Publications by authors named "Silvia Pastorekova"

147 Publications

Bratislava Statement: consensus recommendations for improving pancreatic cancer care.

ESMO Open 2020 11;5(6):e001051

Catalonian Cancer Strategy, Department of Health, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalunya, Spain.

Pancreatic cancer is one of the most lethal tumours, and it is the fourth cause of cancer death in Europe. Despite its important public health impact, no effective treatments exist, nor are there high-visibility research efforts to improve care. This alarming situation is emblematic of a larger group of cancer diseases, known as neglected cancers. To address the impact of these diseases, the European Commission-supported Innovative Partnership for Action Against Cancer launched a multi-stakeholder initiative to determine key steps that healthcare systems can rapidly implement to improve their response. A working group comprising 20 representatives from European medical societies, patient associations, cancer plan organisations and other relevant European healthcare stakeholders was organised. A consensus process based on the results of different studies, discussion of research outcomes, and development and endorsement of draft statements resulted in 22 consensus recommendations (the Bratislava Statement). The statement argues that substantial improvements can be achieved in patient outcomes by centralising pancreatic cancer care around state-of-the-art reference centres, staffed by expert multidisciplinary teams capable of providing high-quality care. This organisational model requires a specific care framework encompassing primary, palliative and survivorship care, and a policy environment prioritising the use of quality criteria and performance assessments as well as research investments dedicated to prevention, risk prediction, early detection and diagnosis. In order to address the challenges posed by neglected cancers in general and pancreatic cancer in particular, a specific control strategy tailored to this reality is required.
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http://dx.doi.org/10.1136/esmoopen-2020-001051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668355PMC
November 2020

CA IX Stabilizes Intracellular pH to Maintain Metabolic Reprogramming and Proliferation in Hypoxia.

Front Oncol 2020 2;10:1462. Epub 2020 Sep 2.

Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.

Tumor hypoxia represents a severe microenvironmental stress that is frequently associated with acidosis. Cancer cells respond to these stresses with changes in gene expression that promote survival at least in part through pH regulation and metabolic reprogramming. Hypoxia-induced carbonic anhydrase IX (CA IX) plays a critical adaptive role in response to hypoxic and acidic environments by catalytically hydrating extracellular CO to produce bicarbonate for buffering intracellular pH (pHi). We used proteome-wide profiling to study the cellular response to transient CA IX knockdown in hypoxia and found a decrease in the levels of key glycolytic enzymes and lactate dehydrogenase A (LDHA). Interestingly, the activity of LDH was also decreased as demonstrated by native in-gel activity assay. These changes led to a significant reduction in glycolytic flux and extracellular lactate levels in cancer cells , contributing to a decrease in proliferation. Interestingly, addition of the alternative LDH substrate alpha-ketobutyrate restored LDHA activity, extracellular acidification, pHi, and cellular proliferation. These results indicate that in the absence of CA IX, reduction of pHi disrupts LDHA activity and hinders the cellular capacity to regenerate NAD and secrete protons to the extracellular space. Hypoxia-induced CA IX therefore mediates adaptation to microenvironmental hypoxia and acidosis directly, by enzymatically converting extracellular CO to bicarbonate, and indirectly, by maintaining glycolysis-permissive intracellular milieu.
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http://dx.doi.org/10.3389/fonc.2020.01462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493625PMC
September 2020

Molecular targeting of bioconjugated graphene oxide nanocarriers revealed at a cellular level using label-free Raman imaging.

Nanomedicine 2020 11 6;30:102280. Epub 2020 Aug 6.

Polymer Institute, Slovak Academy of Sciences, Bratislava, Slovakia. Electronic address:

Two-dimensional materials as graphene oxide (GO) are able to accommodate labels as well as toxins for diagnostics and therapy, respectively. The transmembrane protein carbonic anhydrase (CA IX) is one of the molecules selectively expressed by tumor cells. Here, we demonstrate bioconjugation of GO to biotinylated M75 antibody highly selective towards CA IX. Based on a model system, binding between the bioconjugated GO-M75 and Madin-Darby Canine Kidney (MDCK) cells was evaluated. As proven by fluorescence-activated cell sorting, higher intake was observed for GO-M75 towards MDCK cells ectopically expressing CA IX protein on their surface when compared to control MDCK. In particular, we were able to localize GO nanocarrier crossing the membrane during endocytosis, thanks to the optical cross-sectioning of living cells in real-time employed the label-free confocal Raman microscopy. The increased affinity of the prepared GO-M75 molecular complexes validates the use of two-dimensional materials for future strategies of targeted cancer treatment.
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http://dx.doi.org/10.1016/j.nano.2020.102280DOI Listing
November 2020

CAIX-Mediated Control of LIN28/ Axis Contributes to Metabolic Adaptation of Breast Cancer Cells to Hypoxia.

Int J Mol Sci 2020 Jun 16;21(12). Epub 2020 Jun 16.

Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.

Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. The expression of CAIX in breast cancer patients is associated with poor prognosis and metastases. Importantly, CAIX-positive hypoxic tumor regions are enriched in cancer stem cells (CSCs). Here we investigated the biological effects of -silencing in breast cancer cell lines. We found that CAIX-downregulation in hypoxia led to increased levels of (lethal-7) family members. Simultaneously with the increase of miRNAs in CAIX-suppressed cells, LIN28 protein levels decreased, along with downstream metabolic pathways: pyruvate dehydrogenase kinase 1 (PDK1) and phosphorylation of its substrate, pyruvate dehydrogenase (PDH) at Ser-232, causing attenuation of glycolysis. In addition to perturbed glycolysis, CAIX-knockouts, in correlation with decreased LIN28 (as CSC reprogramming factor), also exhibit reduction of the further CSC-associated markers NANOG (Homeobox protein NANOG) and ALDH1 (Aldehyde dehydrogenase isoform 1). Oppositely, overexpression of CAIX leads to the enhancement of LIN28, ALDH1, and NANOG. In conclusion, CAIX-driven regulation of the LIN28/ axis augments glycolytic metabolism and enhances stem cell markers expression during CAIX-mediated adaptation to hypoxia and acidosis in carcinogenesis.
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http://dx.doi.org/10.3390/ijms21124299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352761PMC
June 2020

Impairment of carbonic anhydrase IX ectodomain cleavage reinforces tumorigenic and metastatic phenotype of cancer cells.

Br J Cancer 2020 05 25;122(11):1590-1603. Epub 2020 Mar 25.

Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505, Bratislava, Slovakia.

Background: Carbonic anhydrase IX (CA IX) is a hypoxia-induced enzyme regulating tumour pH and facilitating cell migration/invasion. It is primarily expressed as a transmembrane cell-surface protein, but its ectodomain can be shed by ADAM17 to extracellular space. This study aims to elucidate the impact of CA IX shedding on cancer cells.

Methods: We generated a non-shed CA IX mutant by deletion of amino acids 393-402 from the stalk region and studied its phenotypic effects compared to full-length, shedding-competent CA IX using a range of assays based on immunodetection, confocal microscopy, in vitro real-time cell monitoring and in vivo tumour cell inoculation using xenografted NMRI and C57BL/6J female mice.

Results: We demonstrated that the impairment of shedding does not alter the ability of CA IX to bind ADAM17, internalise, form oligomers and regulate pH, but induces cancer-promoting changes in extracellular proteome. Moreover, it affects intrinsic properties of cells expressing the non-shed variant, in terms of their increased ability to migrate, generate primary tumours and form metastatic lesions in lungs.

Conclusions: Our results show that the ectodomain shedding controls pro-tumorigenic and pro-metastatic roles of the cell-associated CA IX and suggest that this phenomenon should be considered when developing CA IX-targeted therapeutic strategies.
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http://dx.doi.org/10.1038/s41416-020-0804-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250822PMC
May 2020

A bioconjugated MoS based nanoplatform with increased binding efficiency to cancer cells.

Biomater Sci 2020 Mar;8(7):1973-1980

Department of Multilayers and Nanostructures, Institute of Physics, Slovak Academy of Sciences, Dúbravská cesta 9, 845 11 Bratislava, Slovakia. and Centre for Advanced Material Application, Slovak Academy of Sciences, Dúbravská cesta 9, 845 11 Bratislava, Slovakia.

We evaluate the application of surfactant-free liquid-phase exfoliated MoS2 nanosheets as a nanoplatform for a cancer detection and treatment system equipped with an antibody-antigen based recognition element. Employing antigen-antibody binding, we increased the probability of the endocytosis of MoS2 nanosheets into CAIX expressing cells by 30%. The nanosheets are functionalized with a specific antibody M75, which forms an antigen-antibody complex with CAIX. The bioconjugation of MoS2 nanosheets involves biocompatible components with low cytotoxicity, verified in the tested cell lines by fluorescence-based cell viability assay. The cellular internalization is quantified by flow cytometry, while the internalization is confirmed by label-free confocal Raman imaging. Raman measurements show increased lysosomal activity in the proximity of the internalized nanoplatforms.
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http://dx.doi.org/10.1039/c9bm01975hDOI Listing
March 2020

Carbonic Anhydrase IX-Mouse versus Human.

Int J Mol Sci 2019 Dec 30;21(1). Epub 2019 Dec 30.

Biomedical Research Center, Institute of Virology, Department of Tumor Biology, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia.

In contrast to human carbonic anhydrase IX (hCA IX) that has been extensively studied with respect to its molecular and functional properties as well as regulation and expression, the mouse ortholog has been investigated primarily in relation to tissue distribution and characterization of CA IX-deficient mice. Thus, no data describing transcriptional regulation and functional properties of the mouse CA IX (mCA IX) have been published so far, despite its evident potential as a biomarker/target in pre-clinical animal models of tumor hypoxia. Here, we investigated for the first time, the transcriptional regulation of the gene with a detailed description of its promoter. Moreover, we performed a functional analysis of the mCA IX protein focused on pH regulation, cell-cell adhesion, and migration. Finally, we revealed an absence of a soluble extracellular form of mCA IX and provided the first experimental evidence of mCA IX presence in exosomes. In conclusion, though the protein characteristics of hCA IX and mCA IX are highly similar, and the transcription of both genes is predominantly governed by hypoxia, some attributes of transcriptional regulation are specific for either human or mouse and as such, could result in different tissue expression and data interpretation.
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http://dx.doi.org/10.3390/ijms21010246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982145PMC
December 2019

Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Metabolic Adaptations and Targets in Cancer.

Front Oncol 2019 28;9:1332. Epub 2019 Nov 28.

Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.

