Immunohistochemical Study of Colorectal Tumors for Expression of a Novel Transmembrane Carbonic Anhydrase, MN/CA IX, with Potential Value as a Marker of Cell Proliferation

Saarnio, Juha; Parkkila, Seppo; Parkkila, Anna‐Kaisa; Haukipuro, Kari; Pastoreková, Silvia; Pastorek, Jaromı́r; Kairaluoma, Matti I.; Karttunen, Tuomo J.

doi:10.1016/s0002-9440(10)65569-1

Cited by 223 publications

(165 citation statements)

References 18 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%

“…In gastric carcinomas, the expression of the FL CA IX decreases, but the level of AS is similar as in the normal stomach. In contrast, the expression of the full-length CA IX is absent or very low in the normal colon and rectum (and also in additional normal tissues not analysed in this study) and significantly increases in corresponding tumours (Saarnio et al, 1998). However, the AS variant shows a steady expression level in both normal tissues and colorectal carcinomas.…”

Section: Discussionmentioning

confidence: 49%

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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%

Section: Discussionmentioning

confidence: 49%

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

et al. 2007

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“…Although other members of the CA gene family have been examined in several tumour types (Nogradi, 1998), and it is known that the increased expression of CA IX is associated with aspects of early tumourigenesis in cervix, colon and lung tumours (Liao and Stanbridge, 1996;Saarnio et al, 1998;Vermylen et al, 1999), a prognostic role for CA has not previously been identified in breast cancer. Our recent studies have shown that increased CA IX expression is associated with poor relapse free and overall survival in invasive breast cancer .…”

Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma

et al. 2003

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Hypoxia and pH influence gene expression in tumours, and it is becoming increasingly clear that the pattern of genes expressed by a tumour determines its growth and survival characteristics. Hypoxia-inducible factor-1 (HIF-1) is a key mediator of the cellular response to hypoxia and high HIF-1 expression has been identified as a poor prognostic factor in tumours. Recently, we identified the tumour-associated carbonic anhydrases (CA), CA9 and CA12 as hypoxia-inducible in tumour cell lines. Furthermore, we identified CA IX to be a poor prognostic factor in breast cancer. The aim of this study was to assess the prognostic significance of CA XII. CA XII expression was studied by immunohistochemistry in a series of 103 cases of invasive breast cancer and any association with recognised prognostic factors or relation with the outcome was examined. CA XII expression was present in 77 out of 103 (75%) cases and was associated with lower grade (P ¼ 0.001), positive estrogen receptor status (Po0.001), and negative epidermal growth factor receptor status (Po0.001). Furthermore, although CA XII expression was associated with an absence of necrosis (Po0.001), expression of CA XII in some high-grade tumours was induced in regions directly adjacent to morphological necrosis. Additionally, using univariate analysis, CA XII positive tumours were associated with a lower relapse rate (P ¼ 0.04) and a better overall survival (P ¼ 0.01). In conclusion, CA XII expression is influenced both by factors related to differentiation and hypoxia in breast cancer in vivo and CA XII expression is associated with a better prognosis in an unselected series of invasive breast carcinoma patients.

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“…or MN/CA IX) is a cell membrane protein (Pastoreková et al, 1992;Závada et al, 1993), which is ectopically expressed in various human tumours, mostly carcinomas, for example, cervical, renal, colorectal, lung, mammary and others (Liao et al, 1994(Liao et al, , 1997Saarnio et al, 1998). It has been suggested that CA IX may serve as a biomarker in early stages of tumorigenesis; now it is turning out to be induced in certain tumours by hypoxia, which is connected with poor prognosis (Chia et al, 2001;Giatromanolaki et al, 2001;Koukorakis et al, 2001).…”

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confidence: 99%

Soluble form of carbonic anhydrase IX (CA IX) in the serum and urine of renal carcinoma patients

et al. 2003

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Tumour-associated protein carbonic anhydrase IX (CA IX) has two major forms. One is a cell-associated, transmembrane protein seen on Western blots as a twin band of 54/58 kDa, expressed in gastric mucosa and in several types of cancer. The other is a soluble protein s-CA IX of 50/54 kDa, which is released into the culture medium or into the body fluids, most likely by proteolytic cleavage of the extracellular part from transmembrane and intracellular sequences. While TC media of CA IX-positive tumour cell lines or shortterm cultures of tumour explants contain a relatively high concentration of s-CA IX (20 -50 ng ml À1 ), the level of this antigen in blood serum and urine of renal clear cell carcinoma patients is about 1000 Â lower. The concentration of CA IX in the blood and in urine varies within wide limits and there is no obvious correlation with tumour size. After nephrectomy, s-CA IX is cleared from the blood within a few days. Only an extremely low concentration of CA IX was detectable in the sera and in urine of control individuals.

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Immunohistochemical Study of Colorectal Tumors for Expression of a Novel Transmembrane Carbonic Anhydrase, MN/CA IX, with Potential Value as a Marker of Cell Proliferation

Cited by 223 publications

References 18 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

Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma

Soluble form of carbonic anhydrase IX (CA IX) in the serum and urine of renal carcinoma patients

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