Expression of transmembrane carbonic anhydrases IX and XII in ovarian tumours

Hynninen, Piritta; Vaskivuo, Liisa; Saarnio, Juha; Haapasalo, Hannu; Kivelä, Jyrki; Pastoreková, Silvia; Pastorek, Jaromı́r; Waheed, Abdül; Sly, William S.; Puistola, Ulla; Parkkila, Seppo

doi:10.1111/j.1365-2559.2006.02523.x

Cited by 91 publications

(69 citation statements)

References 40 publications

(98 reference statements)

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“…Although a significant antitumor effect of 6A10 was observed in vivo, our in vitro obtained with HT29 cells, endogenously expressing both CA IX and CA XII, argue for a degree of redundancy between exofacial carbonic anhydrase isoforms. Because CA IX and XII coexpression is found in at least some tumor cells (2,8,10,39,40), and in line with results obtained by Chiche and colleagues (17), it is tempting to speculate that the concurrent and selective inhibition of both enzymes would result in an improved and additive antitumor effect. As hypoxia is already evident in non-vascularized micrometastases, there would also be mileage in investigating whether CA XII inhibition could also impair metastasis formation.…”

Section: Hcomentioning

confidence: 57%

“…In contrast to CA IX, CA XII is upregulated by estrogen and therefore present in many breast cancers (3). More generally, the enzyme is overexpressed in many forms of human cancer, including renal, pancreatic, gut, oral, brain, lung, and ovarian (2,(4)(5)(6)(7)(8)(9)(10)(11), but is also present in some normal tissues, such as kidney, gut, and endometrium (4,6,12), expressed in combination with other carbonic anhydrase isoforms. CA XII has also been found to be overexpressed in glaucoma (13) and in advanced atherosclerotic plaques (14).…”

Section: Introductionmentioning

confidence: 99%

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Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII

et al. 2013

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Carbonic anhydrase XII (CA XII) is a membrane-tethered cell surface enzyme that is highly expressed on many human tumor cells. Carbonic anhydrase members in this class of exofacial molecules facilitate tumor metabolism by facilitating CO 2 venting and intracellular pH regulation. Accordingly, inhibition of exofacial CAs has been proposed as a general therapeutic strategy to target cancer. The recent characterization of 6A10, the first CA XII-specific inhibitory monoclonal antibody, offered an opportunity to evaluate this strategy with regard to CA XII-mediated catalysis. Using functional assays, we showed that 6A10 inhibited exofacial CA activity in CA XIIexpressing cancer cells. 6A10 reduced spheroid growth in vitro under culture conditions where CA XII was active (i.e., alkaline pH) and where its catalytic activity was likely rate-limiting (i.e., restricted extracellular HCO 3 À supply). These in vitro results argued that the antibody exerted its growth-retarding effect by acting on the catalytic process, rather than on antigen binding per se. Notably, when administered in a mouse xenograft model of human cancer, 6A10 exerted a significant delay on tumor outgrowth. These results corroborate the notion that exofacial CA is critical for cancer cell physiology and they establish the immunotherapeutic efficacy of targeting CA XII using an inhibitory antibody. Cancer Res; 73(21); 6494-503. Ó2013 AACR.

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Section: Hcomentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII

et al. 2013

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“…4C, left). CRLX101-treated tumors showed significantly reduced tumor necrosis and carbonic anhydrase IX (CAIX) staining, used as a marker for tumor hypoxia and downstream HIF1a activity (33). When combined with bevacizumab, CRLX101 also slightly reduced CAIX staining (not statistically significant; Fig.…”

Section: Efficacy Of Crlx101 With Bevacizumab Against Ip Implanted mentioning

confidence: 96%

Translational Impact of Nanoparticle–Drug Conjugate CRLX101 with or without Bevacizumab in Advanced Ovarian Cancer

Pham

Birrer

Eliasof

et al. 2015

Clinical Cancer Research

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Purpose: Increased tumor hypoxia and hence elevated hypoxia-inducible factor-1a (HIF1a) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1a. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison.Experimental Design: CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer.

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“…The Car5b gene catalyzes the reversible hydratation of CO 2 to HCO 3 in order to maintain tissue pH homeostasis [36]. In cancer cells, high levels of intracellular lactate give rise to over expression of acid-regulating proteins like carbonic anhydrases [37] (Table 4). Our results infer that MSI of marker Dxmit249 could be a signal that deteriorates pH cell defense mechanisms implicated in ovarian cancer disease.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of Microsatellite Instability in Superoxide Dismutase-1 Knockout Mice: A Possible Predictor of Germ Cell Development or Tumorigenesis

Esteban¹

2014

JFIV Reprod Med Genet

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The superoxide dismutase 1 gene (Sod1) is one of the cell protective mechanisms to eliminate reactive oxygen species damage in order to protect cell components and avoid germinal failure or tumorigenesis. Mouse primordial germinal cells are a population of cells originating from the proximal margin of the epiblast in close proximity to the extra embryonic ectoderm, and from which some cells differentiate into male or female germinal cells. During cell migration across the genital ridge, primordial germinal cells display an extensive proliferation rate and they are exposed to ROS damage. In absence of cell antioxidant mechanisms, primordial germinal cells have increased risk to accumulate specific mutations by free radical damage. We hypothesize that during cell migration, Sod1 knockout primordial germinal cells accumulate microsatellite instability and this could be a signal for primordial germinal cells pool selection, premature ovarian failure or tumor transformation. We dissected and isolated primordial germinal cellsfrom Sod1 +/+ (wild type), Sod1 +/-(heterozygous), and Sod1 -/-(homozygous) mouse strain (B6; 129S7-Sod1 tm1Leb/J ), from the genital ridge at 10. 5 and 18 days post coitum to determine and quantify microsatellite instability in 10 single tandem repeat markers by single cell PCR methods. Our results demonstrate that primordial germinal cells from Sod1knockout mice accumulated microsatellite instability in five markers (4-4-19844, D13mit16, D13mit78, D19mit68, and DXmit249) located near important genes involved in cell proliferation and differentiation. Taken together, this study shows that microsatellite instability is directly related to Sod1 gene disruption that could induce abnormal migration characteristics seen in primordial germinal cells such as germinal premature failure or tumor invasion and metastasis. In conclusion, microsatellite instability could be a signal for primordial germinal cells pool selection, or tumorigenesis.

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Expression of transmembrane carbonic anhydrases IX and XII in ovarian tumours

Cited by 91 publications

References 40 publications

Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII

Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII

Translational Impact of Nanoparticle–Drug Conjugate CRLX101 with or without Bevacizumab in Advanced Ovarian Cancer

Accumulation of Microsatellite Instability in Superoxide Dismutase-1 Knockout Mice: A Possible Predictor of Germ Cell Development or Tumorigenesis

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