The metabolism of cancer cells differs from that of their normal counterparts in a spectrum of attributes, including imbalances in diverse metabolic arms and pathways, metabolic plasticity and extent of adaptive responses, levels, and activities of metabolic enzymes and their upstream regulators and abnormal fluxes of metabolic intermediates and products. These attributes endow cancer cells with the ability to survive stressors of the tumor microenvironment and enable them to landscape and exploit the host terrain, thereby facilitating cancer progression and therapy resistance. Understanding the molecular and physiological principles of cancer metabolism is one of the key prerequisites for the development of better anticancer treatments. Therefore, various aspects of cancer metabolism were addressed at the 5th annual meeting of the International Society of Cancer Metabolism (ISCaM) in Bratislava, Slovakia, on October 17-20, 2018. The meeting presentations and discussions were traditionally focused on mechanistic, translational, and clinical characteristics of metabolism and pH control in cancer, at the level of molecular pathways, cells, tissues, and organisms. In order to reflect major healthcare challenges of the current era, ISCaM has extended its scope to metabolic disorders contributing to cancer, as well as to opportunities for their prevention, intervention, and therapeutic targeting.
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http://dx.doi.org/10.3389/fonc.2019.01332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892776PMC
November 2019

Extracellular AGR3 regulates breast cancer cells migration via Src signaling.

Oncol Lett 2019 Nov 10;18(5):4449-4456. Epub 2019 Sep 10.

INSERM U1242, 'Chemistry, Oncogenesis Stress Signaling', University of Rennes Campus 1, F-35000 Rennes, France.

Human anterior gradient proteins AGR2 and AGR3 are overexpressed in a variety of adenocarcinomas and are often secreted in cancer patients' specimens, which suggests a role for AGR proteins in intra and extracellular compartments. Although these proteins exhibit high sequence homology, AGR2 is predominantly described as a pro-oncogene and a potential prognostic biomarker. However, little is known about the function of AGR3. Therefore, the aim of the present study was to investigate the role of AGR3 in breast cancer. The results demonstrated that breast cancer cells secrete AGR3. Furthermore, it was revealed that extracellular AGR3 (eAGR3) regulates tumor cell adhesion and migration. The current study indicated that the pharmacological and genetic perturbation of Src kinase signaling, through treatment with Dasatinib (protein kinase inhibitor) or investigating cells that express a dominant-negative form of Src, significantly abrogated eAGR3-mediated breast cancer cell migration. Therefore, the results indicated that eAGR3 may control tumor cell migration via activation of Src kinases. The results of the present study indicated that eAGR3 may serve as a microenvironmental signaling molecule in tumor-associated processes.
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http://dx.doi.org/10.3892/ol.2019.10849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781763PMC
November 2019

Type 1 Sodium Calcium Exchanger Forms a Complex with Carbonic Anhydrase IX and Via Reverse Mode Activity Contributes to pH Control in Hypoxic Tumors.

Cancers (Basel) 2019 Aug 9;11(8). Epub 2019 Aug 9.

Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta, 84505 Bratislava, Slovakia.

Hypoxia and acidosis are among the key microenvironmental factors that contribute to cancer progression. We have explored a possibility that the type 1Na/Ca exchanger (NCX1) is involved in pH control in hypoxic tumors. We focused on changes in intracellular pH, co-localization of NCX1, carbonic anhydrase IX (CA IX), and sodium proton exchanger type 1 (NHE1) by proximity ligation assay, immunoprecipitation, spheroid formation assay and migration of cells due to treatment with KB-R7943, a selective inhibitor of the reverse-mode NCX1. In cancer cells exposed to hypoxia, reverse-mode NCX1 forms a membrane complex primarily with CA IX and also with NHE1. NCX1/CA IX/NHE1 assembly operates as a metabolon with a potent ability to extrude protons to the extracellular space and thereby facilitate acidosis. KB-R7943 prevents formation of this metabolon and reduces cell migration. Thus, we have shown that in hypoxic cancer cells, NCX1 operates in a reverse mode and participates in pH regulation in hypoxic tumors via cooperation with CAIX and NHE1.
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http://dx.doi.org/10.3390/cancers11081139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721473PMC
August 2019

CAIX Regulates Invadopodia Formation through Both a pH-Dependent Mechanism and Interplay with Actin Regulatory Proteins.

Int J Mol Sci 2019 Jun 4;20(11). Epub 2019 Jun 4.

Biomedical Research Center, Institute of Virology, Department of Cancer Biology, Slovak Academy of Sciences, Dubravska cesta 9., 845 05 Bratislava, Slovakia.

Tumor metastasis is tightly linked with invasive membrane protrusions, invadopodia, formed by actively invading tumor cells. Hypoxia and pH modulation play a role in the invadopodia formation and in their matrix degradation ability. Tumor-associated carbonic anhydrase IX (CAIX), induced by hypoxia, is essential for pH regulation and migration, predisposing it as an active component of invadopodia. To investigate this assumption, we employed silencing and inhibition of CA9, invadopodia isolation and matrix degradation assay. Quail chorioallantoic membranes with implanted tumor cells, and lung colonization assay in murine model were used to assess efficiency of invasion and the impact of CAIX targeting antibodies. We showed that CAIX co-distributes to invadopodia with cortactin, MMP14, NBCe1, and phospho-PKA. Suppression or enzymatic inhibition of CAIX leads to impaired invadopodia formation and matrix degradation. Loss of CAIX attenuated phosphorylation of Y421-cortactin and influenced molecular machinery coordinating actin polymerization essential for invadopodia growth. Treatment of tumor cells by CAIX-specific antibodies against carbonic or proteoglycan domains results in reduced invasion and extravasation . For the first time, we demonstrated localization of CAIX within invadopodia. Our findings confirm the key role of CAIX in the metastatic process and gives rationale for its targeting during anti-metastatic therapy.
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http://dx.doi.org/10.3390/ijms20112745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600150PMC
June 2019

A Multifunctional Graphene Oxide Platform for Targeting Cancer.

Cancers (Basel) 2019 May 29;11(6). Epub 2019 May 29.

Polymer Institute, SAS, Dúbravská cesta 9, 845 41 Bratislava, Slovakia.

