Expression of Carbonic Anhydrase IX (CA IX), a Hypoxia-Related Protein, Rather Than Vascular-Endothelial Growth Factor (VEGF), a Pro-Angiogenic Factor, Correlates With an Extremely Poor Prognosis in Esophageal and Gastric Adenocarcinomas

Driessen, Ann; Landuyt, Willy; Pastorekova, S; Moons, Johnny; Goethals, Laurence; Haustermans, Karin; Nafteux, Philippe; Penninckx, Freddy; Geboes, Karel; Lerut, Toni; Ectors, Nadine

doi:10.1097/01.sla.0000201452.09591.f3

Cited by 102 publications

(113 citation statements)

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“…Further studies are therefore necessary to clarify the mechanisms responsible for survival in an environment with a partial oxygen tension o10 mm Hg. It has been reported that tumour hypoxia is associated with more aggressive tumour phenotypes, which may lead to a poorer prognosis for patients (Imai et al, 2003;Driessen et al, 2006;Mayer et al, 2008). Our hypoxia models using OCUM-12/Hypo cells showed frequent lymph node metastasis.…”

Section: Discussionmentioning

confidence: 80%

“…Cancer cells under hypoxic conditions are reported to show malignant features, such as high metastatic ability and resistance to various anti-cancer therapies (Harris and Shrieve, 1979;Ludwig, 1984;Driessen et al, 2006); however, the mechanisms by which hypoxia affects cancer progression remain unclear. Hypoxia alters important intracellular pathways, and it is recognized as a stimulus for the malignant potential (Semenza, 2002;Subarsky and Hill, 2003;Vaupel, 2004).…”

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confidence: 99%

“…Most solid tumours are hypovascular and possess microscopically heterogeneous hypoxic regions (Vaupel et al, 1987(Vaupel et al, , 2003Hockel et al, 1996;Driessen et al, 2006;Mayer et al, 2008). Cancer cells under hypoxic conditions are reported to show malignant features, such as high metastatic ability and resistance to various anti-cancer therapies (Harris and Shrieve, 1979;Ludwig, 1984;Driessen et al, 2006); however, the mechanisms by which hypoxia affects cancer progression remain unclear.…”

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confidence: 99%

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Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

et al. 2010

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BACKGROUND: Many kinds of solid tumour have heterogeneously a hypoxic environment. Tumour hypoxia reported to be associated with more aggressive tumour phenotypes such as high metastatic ability and resistance to various anti-cancer therapies which may lead to a poorer prognosis. However, the mechanisms by which hypoxia affects the aggressive phenotypes remain unclear. METHODS: We established a scirrhous gastric carcinoma cell line (OCUM-12) from ascites associated with scirrhous gastric carcinoma, and a hypoxia-resistant cancer cell line (OCUM-12/Hypo) was cloned from OCUM-12 cells by continuous exposure to 1% oxygen. RESULTS: Histologic findings from orthotopic tumours derived from parent OCUM-12 cells and daughter OCUM-12/Hypo cells revealed poorly differentiated adenocarcinoma with extensive fibrosis that resembled human scirrhous gastric cancer. Necrotic lesions were frequently detected in the OCUM-12 tumours but were rarely found in the OCUM-12/Hypo tumours, although both types had multiple hypoxic loci. Apoptosis rate of OCUM-12 cells was increased to 24.7% at 1% O 2 , whereas that of OCUM-12/ Hypo was 5.6%. The OCUM-12/Hypo orthotopic models developed multiple metastases to the peritoneum and lymph nodes, but the OCUM-12 models did not. OCUM-12/Hypo cells showed epithelial-to-mesenchymal transition and high migratory and invasive activities in comparison with OCUM-12 cells. The mRNA expression levels of both E-cadherin and zonula occludens ZO-1 and ZO-2 decreased in OCUM-12/Hypo cells, and that of vimentin, Snail-1, Slug/Snail-2, Twist, ZEB-1, ZEB-2, matrix metalloproteinase-1 (MMP-1), and MMP-2 were increased in OCUM-12/Hypo cells. CONCLUSION: OCUM-12 and OCUM-12/Hypo may be useful for the elucidation of disease progression associated with scirrhous gastric cancer in the setting of chronic hypoxia.

