Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer

Choschzick, Matthias; Oosterwijk, Egbert; Müller, Volkmar; Woelber, Linn; Simon, Ronald; Moch, Holger; Tennstedt, Pierre

doi:10.1007/s00428-011-1105-y

Cited by 61 publications

(53 citation statements)

References 24 publications

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“…However, newer models point to an active role for the membrane bound carbonic anhydrase IX (CAIX) in establishing extracellular acidity (22). This is relevant, as CAIX is an independent negative prognostic indicator in a number of cancers including, inter alia , breast (23), lung (24), and ovarian (25) cancers. Tumor acidity is important to tumor progression, as it has been shown to promote local invasion and metastasis (26), and metastasis can be inhibited by neutralization of acidity with oral buffers (27,28).…”

Section: Introductionmentioning

confidence: 99%

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

et al. 2016

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Cancer immunotherapies, such as immune checkpoint blockade or adoptive T cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of anti-tumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy immunotherapy. An acidic pH environment blocked T cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was post-translational. Acidification did not affect cytoplasmic pH, such that signals transduced by external acidity were like mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T cell infiltration. Further, combining bicarbonate therapy with anti-CTLA-4, anti-PD1 or adoptive T cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

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Section: Introductionmentioning

confidence: 99%

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

et al. 2016

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“…[71], [72], [73]. The mechanism for this difference is unclear, however one possible explanation relates to aberrations in VHL, which have been detected in the majority of RCCs [65].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Carbonic Anhydrase IX Immunohistochemical Expression in Renal Cell Carcinoma: A Meta-Analysis of the Literature

Zhao

Liao

et al. 2014

PLoS ONE

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BackgroundCarbonic anhydrase IX (CAIX) protein has been correlated with progression and survival in patients with renal cell carcinoma (RCC). The prognostic value of CAIX in RCC however, remains inconclusive according to published works. This study aimed to analyze CAIX as a biological marker to predict RCC patient prognosis.MethodsA literature search of the PubMed and Web of Knowledge databases was performed to retrieve original studies from their inception to December of 2013. Fifteen studies, collectively including a total of 2611 patients with renal cell carcinoma, were carefully reviewed. Standard meta-analysis methods were applied to evaluate the prognostic impact of CAIX expression on patient prognosis. The hazard ratio (HR) and its 95% confidence interval (CI) were recorded for the relationship between CAIX expression and survival, and the data were analyzed using Review Manager 5.2 software and Stata software 11.0.ResultsIn patients with RCC, low CAIX expression was associated with poor disease-specific survival (HR = 1.89, 95% CI: 1.20–2.98, P = 0.006), unfavorable progression-free survival (HR = 2.62, 95% CI: 1.14–6.05, P = 0.02) and worse overall survival (HR = 2.03, 95% CI: 1.28–3.21, P = 0.002). Furthermore, low CAIX expression was significantly associated with the presence of lymph node metastases (odds ratio (OR) = 0.31, 95% CI = 0.15–0.62, P = 0.0009) and distant metastases (OR = 0.66, 95% CI = 0.46–0.96, P = 0.03) and predicted a higher tumor grade (OR = 0.41, 95% CI = 0.31–0.54, P<0.00001).ConclusionsLow CAIX expression most likely indicates poor prognosis in RCC patients. Moreover, low CAIX expression was significantly associated with unfavorable clinicopathological factors. To strengthen our findings, further well-designed prospective studies should be conducted to investigate the role of CAIX expression in RCC.

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“…We found particularly low expression in lung adenocarcinomas with a high papillary component. Of interest, CAIX expression is also lower in papillary renal cell carcinomas than in clear cell kidney carcinomas, 19,20 and CAIX expression also varies with subtype in ovarian 21 and breast 22–25 cancers.…”

Section: Discussionmentioning

confidence: 99%

Membrane Carbonic Anhydrase IX Expression and Relapse Risk in Resected Stage I–II Non–Small-Cell Lung Cancer

Nunez

Behrens

Liu

et al. 2014

Journal of Thoracic Oncology

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Background Adjuvant chemotherapy reduces recurrences of non-small cell lung cancer (NSCLC). To determine which patients need adjuvant chemotherapy, we assessed factors associated with time to relapse (TTR). Methods In 230 resected stages I-II NSCLCs we correlated immunohistochemistry (IHC) scores for factors associated with cell growth rate, growth regulation, hypoxia, cell survival, and cell death with TTR. Results With a median follow-up of 82 (1-158) months for those alive and relapse-free at last follow-up, median time to recurrence was not reached. The 2- and 5-year probabilities of maintaining freedom from recurrence were 80.7% (95% confidence interval [CI]:(75.3%, 86.4%)) and 74.6% (95% CI:(68.6%, 81.2%)), respectively. TTR curves flattened at an apparent cure rate of 70%. In multicovariate Cox models, factors correlating with shorter TTR were membranous carbonic anhydrase IX (mCAIX) staining (any vs none, hazard ratio [HR]=2.083, p=0.023) and node stage (N1 vs N0, HR=2.591, p=0.002). mCAIX scores correlated positively with tumor size, grade, squamous histology, necrosis, mitoses, Ki67, p53, nuclear DNMT1 and cytoplasmic SHARP2, and correlated inversely with papillary histology, EGFR mutation (trend), CTR1, and cytoplasmic HIF-1α, VEGF, DNMT1, and ERCC1. Conclusion Nodal stage and mCAIX IHC were the strongest independent predictors of shorter TTR in resected NSCLCs. mCAIX correlated with tumor size, markers of tumor proliferation and necrosis, and tumor genetic characteristics, and paradoxically correlated inversely with the hypoxia markers HIF-1α and VEGF. Presence of mCAIX could help determine patients with high-risk of recurrence who might require adjuvant chemotherapy.

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Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer

Cited by 61 publications

References 24 publications

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Prognostic Value of Carbonic Anhydrase IX Immunohistochemical Expression in Renal Cell Carcinoma: A Meta-Analysis of the Literature

Membrane Carbonic Anhydrase IX Expression and Relapse Risk in Resected Stage I–II Non–Small-Cell Lung Cancer

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