Diagnosis of oncological diseases remains at the forefront of current medical research. Carbonic Anhydrase IX (CA IX) is a cell surface hypoxia-inducible enzyme functionally involved in adaptation to acidosis that is expressed in aggressive tumors; hence, it can be used as a tumor biomarker. Herein, we propose a nanoscale graphene oxide (GO) platform functionalized with magnetic nanoparticles and a monoclonal antibody specific to the CA IX marker. The GO platforms were prepared by a modified Hummers and Offeman method from exfoliated graphite after several centrifugation and ultrasonication cycles. The magnetic nanoparticles were prepared by a chemical precipitation method and subsequently modified. Basic characterization of GO, such as the degree of oxidation, nanoparticle size and exfoliation, were determined by physical and chemical analysis, including X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), energy dispersive X-ray analysis (EDX), and atomic force microscopy (AFM). In addition, the size and properties of the poly-L-lysine-modified magnetic nanoparticles were characterized. The antibody specific to CA IX was linked via an amidic bond to the poly-L-lysine modified magnetic nanoparticles, which were conjugated to GO platform again via an amidic bond. The prepared GO-based platform with magnetic nanoparticles combined with a biosensing antibody element was used for a hypoxic cancer cell targeting study based on immunofluorescence.
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http://dx.doi.org/10.3390/cancers11060753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627436PMC
May 2019

The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond.

Cancer Metastasis Rev 2019 06;38(1-2):65-77

Department of Cancer Physiology, H. Lee Moffitt Cancer Center, 12902 Magnolia Avenue, Tampa, FL, 33612, USA.

Cancer development is a complex process that follows an intricate scenario with a dynamic interplay of selective and adaptive steps and an extensive cast of molecules and signaling pathways. Solid tumor initially grows as an avascular bulk of cells carrying oncogenic mutations until diffusion distances from the nearest functional blood vessels limit delivery of nutrients and oxygen on the one hand and removal of metabolic waste on the other one. These restrictions result in regional hypoxia and acidosis that select for adaptable tumor cells able to promote aberrant angiogenesis, remodel metabolism, acquire invasiveness and metastatic propensity, and gain therapeutic resistance. Tumor cells are thereby endowed with capability to survive and proliferate in hostile microenvironment, communicate with stroma, enter circulation, colonize secondary sites, and generate metastases. While the role of oncogenic mutations initializing and driving these processes is well established, a key contribution of non-genomic, landscaping molecular players is still less appreciated despite they can equally serve as viable targets of anticancer therapies. Carbonic anhydrase IX (CA IX) is one of these players: it is induced by hypoxia, functionally linked to acidosis, implicated in invasiveness, and correlated with therapeutic resistance. Here, we summarize the available experimental evidence supported by accumulating preclinical and clinical data that CA IX can contribute virtually to each step of cancer progression path via its enzyme activity and/or non-catalytic mechanisms. We also propose that targeting tumor cells that express CA IX may provide therapeutic benefits in various settings and combinations with both conventional and newly developed treatments.
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http://dx.doi.org/10.1007/s10555-019-09799-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647366PMC
June 2019

Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Cancer Metabolism.

Front Oncol 2018 3;8:329. Epub 2018 Oct 3.

Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Tumors are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These metabolic networks are directly linked with cancer progression, treatment, resistance, and relapse. Conversely, metabolic alterations in cancer are exploited for anticancer therapy, imaging, and stratification for personalized treatments. These topics were addressed at the 4th annual meeting of the International Society of Cancer Metabolism (ISCaM) in Bertinoro, Italy, on 19-21 October 2017.
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http://dx.doi.org/10.3389/fonc.2018.00329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179103PMC
October 2018

Label-free tracking of nanosized graphene oxide cellular uptake by confocal Raman microscopy.

Analyst 2018 Jul;143(15):3686-3692

Faculty of Mathematics Physics and Informatics, Comenius University, Mlynská dolina F1, 842 48 Bratislava, Slovakia.

Graphene oxide (GO), a partially oxidized two-dimensional allotrope of carbon, is an attractive nanocarrier for cancer diagnostics and therapy. The nanometer-sized GO is known to permeate cell membranes. Herein we studied the cellular uptake pathways of GO nanoflakes by cancer and non-cancerous cell lines. By employing confocal Raman imaging, we were able to track the GO cellular uptake in living cells (C33 and MDCK) without any additional fluorescent or plasmonic labels. This specific progress in label-free Raman imaging of GO facilitates the monitoring of nanoflakes at the cellular level.
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http://dx.doi.org/10.1039/c8an00225hDOI Listing
July 2018

The proteoglycan-like domain of carbonic anhydrase IX mediates non-catalytic facilitation of lactate transport in cancer cells.

Oncotarget 2018 Jun 15;9(46):27940-27957. Epub 2018 Jun 15.

Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany.

Highly glycolytic tumor cells release vast amounts of lactate and protons via monocarboxylate transporters (MCTs), which exacerbate extracellular acidification and support the formation of a hostile environment. Transport activity of MCTs can be facilitated by non-catalytic interaction with carbonic anhydrase IX (CAIX), the expression of which has been shown to be upregulated under hypoxia. We have now studied the mechanisms that enable CAIX-mediated facilitation of proton-coupled lactate transport in breast cancer cells and oocytes. Our results indicate that the proteoglycan like (PG) domain of CAIX could function as 'proton antenna' to facilitate MCT transport activity. Truncation of the PG domain and application of a PG-binding antibody significantly reduced proton-coupled lactate transport in MCT-expressing oocytes and hypoxic breast cancer cells, respectively. Furthermore, application of the PG-binding antibody reduced proliferation and migration of hypoxic cancer cells, suggesting that facilitation of proton-coupled lactate flux by the CAIX PG domain contributes to cancer cell survival under hypoxic conditions.
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http://dx.doi.org/10.18632/oncotarget.25371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021347PMC
June 2018

d,l-lysine functionalized FeO nanoparticles for detection of cancer cells.

