. 2019

Cancer Metastasis Rev

122

110

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Cancer cells are characterized by a metabolic shift in cellular energy production, orchestrated by the transcription factor HIF-1α, from mitochondrial oxidative phosphorylation to increased glycolysis, regardless of oxygen availability (Warburg effect). The constitutive upregulation of glycolysis leads to an overproduction of acidic metabolic products, resulting in enhanced acidification of the extracellular pH (pHe~6.5), which is a salient feature of the tumor microenvironment. Despite the importance of pH and tumor acidosis, there is currently no established clinical tool available to image the spatial distribution of tumor pHe. The purpose of this review is to describe various imaging modalities for measuring intracellular and extracellular tumor pH. For each technique, we will discuss main advantages and limitations, pH accuracy and sensitivity of the applied pH-responsive probes and potential translatability to the clinic. Particular attention is devoted to methods that can provide pH measurements at high spatial resolution useful to address the task of tumor heterogeneity and to studies that explored tumor pH imaging for assessing treatment response to anticancer therapies.

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Section: Mrs-1 Hmentioning

confidence: 99%

Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH

Anemone

Consolino

Arena

et al. 2019

Cancer Metastasis Rev

122

110

View full text Add to dashboard Cite

show abstract

“…MCT4 exports lactate, thereby affecting the proliferation of tumor cells [2]. An alternative major cause of extracellular acidity in tumor tissue results from the hydration of CO 2 by tumor carbonic anhydrase IX [3,4]. HIF-1 activation in tumors up-regulates angiogenesis and/or lymphangiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Adaptation to chronic acidic extracellular pH elicits a sustained increase in lung cancer cell invasion and metastasis

Sutoo

Maeda

Suzuki

et al. 2019

Clin Exp Metastasis

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Acidic extracellular pH (pH e) is an important microenvironment for cancer cells. This study assessed whether adaptation to acidic pH e enhances the metastatic phenotype of tumor cells. The low metastatic variant of Lewis lung carcinoma (LLCm1) cells were subjected to stepwise acidification, establishing acidic pH e-adapted (LLCm1A) cells growing exponentially at pH 6.2. These LLCm1A cells showed increased production of matrix metalloproteinases (MMPs), including MMP-2,-3,-9, and-13, and pulmonary metastasis following injection into mouse tail veins. Although LLCm1A cells exhibited a fibroblastic shape, keratin-5 expression was increased and α-smooth muscle actin expression was reduced. Despite serial passage of these cells at pH 7.4, high invasive activity through Matrigel ® was sustained for at least 28 generations. Thus, adaptation to acidic pH e resulted in a more invasive phenotype, which was sustained during passage at pH 7.4, suggesting that an acidic microenvironment at the primary tumor site is important in the acquisition of a metastatic phenotype.

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“…2b(3)). This latter effect has been documented in 3D spheroids of cancer cells in vitro [54] and in xenografts in vivo [55], and is believed to be important in the acid-selection process in cancer [6,22].…”

Section: Diffusion and Chemical Equilibrationmentioning

confidence: 79%

What is pH regulation, and why do cancer cells need it?

Swietach¹

2019

Cancer Metastasis Rev

Self Cite

107

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Metabolism is a continuous source of acids. To keep up with a desired metabolic rate, tumors must establish an adequate means of clearing their acidic end-products. This homeostatic priority is achieved by various buffers, enzymes, and transporters connected through the common denominator of H + ions. Whilst this complexity is proportionate to the importance of adequate pH control, it is problematic for developing an intuition for tracking the route taken by acids, assessing the relative importance of various acidhandling proteins, and predicting the outcomes of pharmacological inhibition or genetic alteration. Here, with the help of a simplified mathematical framework, the genesis of cancer pH regulation is explained in terms of the obstacles to efficient acid venting and how these are overcome by specific molecules, often associated with cancer. Ultimately, the pH regulatory apparatus in tumors must (i) provide adequate lactic acid permeability through membranes, (ii) facilitate CO 2 /HCO 3 − /H + diffusivity across the interstitium, (iii) invest in a form of active transport that strikes a favorable balance between intracellular pH and intracellular lactate retention under the energetic constraints of a cell, and (iv) enable the necessary feedback to complete the homeostatic loop. A more informed and quantitative approach to understanding acid-handling in cancer is mandatory for identifying vulnerabilities, which could be exploited as therapeutic targets.

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Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo

Abstract: CAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. We propose that CAIX thus acts as an extracellular pH-stat, maintaining an acidic tumour extracellular pH that is tolerated by cancer cells and favours invasion and metastasis.

Cited by 99 publications

References 44 publications

Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH

Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH

Adaptation to chronic acidic extracellular pH elicits a sustained increase in lung cancer cell invasion and metastasis

What is pH regulation, and why do cancer cells need it?

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