Abstract
Background and PurposeCarbonic anhydrase IX (CAIX) plays a pivotal role in pH homeostasis, which is essential for tumor cell survival. We examined the effect of the CAIX inhibitor 4-(3′(3″,5″-dimethylphenyl)-ureido)phenyl sulfamate (S4) on the tumor microenvironment in a laryngeal tumor model by analyzing proliferation, apoptosis, necrosis, hypoxia, metabolism and CAIX ectodomain shedding.MethodsSCCNij202 tumor bearing-mice were treated with S4 for 1, 3 or 5 days. CAIX ectodomain shedding was measured in the serum after therapy. Effects on tumor cell proliferation, apoptosis, necrosis, hypoxia (pimonidazole) and CAIX were investigated with quantitative immunohistochemistry. Metabolic transporters and enzymes were quantified with qPCR.ResultsCAIX ectodomain shedding decreased after treatment with S4 (p<0.01). S4 therapy did neither influence tumor cell proliferation nor the amount of apoptosis and necrosis. Hypoxia (pimonidazole) and CAIX expression were also not affected by S4. CHOP and MMP9 mRNA as a reference of intracellular pH did not change upon treatment with S4. Compensatory mechanisms of pH homeostasis at the mRNA level were not observed.ConclusionAs the clinical and biological meaning of the decrease in CAIX ectodomain shedding after S4 therapy is not clear, studies are required to elucidate whether the CAIX ectodomain has a paracrine or autocrine signaling function in cancer biology. S4 did not influence the amount of proliferation, apoptosis, necrosis and hypoxia. Therefore, it is unlikely that S4 can be used as single agent to influence tumor cell kill and proliferation, and to target primary tumor growth.
Highlights
Tumor metabolism produces large amounts of acids by converting glucose into lactate acid and protons through glycolysis, and carbon dioxide (CO2) through oxidative phosphorylation and the pentose phosphate pathway [1]
Carbonic anhydrase IX (CAIX) expression was observed in non-pimonidazole areas, which could indicate intermediate hypoxia as CAIX is upregulated below a pO2 of 20 mmHg and pimonidazole below a pO2 of 10 mmHg (Figure 1B) [24]
In this study we examined the effect of S4 on the tumor microenvironment in a laryngeal tumor model
Summary
Tumor metabolism produces large amounts of acids by converting glucose into lactate acid and protons through glycolysis, and carbon dioxide (CO2) through oxidative phosphorylation and the pentose phosphate pathway [1]. An important regulator of pH homeostasis is the hypoxia-inducible factor 1 (HIF-1), which enhances the expression of several membrane-located transporters and enzymes including monocarboxylate transporters (MCT), and carbonic anhydrase IX and XII (CAIX, CAXII) [1,2,3]. Carbonic anhydrase IX (CAIX) plays a pivotal role in pH homeostasis, which is essential for tumor cell survival. We examined the effect of the CAIX inhibitor 4-(39(30,50-dimethylphenyl)-ureido)phenyl sulfamate (S4) on the tumor microenvironment in a laryngeal tumor model by analyzing proliferation, apoptosis, necrosis, hypoxia, metabolism and CAIX ectodomain shedding
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