Colloids Surf B Biointerfaces 2018 Mar 21;163:236-245. Epub 2017 Dec 21.

Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice, Slovakia.

Amino-modified magnetic nanoparticles were prepared by direct chemisorption of biocompatible d,l-lysine (DLL) on electrostatically stabilized magnetic nanoparticles with the aim to bind specific antibodies (Ab) able to detect cancer cells. The magnetic nanoparticles prepared by coprecipitation were stabilized in an acidic medium. A full optimization study of amino modification performed by UV/Vis spectroscopy and Dynamic Light Scattering measurement (DLS) confirmed an optimal DLL/FeO weight ratio of 2. The sample was subjected to complex characterizations using different techniques such as UV/Vis, FTIR and X-ray photoelectron spectroscopies (XPS) together with transmission electron microscopy and size/zeta potential measurements. While FTIR spectroscopy, UV/Vis spectroscopy and XPS confirmed the successful amino modification of FeO nanoparticles, a characterization using a vibrating sample magnetometer (VSM) indicated superparamagnetic behavior in all the prepared samples, suggesting that the coating process did not significantly affect the size and structure of the FeO nanoparticles. Magnetic nanoparticles with the optimal DLL content were conjugated with the M75 monoclonal antibody specific to carbonic anhydrase IX (CA IX), which is considered one of the best markers of tumor hypoxia and a prognostic indicator of cancer progression. The results demonstrate that all tested cell lines survived and even proliferated in the presence of amino-modified magnetic nanoparticles. Even the tubulin cytoskeletal structure was not disrupted after the exposure of cells to surface-modified magnetic nanoparticles. In contrast, internalization of the antibody-conjugated magnetic nanoparticles led to abrogation of the formation of long and extended microtubules. Finally, the finding supports the view that the M75 antibody conjugated to nanoparticles mediates their specific uptake and intracellular accumulation and that the antibody conjugated magnetic nanoparticles can be potentially used for the selective growth inhibition of CA IX-expressing cells.
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http://dx.doi.org/10.1016/j.colsurfb.2017.12.022DOI Listing
March 2018

Lactate stimulates CA IX expression in normoxic cancer cells.

Oncotarget 2017 Sep 12;8(44):77819-77835. Epub 2017 Sep 12.

Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.

Besides hypoxia, other factors and molecules such as lactate, succinate, and reactive oxygen species activate transcription factor hypoxia-inducible factor-1 (HIF-1) even in normoxia. One of the main target gene products of HIF-1 is carbonic anhydrase IX (CA IX). CA IX is overexpressed in many tumors and serves as prognostic factor for hypoxic, aggressive and malignant cancers. CA IX is also induced in normoxia in high cell density. In this study, we observed that lactate induces CA IX expression in normoxic cancer cells and . We further evidenced that participation of both HIF-1 and specificity protein 1 (SP1) transcription factors is crucial for lactate-driven normoxic induction of the gene. By inducing CA IX, lactate can facilitate the maintenance of cancer cell aggressive behavior in normoxia.
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http://dx.doi.org/10.18632/oncotarget.20836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652817PMC
September 2017

Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity.

Oncotarget 2017 Sep 7;8(40):66960-66974. Epub 2017 Apr 7.

Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.

Aggressive cancers are characterized by hypoxia, which is a key driver of tumor development and treatment resistance. Proteins specifically expressed in the hypoxic tumor microenvironment thus represent interesting candidates for targeted drug delivery strategies. Carbonic anhydrase (CAIX) has been identified as an attractive treatment target as it is highly hypoxia specific and expressed at the cell-surface to promote cancer cell aggressiveness. Here, we find that cancer cell internalization of CAIX is negatively regulated by post-translational modification with chondroitin or heparan sulfate glycosaminoglycan chains. We show that perturbed glycosaminoglycan modification results in increased CAIX endocytosis. We hypothesized that perturbation of CAIX glycosaminoglycan conjugation may provide opportunities for enhanced drug delivery to hypoxic tumor cells. In support of this concept, pharmacological inhibition of glycosaminoglycan biosynthesis with xylosides significantly potentiated the internalization and cytotoxic activity of an antibody-drug conjugate (ADC) targeted at CAIX. Moreover, cells expressing glycosaminoglycan-deficient CAIX were significantly more sensitive to ADC treatment as compared with cells expressing wild-type CAIX. We find that inhibition of CAIX endocytosis is associated with an increased localization of glycosaminoglycan-conjugated CAIX in membrane lipid raft domains stabilized by caveolin-1 clusters. The association of CAIX with caveolin-1 was partially attenuated by acidosis, another important feature of malignant tumors. Accordingly, we found increased internalization of CAIX at acidic conditions. These findings provide first evidence that intracellular drug delivery at pathophysiological conditions of malignant tumors can be attenuated by tumor antigen glycosaminoglycan modification, which is of conceptual importance in the future development of targeted cancer treatments.
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http://dx.doi.org/10.18632/oncotarget.16921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620149PMC
September 2017

Hypoxia induces cancer-associated cAMP/PKA signalling through HIF-mediated transcriptional control of adenylyl cyclases VI and VII.

Sci Rep 2017 08 31;7(1):10121. Epub 2017 Aug 31.

Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.

