Expression of a Hypoxia-Associated Protein, Carbonic Anhydrase-9, Correlates with Malignant Phenotypes of Gastric Carcinoma

Abstract

Background/Aims: Gastric cancers are characterized by a heterogeneously hypoxic environment. Hypoxia might stimulate the malignant potential of cancer cells. The purpose of our study was to clarify the significance of hypoxia in gastric carcinoma by evaluating the expression of a hypoxic marker, namely carbonic anhydrase-9 (CA-9). Methods: A total of 265 patients who had undergone a resection of the primary tumor and were confirmed histologically to have sporadic gastric cancer were enrolled in this study. We evaluated the immunohistochemical expression of CA-9 in the paraffin-embedded specimens of 265 gastric adenocarcinomas. Results: The CA-9 expression was positive in 88 (33%) of 265 gastric carcinomas. The CA-9 expression level was significantly high in cases of type 4 carcinoma (60%, p < 0.001) and diffuse type carcinoma (41%, p < 0.001), and significantly correlated with the invasion depth (p < 0.001), lymph node metastasis (p < 0.001) and lymphatic invasion p = 0.002). The prognosis for CA-9-positive patients was significantly poorer than that of CA-9-negative patients (p = 0.003, log-rank). Conclusion: Hypoxia might be associated with aggressive tumor phenotypes of gastric carcinomas. The hypoxic marker CA-9 may be a useful prognostic indicator.

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

“…An immunohistochemical study indicated that LOX expression was associated with a hypoxic microenvironment evaluated by CA9, and that it is overexpressed in response to tumor hypoxia in many common tumor types [51][52][53][54]. We previously reported that the expression of CA9 might be associated with aggressive tumor phenotypes of gastric carcinomas [41]. Some studies have also demonstrated that LOX is a hypoxia-responsive gene correlated with the migration and invasion of cancer cells [25,31,32].…”

“…Expression was considered positive when the scores was 5 or more and was considered negative when the score was 4 or less. CA9 expression was evaluated as previously reported [41]. Evaluation was done by two double-blinded independent observers who were unaware of the clinical data and outcome.…”

Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia

“…Hypoxia increased the expression level of IGF1R in PDAC cells in comparison with that under normoxia. CA9, a hypoxia-associated endogenous protein, is considered as a cellular biomarker of hypoxic regions in solid tumors[ 31 , 32 ]. It has been reported that IGF1 is upregulated in PDAC tissues, but not in surrounding noncancerous tissues[ 33 ].…”

Carbonic anhydrase IX correlates with survival and is a potential therapeutic target for neuroblastoma

“…A hypoxic microenvironment furthers the exploitation of both genetic and adaptive means of tumor cells to survive and proliferate 26,27 . For example, this microenviroment can lead to a natural selection of aggressive and metastasizing tumor cell clones 26 .…”

“…HIF-1alpha, CAIX and GT-1 (glucose transporter-1) are well-established prognostic markers in solid cancers 26 . The hypoxia-dependent expression of CAIX has been described for many solid tumors, including gastric cancer 26,27 , breast cancer 28 , prostate cancer 14 , colon cancer 29 , oral squamous cell cancer 16 , esophageal cancer 30,31 , where it is associated with malignant phenotype 31 , adverse clinicopathological factors 18 , tumor cell dissemination 29,32,33 and poor survival 15,16,26,30,31 . Carbonic anhydrase IX has been shown to be involved in numerous pathological processes including tumorgenicity 16 and was suggested to be involved in malignant transformation 34 .…”