Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use

Pastorek, Jaromı́r; Pastoreková, Silvia

doi:10.1016/j.semcancer.2014.08.002

Cited by 272 publications

(245 citation statements)

References 168 publications

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“…CA9 expression in tumor and stromal tissue can be considered as a marker of hypoxia (14). Ectodomain shedding of CA9 mainly occurs by hypoxic cancer cells and leads to an increase in circulating levels (39).…”

Section: Discussionmentioning

confidence: 99%

“…CA9 is a transmembrane enzyme involved in essential physiologic processes including pH regulation and ion transport. CA9 distribution in tumor tissues corresponds with its HIF-governed regulation (14) .…”

Section: Introductionmentioning

confidence: 98%

“…Hypoxia is a hallmark of growing tumors and can induce a spectrum of adaptive processes, among which is increased angiogenesis (14). The hypoxia-induced transcriptional program is activated by the hypoxia-inducible factors (HIF), mainly from stabilization of HIF1a protein.…”

Section: Introductionmentioning

confidence: 99%

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Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

Lam

Nota

Jager³

et al. 2016

Clinical Cancer Research

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Purpose: We examined whether pretreatment levels of angiogenesis-or hypoxia-related proteins and their changes after one cycle of first-line bevacizumab-based therapy were associated with response, PFS, or OS in patients with metastatic breast cancer.Experimental Design: We included 181 patients enrolled in the phase II ATX trial evaluating first-line paclitaxel and bevacizumab without or with capecitabine (NTR1348). Plasma samples were analyzed for VEGF-A, soluble VEGFR2 (sVEGFR2), angiopoietin 2 (ANG2), soluble TIE2 (sTIE2), IL6, IL8, and carbonic anhydrase 9 (CA9). Baseline serum CA15-3 was documented. HR was adjusted for confounding factors. Where appropriate, an optimal cut-off value defining a high and a low group was determined with Martingale residuals.Results: At baseline, multiple proteins were significantly associated with PFS (ANG2, IL6, IL8, CA9, CA15-3) and OS (ANG2, sTIE2, IL6, IL8, CA9, CA15-3). After one cycle, VEGF-A, ANG2, sTIE2, and IL8 significantly decreased, while sVEGFR2 and CA9 significantly increased. The relative change in sVEGFR2 (P ¼ 0.01) and IL8 (P ¼ 0.001) was associated with response. Defining optimal cut-off, patients with a high CA9 rise (>2.9%) had better PFS (HR 0.45) and OS (HR 0.54) than those with low/no rise.Conclusions: Multiple angiogenesis-or hypoxia-related proteins were prognostic for PFS and OS. Molecular agents targeting these proteins might be beneficial in patients with high levels. Changes in IL8 or sVEGFR2 levels at second cycle appear predictive for response. Changes in CA9 levels during bevacizumabbased therapy for prediction of PFS and OS merit further study.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

Lam

Nota

Jager³

et al. 2016

Clinical Cancer Research

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“…Target genes include enzymes that make up the glycolytic machinery, erythropoietin, which acts effectors of the transcriptional response to tumor hypoxia include carbonic anhydrase IX (CAIX), monocarboxylate transporter 4 (MCT4), and programmed death-ligand 1 (PD-L1). CAIX plays a pivotal role in biological processes required for cancer progression and it is expressed in the hypoxic regions of many types of solid tumor (8). MCT4 is involved in the export of lactate from tumor cells and contributes to metastasis and angiogenesis (9,10).…”

Section: Introductionmentioning

confidence: 99%

HIF1α and metabolic reprogramming in inflammation

Corcoran¹,

O’Neill²

2016

Journal of Clinical Investigation

529

409

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“…Precise biological function of soluble CA IX is yet unclear but it is assumed that it might be involved in intercellular paracrine signaling. It is important that hypoxia itself does not infl uence the rate of CA IX ectodomain shedding, thus the amount of soluble CA IX in body fl uids should refl ect the amount of CA IX produced by the hypoxic cells (11,12).…”

Section: Introductionmentioning

confidence: 99%

High serum carbonic anhydrase IX predicts shorter survival in head and neck cancer

Rosenberg¹,

Pastorekova²,

Zaťovičová³

et al. 2016

BLL

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OBJECTIVES: The objective of the study was to investigate prognostic and predictive value of pretreatment soluble carbonic anhydrase IX (CA IX) blood serum concentration in patients with locally advanced head and neck cancer. BACKGROUND: Increased expression of CA IX in tumor tissues has been associated with treatment resistance and worth prognosis. Soluble form of CA IX, released from tumor cells, is detectable in blood serum and could be a convenient predictive factor of treatment effectiveness that would enable treatment individualization. METHODS: The prospective study evaluated 48 patients with locally advanced squamous cell carcinomas of head and neck, treated by radiotherapy or chemo-radiotherapy. Pretreatment soluble CA IX serum concentrations were examined using enzyme-linked immunosorbent assay. RESULTS: Soluble CA IX serum concentration failed to predict radiotherapy effectiveness in the studied patient population (p = 0.26). However, high CA IX serum concentrations have been associated with shorter overall survival (p = 0.035) CONCLUSION: High pretreatment CA IX serum concentration is a negative prognostic factor in locally advanced head and neck cancer patients (Tab. 1, Fig. 2

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Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use

Cited by 272 publications

References 168 publications

Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

HIF1α and metabolic reprogramming in inflammation

High serum carbonic anhydrase IX predicts shorter survival in head and neck cancer

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