Hypoxia is a phenomenon often arising in solid tumours, linked to aggressive malignancy, bad prognosis and resistance to therapy. Hypoxia-inducible factor-1 has been identified as a key mediator of cell and tissue adaptation to hypoxic conditions through transcriptional activation of many genes involved in glucose metabolism and other cancer-related processes, such as angiogenesis, cell survival and cell invasion. Cyclic adenosine 3'5'-monophosphate is one of the most ancient and evolutionarily conserved signalling molecules and the cAMP/PKA signalling pathway plays an important role in cellular adaptation to hypoxia. We have investigated possible new mechanisms behind hypoxic activation of the cAMP/PKA pathway. For the first time, we have shown that hypoxia induces transcriptional up-regulation of the system of adenylyl cyclases, enzymes responsible for cAMP production, in a panel of carcinoma cell lines of various origin. Our data prove functional relevance of the hypoxic increase of adenylyl cyclases VI and VII at least partially mediated by HIF-1 transcription factor. We have identified adenylyl cyclase VI and VII isoforms as mediators of cellular response to hypoxia, which led to the elevation of cAMP levels and enhanced PKA activity, with an impact on cell migration and pH regulation.
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http://dx.doi.org/10.1038/s41598-017-09549-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578998PMC
August 2017

Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Metabolic Networks in Cancer.

Front Pharmacol 2017 4;8:411. Epub 2017 Jul 4.

Rizzoli Orthopaedic InstituteBologna, Italy.

Cancers are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These metabolic networks are directly linked with cancer progression, treatment resistance and relapse. Conversely, metabolic alterations in cancer are exploited for anticancer therapy, imaging and personalized medicine. These topics were addressed at the 3rd annual meeting of the International Society of Cancer Metabolism (ISCaM) in Brussels, Belgium, on 26-29 October 2016.
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http://dx.doi.org/10.3389/fphar.2017.00411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496414PMC
July 2017

Role of carbonic anhydrases in skin wound healing.

Exp Mol Med 2017 05 19;49(5):e334. Epub 2017 May 19.

Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Skin wound closure occurs when keratinocytes migrate from the edge of the wound and re-epithelialize the epidermis. Their migration takes place primarily before any vascularization is established, that is, under hypoxia, but relatively little is known regarding the factors that stimulate this migration. Hypoxia and an acidic environment are well-established stimuli for cancer cell migration. The carbonic anhydrases (CAs) contribute to tumor cell migration by generating an acidic environment through the conversion of carbon dioxide to bicarbonate and a proton. On this basis, we explored the possible role of CAs in tissue regeneration using mouse skin wound models. We show that the expression of mRNAs encoding CA isoforms IV and IX are increased (~25 × and 4 ×, respectively) during the wound hypoxic period (days 2-5) and that cells expressing CAs form a band-like structure beneath the migrating epidermis. RNA-Seq analysis suggested that the CA IV-specific signal in the wound is mainly derived from neutrophils. Due to the high level of induction of CA IV in the wound, we treated skin wounds locally with recombinant human CA IV enzyme. Recombinant CA IV significantly accelerated wound re-epithelialization. Thus, CA IV could contribute to wound healing by providing an acidic environment in which the migrating epidermis and neutrophils can survive and may offer novel opportunities to accelerate wound healing under compromised conditions.
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http://dx.doi.org/10.1038/emm.2017.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454449PMC
May 2017

Prognostic value of intratumoral carbonic anhydrase IX expression in testicular germ cell tumors.

Oncol Lett 2017 Apr 14;13(4):2177-2185. Epub 2017 Feb 14.

Translational Research Unit, Faculty of Medicine, Comenius University, 833 10 Bratislava, Slovak Republic.

Testicular germ cell tumors (TGCTs) represent a highly curable malignancy, however a small proportion of patients fails to be cured with cisplatin-based chemotherapy. Carbonic anhydrase IX (CA IX) is upregulated by hypoxia in several cancer types and correlates with a poor prognosis. The present translational study evaluated expression and prognostic value of CA IX in TGCTs. Surgical specimens from 228 patients with TGCTs were processed by the tissue microarray method and subjected to immunohistochemistry with the M75 monoclonal antibody. CA IX expression was evaluated in tumors vs. adjacent normal testicular tissues and correlated with clinicopathological characteristics and clinical outcome. CA IX expression was detected in 62 (30.2%) of TGCTs compared to 0 (0%) of normal tissue adjacent to testicular tumor (P<0.001). The highest frequency of the CA IX expression was detected in teratoma (39.0%), followed by seminoma (22.7%), yolk sac tumor (22.2%), embryonal carcinoma (11.9%) and choriocarcinoma (7.7%). None of germ cell neoplasias (GCNIS) exhibited CA IX expression. Patients without the CA IX tumor expression showed significantly better progression-free survival, but not overall survival, compared to patients with the CA IX expression [hazard ratio (HR), 0.57; 95% CI, 0.32-1.02; P=0.037 and HR, 0.58; 95% CI, 0.29-1.16; P=0.088, respectively]. There was no significant correlation between the CA IX expression and clinicopathological variables. The intratumoral CA IX expression can serve as a prognostic marker in the TGCT patients. These results suggest that activation of the hypoxia-induced pathways may be important in the treatment failure in TGCTs patients.
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http://dx.doi.org/10.3892/ol.2017.5745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403396PMC
April 2017

New approach of delivering cytotoxic drugs towards CAIX expressing cells: A concept of dual-target drugs.

Eur J Med Chem 2017 Feb 19;127:691-702. Epub 2016 Oct 19.

Department of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Universiteitssingel 50/23, 6229 ER Maastricht, The Netherlands.

