Carbonic anhydrases in normal gastrointestinal tract and gastrointestinal tumours

Kivelä, Antti; Kivelä, Jyrki; Saarnio, Juha; Parkkila, Seppo

doi:10.3748/wjg.v11.i2.155

Cited by 133 publications

(86 citation statements)

References 115 publications

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“…Reverse transcriptase PCR revealed the presence of the AS variant in all examined tissues ( Figure 2C). In accord with the previous studies, FL transcript was found only in the normal stomach and in tumours derived from the colon and rectum (Saarnio et al, 1998;Kivela et al, 2005).…”

Section: Expression Of Human As Ca IX In Tumour Cell Lines and Tissuessupporting

confidence: 91%

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Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

et al. 2007

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CA IX is a hypoxia-induced, cancer-associated carbonic anhydrase isoform with functional involvement in pH control and cell adhesion. Here we describe an alternative splicing variant of the CA9 mRNA, which does not contain exons 8 -9 and is expressed in tumour cells independently of hypoxia. It is also detectable in normal tissues in the absence of the full-length transcript and can therefore produce false-positive data in prognostic studies based on the detection of the hypoxia-and cancer-related CA9 expression. The splicing variant encodes a truncated CA IX protein lacking the C-terminal part of the catalytic domain. It shows diminished catalytic activity and is intracellular or secreted. When overexpressed, it reduces the capacity of the full-length CA IX protein to acidify extracellular pH of hypoxic cells and to bind carbonic anhydrase inhibitor. HeLa cells transfected with the splicing variant cDNA generate spheroids that do not form compact cores, suggesting that they fail to adapt to hypoxic stress. Our data indicate that the splicing variant can functionally interfere with the full-length CA IX. This might be relevant particularly under conditions of mild hypoxia, when the cells do not suffer from severe acidosis and do not need excessive pH control. British Journal of Cancer (2008) Carbonic anhydrase IX (CA IX) is one of 12 enzymatically active carbonic anhydrase isoforms expressed in the human body. These zinc metalloenzymes catalyse a reversible conversion of carbon dioxide to bicarbonate and proton, and thereby contribute to modulation of ion transport and maintenance of acid-base balance. The CA isoforms show remarkable diversity in their enzyme activity, kinetic properties, distribution in tissues, localisation in subcellular compartments and sensitivity to inhibitors. This diversity enables them to fulfill specific roles in metabolically active organs and in various physiological situations .In contrast to the majority of CA isoforms that are mostly present in differentiated cells of the normal tissues, CA IX expression is predominantly associated with a broad range of tumours derived from cells, which contain no or low level of CA IX (Potter and Harris, 2003). The only normal tissues that show moderate-to-abundant expression of CA IX belong to gastrointestinal tract and comprise epithelia of the glandular stomach, small intestine, and gallbladder (Pastorekova et al, 1997).The tumour-related expression pattern of CA IX is principally determined by a strong activation of CA9 gene transcription via a hypoxia-inducible factor (HIF), which binds to hypoxia responsive element (HRE) localised in the minimal CA9 promoter proximal to transcription start site at À10/À3 position (Wykoff et al, 2000). The HIF transcription factor significantly changes the expression profile of weakly oxygenated tumour cells by the activation of genes that either support their survival and adaptation to hypoxic stress or lead to their death. As a result, hypoxia selects more aggressive tumour cells with increased capability...

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Section: Expression Of Human As Ca IX In Tumour Cell Lines and Tissuessupporting

confidence: 91%

“…Human tissues were selected from the collection described previously (Kivela et al, 2005). M75 and V/10 mouse MAbs specific for the human MN/CA IX protein were characterised earlier (Pastorekova et al, 1992;Zatovicova et al, 2003).…”

Section: Cell Culture Tissues and Antibodiesmentioning

confidence: 99%

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

et al. 2007

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“…Multiple studies have analyzed the organ-specific expression of Car1 (12,13,16,17). In the gastrointestinal tract, Car1 is expressed in the colon but not in the small intestine, with highest expression in the proximal colon (16).…”

Section: Resultsmentioning

confidence: 99%

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Tetteh

Kretzschmar

Begthel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1 CreER knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1 CreER KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4. Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1 CreER KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.

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“…On the basis of H&E-stained slides, a neuropathologist (H. Haapasalo) did an evaluation of the tumors according to the WHO 2000 criteria (12). These criteria divide diffusely infiltrating astrocytomas into three grades (2)(3)(4) according to the presence of atypia, mitotic activity, necrosis, and endothelial proliferation. The neuropathologist pinpointed one histologically representative tumor region in each sample specimen.…”

Section: Methodsmentioning

confidence: 99%

Expression of Carbonic Anhydrase IX in Astrocytic Tumors Predicts Poor Prognosis

Haapasalo

Nordfors

Hilvo

et al. 2006

Clinical Cancer Research

121

101

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Purpose: Carbonic anhydrase IX (CA IX) is a hypoxia-inducible enzyme, which is associated with neoplastic growth. Ectopic CA IX expression has been observed in several tumors, whose normal counterparts do not express this enzyme. Normal human brain tissue shows only slight or no expression of CA IX. Experimental Design: We describe CA IX expression in human diffusely infiltrating astrocytomas. The association of CA IX is evaluated with clinicopathologic and molecular factors including cell proliferation and apoptosis as well as the expression of p53 and epidermal growth factor receptor. Results: CA IX immunopositivity was observed in 284 cases of 362 (78%) tumors.The positive areas were often located in close proximity to necrotic regions (P < 0.001). The CA IX immunoreactivity showed strong association with tumor malignancy grades (P < 0.0001). CA IX showed no association with p53 expression nor did it correlate with epidermal growth factor receptorâ mplification, apoptosis, or cell proliferation. CA IX intensity had significant prognostic value in univariate (P=0.0011, log-rank test) and multivariate survival analysis (P = 0.038, Cox analysis). Conclusions: CA IX expression is common in diffusely infiltrating high-grade astrocytomas. Our results suggest that CA IX is a useful biomarker for predicting poor prognosis of astrocytic tumors. It may also be a promising target molecule for the improvement of therapeutic interventions in astrocytomas.

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Carbonic anhydrases in normal gastrointestinal tract and gastrointestinal tumours

Cited by 133 publications

References 115 publications

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Expression of Carbonic Anhydrase IX in Astrocytic Tumors Predicts Poor Prognosis

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