Clinicopathological Implications of the Expression of Hypoxia-related Proteins in Gastric Cancer

Abstract

Objectives: Tumor hypoxia confers poor prognosis of a wide range of solid tumors due to increased malignancy, increased likelihood of metastasis and treatment resistance. The aim of this study was to assess the significance of the expression of HIF-1α and HIF-1α-inducible proteins in gastric cancer and their impact on prognosis. Materials and Methods: The expression of HIF-1α, GLUT-1, CA-9, and iNOS proteins was analyzed by immunohistochemistry in 193 gastric adenocarcinomas (GAs) and 20 normal gastric mucosa. Results: HIF-1α, GLUT-1, CA-9 and iNOS were expressed in 52.3%, 43.0%, 57.0%, and 43.0% of GAs, respectively, which are higher than the normal counterparts except for CA-9. HIF-1α expression was positively correlated with the expression of GLUT-1, CA-9 and iNOS. GLUT-1 expression was higher in the intestinal type (p = 0.012); however, iNOS expression was higher in the less-differentiated type and the diffuse type (p = 0.006, p = 0.032, respectively). The expression of HIF-1α and GLUT-1 was significantly correlated with lymph node metastasis (p = 0.009, p = 0.008, respectively), while the expression of GLUT-1 and iNOS was significantly correlated with the depth of invasion and advanced stage (p = 0.044, p = 0.004; p = 0.009, p = 0.008, respectively). Overall survival was shorter in patients with GLUT-1 expression than in those without GLUT-1 expression, which was statistically significant by univariate analysis (p = 0.042). On multivariate analysis, however, stage was determined as the only independent prognostic marker (p < 0.001). Conclusions: Our data suggest that overexpression of HIF-1α, GLUT-1, and iNOS may play an important role in gastric cancer progression. GLUT-1 is a potential candidate for predicting patient survival.

Signature of cytokines and angiogenic factors (CAFs) defines a clinically distinct subgroup of gastric cancer

“…Previous reports showed sCA9, SCF, and MIP-1a are associated with a hypoxic signature [18,[28][29][30]. As intestinal-type GC is partially caused by Helicobacter pylori-associated metaplasia and mediated by hypoxia-induced angiogenesis [31,32], as such, increased levels of sCA9 in intestinal-type disease compared to the diffuse-type disease would be reasonable. Moreover, as signet ring cell pathology is associated with diffuse-type disease [21,33], it is expected that serum levels of SCF and MIP-1a would be lower in patients with signet ring cell components.…”

GLUT-1 Expression in Cutaneous Basal and Squamous Cell Carcinomas

“…9 GLUT-1 expression is associated with poor prognosis in several tumors such as cervical squamous cell carcinoma, 10 epithelial ovarian cancer, 11 and gastric carcinoma. 12 In Egypt, skin cancer is common among elderly males; its etiology is related to sun exposure and it represents 5% of the malignant tumors of the entire body. Basal cell carcinoma (BCC; 77%) was the most common skin cancer followed by squamous cell carcinomas (SCCs; 15%) and melanomas (8%).…”

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

“…Its expression in gastric cancer is associated with increased invasion, supporting the hypothesis that increased CAIX expression may contribute to invasion and thus advanced disease and tumor progression 34 . The presence of CAIX has also been linked with poorer survival/prognosis in several other solid tumors 15,16,26,30,31 . In neuroblastoma, a previous study has shown that CAIX is expressed at significantly higher levels in tumors from patients with adverse clinicopathological and biological factors 18 .…”

“…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 .…”

“…breast cancer 13 , prostate cancer 14 , gastric cancer 15 , oral squamous cell cancer 16 , leads to an increased malignancy with an increased metastatic rate and treatment resistance with a poor prognosis. In breast cancer, CAIX is vital for growth and metastasis of hypoxic tumors, and has been shown to be a specific and targetable biomarker for metastasis 13,17 .…”