Carbonic anhydrase IX (CAIX) is a hypoxia-regulated and tumor-specific protein that maintains the pH balance of cells. Targeting CAIX might be a valuable approach for specific delivery of cytotoxic drugs, thereby reducing normal tissue side-effects. A series of dual-target compounds were designed and synthesized incorporating a sulfonamide, sulfamide, or sulfamate moiety combined with several different anti-cancer drugs, including the chemotherapeutic agents chlorambucil, tirapazamine, and temozolomide, two Ataxia Telangiectasia and Rad3-related protein inhibitors (ATRi), and the anti-diabetic biguanide agent phenformin. An ATRi derivative (12) was the only compound to show a preferred efficacy in CAIX overexpressing cells versus cells without CAIX expression when combined with radiation. Its efficacy might however not solely depend on binding to CAIX, since all described compounds generally display low activity as carbonic anhydrase inhibitors. The hypothesis that dual-target compounds specifically target CAIX expressing tumor cells was therefore not confirmed. Even though dual-target compounds remain an interesting approach, alternative options should also be investigated as novel treatment strategies.
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http://dx.doi.org/10.1016/j.ejmech.2016.10.037DOI Listing
February 2017

Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models.

Oncotarget 2016 Jun;7(26):40531-40545

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, 20892, USA.

Hypoxia is a common feature of solid tumors that activates a plethora of pathways, resulting in proliferation and resistance of cancer cells to radio- and chemotherapy. Pheochromocytomas/paragangliomas (PHEOs/PGLs) with mutations in the gene coding for the subunit B of succinate dehydrogenase (SDHB) are the most aggressive forms of the disease, which is partially due to their pseudohypoxic character, metabolic abnormalities, and elevated reactive oxygen species (ROS) levels. We investigated the effect of piperlongumine (PL), a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular ROS levels, on PHEO cells. Here we report for the first time that PL mediates PHEO cell death by activating both apoptosis and necroptosis in vitro and in vivo. This effect is magnified in hypoxic conditions, making PL a promising potential candidate for use as a therapeutic option for patients with PHEO/PGL, including those with SDHB mutations.
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http://dx.doi.org/10.18632/oncotarget.9643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130026PMC
June 2016

Prognostic value of serum carbonic anhydrase IX in testicular germ cell tumor patients.

Oncol Lett 2016 Oct 16;12(4):2590-2598. Epub 2016 Aug 16.

Translational Research Unit, Faculty of Medicine, Comenius University, 811 02 Bratislava, Slovakia; Department of Oncology, National Cancer Institute, 833 10 Bratislava, Slovakia; Second Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia.

Despite the fact that testicular germ cell tumors (TGCTs) are one of the most chemosensitive solid tumors, a small proportion of patients fail to be cured following cisplatin-based first line chemotherapy. Upregulation of carbonic anhydrase IX (CA IX) in various solid tumors is associated with poor outcome. The current prospective study investigated the prognostic value of serum CA IX level in TGCTs. In total, 83 patients (16 non-metastatic following orchiectomy with no evidence of disease, 57 metastatic chemotherapy-naïve and 10 metastatic relapsed chemotherapy-pretreated) starting adjuvant and/or new line of chemotherapy and 35 healthy controls were enrolled in the study. Serum CA IX values were determined using an enzyme-linked immunosorbent assay, and intratumoral CA IX was analyzed by immunohistochemistry. Metastatic chemotherapy-naïve patients had significantly higher mean CA IX serum levels than healthy controls (490.6 vs. 249.6 pg/ml, P=0.005), while there was no difference in serum CA IX levels in non-metastatic or relapsed TGCT patients compared with healthy controls. There was no significant difference in the mean serum CA IX levels between different groups of patients and between the first and second cycle of chemotherapy, nor association with patients/tumor characteristics. Serum CA IX was not prognostic for progression-free survival [hazard ratio (HR)=0.81, P=0.730] or overall survival (HR=0.64, P=0.480). However, there was a significant association between intratumoral CA IX expression and serum CA IX concentration (rho=0.51, P=0.040). These results suggest that serum CA IX level correlates with tumor CA IX expression in TGCT patients, but fails to exhibit either a prognostic value or an association with patients/tumor characteristics.
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http://dx.doi.org/10.3892/ol.2016.5010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038507PMC
October 2016

Carbonic anhydrase enzymes II, VII, IX and XII in colorectal carcinomas.

World J Gastroenterol 2016 Sep;22(36):8168-77

Pia Viikilä, Seppo Parkkila, School of Medicine, University of Tampere and Fimlab Ltd, Tampere University Hospital, 33014 Tampere, Finland.

Aim: To investigate expression of four alpha-carbonic anhydrases (CAs) in colorectal carcinomas (CRC) and compare the results with patients' survival.

Methods: Colorectal carcinoma samples from 539 CRC patients and control tissues were arranged as tissue microarrays and analyzed with antibodies against CA II, CA VII, CA IX, and CA XII. Intensity and extent of staining were both scored from 0 to 3 in each sample. These enzyme expression levels were then correlated to patients' survival and clinicopathological parameters, which were tumor differentiation grade and stage, site of tumor, patients' age, and gender. Kaplan-Meier analysis and Cox regression hazard ratio model were used to analyze survival data.