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Section: Discussionmentioning

confidence: 80%

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confidence: 99%

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Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

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“…NSCLC and gastric cancer are 2 of several tumor indications showing CAIX expression as well as sensitivity to taxanes (29)(30)(31). The expression of CAIX varies between tumor indications as well as between individual patients with a tumor of the same histologic origin.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9

Petrul

Schatz

Kopitz

et al. 2012

Molecular Cancer Therapeutics

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Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs. Highest affinity Fabs were converted to full-length IgGs and subjected to further characterization based upon their avidity and selectivity for CAIX, their capacity to undergo internalization in CAIX-expressing cell lines, and their selective localization to CAIX-positive human xenografted tumors when administered to mice as fluorescent conjugates. Through this selection process, the 3ee9 mAb was identified, which upon conjugation to monomethyl auristatin E through a self-immolative enzyme-cleavable linker yielded the potent and selective CAIX antibody-drug conjugate CAIX-ADC (BAY 79-4620). In preclinical human xenograft models in mice representing several tumor indications, BAY 79-4620 showed potent antitumor efficacy and in some models showed partial and complete tumor shrinkage even following a single dose. The mechanism of action was shown by histology to involve the sequelae of events typical of antitubulin agents. Efficacy in murine preclinical models correlated semiquantitatively, with CAIX expression levels as determined by immunohistochemistry and ELISA. These preclinical data collectively support the development of BAY 79-4620 for the treatment of cancer patients with CAIX overexpressing tumors. Mol Cancer Ther; 11(2); 340-9. Ó2011 AACR.

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“…It has been reported that CA9 expression is an independent prognostic marker in oesophageal and gastric adenocarcinomas (Driessen et al, 2006), but the relationship between prognosis and CA9 expression in oesophageal squamous cell carcinoma (ESCC) remains controversial.…”

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Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma

et al. 2008

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Carbonic anhydrase 9 (CA9) is a protein to be upregulated under exposure to hypoxic conditions. Hypoxic conditions are known to be associated with resistance to chemotherapy and radiotherapy, and with poor cancer prognosis. We examined CA9 expression in surgical specimens from oesophageal squamous cell carcinoma (ESCC) patients (n ¼ 127) using immunohistochemistry and real-time RT -PCR. We also examined CA9 expression and cell proliferation in ESCC cell lines (TE-2, TE-8 and TE-15) and an immortalised human oesophageal cell line (CHEK-1) using real-time RT -PCR, Western blotting, ELISA and MTT assay. Immunohistochemistry, high expression of CA9 was found in 63 of the 127 primary tumour specimens and was correlated with poor outcome (P ¼ 0.0003) and more aggressive/less favourable clinicopathological parameters (tumour size (P ¼ 0.0235), tumour depth (Po0.0001), regional lymph node metastasis (P ¼ 0.0031), distant lymph node metastasis (P ¼ 0.0077), stage (Po0.0001) and blood vessel invasion (P ¼ 0.006)). In vitro, CA9 expression in cultured cells and culture medium was also induced by hypoxia (Po0.01). CA9 is correlated with poor prognosis and malignant phenotype in patients with ESCC, and was upregulated by hypoxia. It is suggested that control of CA9 expression might improve the effectiveness of chemotherapy and radiotherapy in ESCC.

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Expression of Carbonic Anhydrase IX (CA IX), a Hypoxia-Related Protein, Rather Than Vascular-Endothelial Growth Factor (VEGF), a Pro-Angiogenic Factor, Correlates With an Extremely Poor Prognosis in Esophageal and Gastric Adenocarcinomas

Cited by 102 publications

References 41 publications

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

Therapeutic Mechanism and Efficacy of the Antibody–Drug Conjugate BAY 79-4620 Targeting Human Carbonic Anhydrase 9

Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma

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