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Carbonic Anhydrase IX: From Biology to Therapy

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Hypoxia and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Growing tumor tissues develop a stressful microenvironment characterized by hypoxia and acidosis. Tumor cells can survive these stresses via induction of adaptive transcriptional changes mediated primarily by the hypoxia-inducible factor (HIF), and via stimulation of ion transport machinery maintaining normal intracellular pH. In addition, through these adaptive responses tumor cells acquire new features endowing them with selective advantage in migration, invasion, metastasis, and resistance to therapy. Carbonic anhydrase IX (CA IX), a highly active cancer-related carbonic anhydrase isoform, is linked to both hypoxia, as a direct transcriptional target of HIF, and acidosis, as a component of mechanisms that facilitate ion transport across the plasma membrane and thereby counteract the intracellular accumulation of acidic metabolic products. Expression pattern of CA IX in human tumors reflects the activation of the HIF pathway by physiologic hypoxia, genetic defects, and/or oncogenic events. Moreover, CA IX plays an active role not only in pH regulation but also in cell migration and invasion. Thus, it is often exploited and/or investigated as an intrinsic marker of hypoxia, a prognostic indicator, and a therapeutic target for antibodies or inhibitors of the enzyme activity. It is believed that these CA IX-targeted therapeutic approaches can mediate the selective killing of CA IX-positive cells or sensitize tumor cells to conventional treatment modalities. In addition, both CA IX-specific antibodies and CA IX-selective inhibitors can serve as imaging tools allowing for selection of patients potentially benefiting from CA IX-directed therapy. Recent advances in understanding CA IX regulation and functional involvement in tumor progression as well as development of CA IX-binding drugs provide novel opportunities for treatment of hypoxic tumors.

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Abbreviations

CA IX:

carbonic anhydrase IX protein

CA9:

carbonic anhydrase 9 gene/promoter

CAI:

carbonic anhydrase inhibitor

Car:

mouse CA gene

FIH:

factor inhibiting HIF

GLUT:

glucose transporter

HIF:

hypoxia-inducible factor

HRE:

hypoxia-response element

LDH:

lactate dehydrogenase

MAPK:

mitogen activated protein kinase

MCT:

monocarboxylate transporter

NBC:

Na + /bicarbonate co-transporter

NHE:

Na + /H + exchanger

PDK:

pyruvate dehydrogenase kinase

PG:

proteoglycan-like domain

PHD:

prolyl hydroxylase

pHe:

extracellular pH

pHi:

intracellular pH

PI3K:

phosphatidyl inositol-3 kinase

RCC:

renal cell carcinoma

VEGF:

vascular endothelial growth factor

VHL:

von Hippel Lindau

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Acknowledgment

The authors’ research is supported by grants from the EU 7th Framework program (Collaborative project METOXIA), from the Research and Development Support Agency (DO7RP-0017-09 and APVV-0658-11), and from the Research & Development Operational Program funded by the ERDF (project ITMS 26240120027).

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Authors and Affiliations

  1. Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovak Republic

    Silvia Pastorekova

  2. Polo Scientifico, NEUROFARBA Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019, Florence, Italy

    Claudiu T. Supuran

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  1. Silvia Pastorekova
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  2. Claudiu T. Supuran
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Correspondence to Silvia Pastorekova .

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  1. Bristol-Myers Squibb, Princeton, New Jersey, USA

    Giovanni Melillo

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Pastorekova, S., Supuran, C. (2014). Carbonic Anhydrase IX: From Biology to Therapy. In: Melillo, G. (eds) Hypoxia and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9167-5_6

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