Results: CA II and CA XII staining intensities correlated with patients' survival in that higher expression indicated poorer prognosis. In Cox regression analysis one unit increase in the CA II intensity increased the hazard ratio to 1.19 fold (CI: 1.04-1.37, P = 0.009). A significant correlation was also found when comparing CA XII staining intensity with survival of CRC patients (HR = 1.18, 95%CI: 1.01-1.38, P = 0.036). The extent of CA XII immunostaining did not correlate to the patients' survival (P = 0.242, Kaplan-Meier analysis). A significant interaction between age group and extent of the CA II staining was found. Increased extent of CA II had a significant hazard ratio among patients 65 years and older (1.42, 95%CI: 1.16-1.73, P = 0.0006). No correlations were found between CA VII (intensity P = 0.566, extent P = 0.495, Kaplan-Meier analysis), or CA IX (intensity P = 0.879, extent P = 0.315, Kaplan-Meier analysis) immunostaining results and survival, or the other parameters.

Conclusion: The present findings indicate that CA II and CA XII could be useful in predicting survival in CRC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037085PMC
http://dx.doi.org/10.3748/wjg.v22.i36.8168DOI Listing
September 2016

Sulforaphane-induced apoptosis involves the type 1 IP3 receptor.

Oncotarget 2016 Sep;7(38):61403-61418

Institute of Clinical and Translational Research, Biomedical Research Center, SAS, Bratislava, Slovakia.

In this study we show that anti-tumor effect of sulforaphane (SFN) is partially realized through the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1). This effect was verified in vitro on three different stable cell lines and also in vivo on the model of nude mice with developed tumors. Early response (6 hours) of A2780 ovarian carcinoma cells to SFN treatment involves generation of mitochondrial ROS and increased transcription of NRF2 and its downstream regulated genes including heme oxygenase 1, NAD(P)H:quinine oxidoreductase 1, and KLF9. Prolonged SFN treatment (24 hours) upregulated expression of NRF2 and IP3R1. SFN induces a time-dependent phosphorylation wave of HSP27. Use of IP3R inhibitor Xestospongin C (Xest) attenuates both SFN-induced apoptosis and the level of NRF2 protein expression. In addition, Xest partially attenuates anti-tumor effect of SFN in vivo. SFN-induced apoptosis is completely inhibited by silencing of IP3R1 gene but only partially blocked by silencing of NRF2; silencing of IP3R2 and IP3R3 had no effect on these cells. Xest inhibitor does not significantly modify SFN-induced increase in the rapid activity of ARE and AP1 responsive elements. We found that Xest effectively reverses the SFN-dependent increase of nuclear content and decrease of reticular calcium content. In addition, immunofluorescent staining with IP3R1 antibody revealed that SFN treatment induces translocation of IP3R1 to the nucleus. Our results clearly show that IP3R1 is involved in SFN-induced apoptosis through the depletion of reticular calcium and modulation of transcription factors through nuclear calcium up-regulation.
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http://dx.doi.org/10.18632/oncotarget.8968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308660PMC
September 2016

Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms.

Int J Oncol 2016 Oct 14;49(4):1277-88. Epub 2016 Jul 14.

Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.

Dexamethasone is a synthetic glucocorticoid frequently used to suppress side-effects of anticancer chemotherapy. In the present study, we showed that dexamethasone treatment leads to concentration-dependent downregulation of cancer-associated marker, carbonic anhydrase IX (CA IX), at the level of promoter activity, mRNA and protein expression in 2D and 3D cancer cell models. The effect of dexamethasone on CA IX expression under hypoxic conditions is predominantly mediated by impaired transcriptional activity and decreased protein level of the main hypoxic transcription factor HIF-1α. In addition, CA9 downregulation can be caused by protein-protein interactions between activated glucocorticoid receptors, major effectors of glucocorticoid action, and transcription factors that trigger CA9 transcription (e.g. AP-1). Moreover, we identified a potential NF-κB binding site in the CA9 promoter and propose the involvement of NF-κB in the dexamethasone-mediated inhibition of CA9 transcription. As high level of CA IX is often linked to aggressive tumor behavior, poor prognosis and chemo- and radiotherapy resistance, uncovering its reduction after dexamethasone treatment and implication of additional regulatory mechanisms can be relevant for the CA IX-related clinical applications.
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http://dx.doi.org/10.3892/ijo.2016.3621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021256PMC
October 2016

Carbonic anhydrase IX deposits are associated with increased ascending aortic dilatation.

Scand Cardiovasc J 2016 Jun 9;50(3):162-6. Epub 2016 May 9.

a Heart Center , Tampere University Hospital , Tampere , Finland ;

Objectives: Carbonic anhydrase IX (CA IX) expression is induced by local hypoxia. We studied whether CA IX deposits associate with ascending aortic dilatation.

Design: Aortic wall histology, CA IX expression, presence of leukocytes, plasma cells, macrophages, endothelial cells, smooth muscle cells, cell proliferation, elastin and collagen were studied in histological specimens collected from 30 patients who underwent surgery for ascending aorta. The samples were grouped according to presence of CA IX deposits.

Results: Twenty out of 30 patients had CA IX-positive deposits within the adventitia, whereas 10 specimens remained negative. Adventitial inflammation was increased in CA IX-positive samples as compared with CA IX-negative ones (p < 0.01). The mean diameter of the ascending aorta at the sinotubular junction increased significantly in patients with CA IX-positive staining as compared with CA IX-negative cases (63 ± 3 vs 53 ± 2 mm, p < 0.02). Receiver operating characteristic curve analysis confirmed the association of CA IX positivity with increased ascending aortic dilatation (AUC 0.766; S.E. 0.090; p = 0.020; 95% C.I. 0.590-0.941).

Conclusions: Positive CA IX staining in certain aortic specimens suggests that increased CA activity may contribute to ascending aortic dilatation.
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http://dx.doi.org/10.3109/14017431.2016.1158416DOI Listing
June 2016