Vascular Endothelial Growth Factor, Hypoxia-Inducible Factor 1 Alpha and CD34 Expressions in Early-Stage Gastric Tumors: Relationship with Pathological Factors and Prognostic Impact on Survival

Abstract

Background: Angiogenesis is one of the key steps in solid tumor growth and metastasis. We planned to investigate the prognostic significance of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α) and CD34 expressions as markers of angiogenesis in gastric cancer. Patients and Methods: We retrospectively reviewed the medical records of 51 gastric cancer patients who had total or subtotal gastrectomy at Marmara University Hospital from 1990 to 2004 and evaluated the expression of VEGF, HIF-1α and CD34 by immunohistochemistry in their archival tumor tissues. We recorded the clinical and pathological characteristics of these patients and analyzed their survival outcome. Results: Thirty out of 51 patients were males. The median age was 63 years (range 34–81). The median follow-up was 17 months. Thirty-six patients had node-positive disease. The majority of patients (n = 43) had T2 and T3 disease. Vascular and lymphatic invasions were present in 57 and 77% of tumors, respectively. VEGF and HIF-1α were positive in 65 and 71% of tumors. The median CD34 staining score was 19 (3–68). VEGF, HIF-1α and CD34 expressions were more frequent in tumors without serosal invasion (p = 0.01, p = 0.01 and p = 0.003, respectively). CD34 expression was significantly more frequent in tumors with VEGF and HIF-1α expression (p = 0.00, p = 0.00). HIF-1α expression was more frequent in tumors with VEGF expression (p = 0.00). The 5-year overall survival was 45%. VEGF, HIF-1α, CD34 expressions and other pathological characteristics were found to have no impact on survival. Conclusion: VEGF, HIF-1α and CD34 expressions were more common in tumors without serosal invasion. As a future perspective, biological agents targeting VEGF and HIF-1α might be more effective at earlier stages of gastric cancer.

HIF-1α determines the metastatic potential of gastric cancer cells

“…We provide experimental evidence for reduced metastatic properties of gastric cancer cells through functional inactivation of HIF-1a, even under conditions of ambient oxygen. Our characterisation of the temporospatial expression patterns of HIF-1a protein during the pathogenesis of human gastric adenocarcinoma are in line with earlier studies showing HIF-1a protein expression in the majority of human gastric cancer samples (Urano et al, 2006;Cabuk et al, 2007;Griffiths et al, 2007). In contrast, two Japanese studies reported lower percentages of HIF-1a-positive tumour cells in human gastric adenocarcinoma samples Sumiyoshi et al, 2006).…”

“…Our analysis of EGC samples detected specific nuclear expression of HIF-1a in only 15% of the examined cases. Although this result is in line with one previous study showing specific HIF-1a staining in 29% of T1 tumours (Sumiyoshi et al, 2006), two other articles reported strikingly different results (HIF-1a positivity in 68 and 100% of T1 tumours) (Urano et al, 2006;Cabuk et al, 2007). Given these sharp contrasts, a definite agreement on the expression pattern of HIF-1a in T1 gastric adenocarcinomas cannot be reached at this point and should be clarified by future work.…”

“…Although two studies have assessed HIF-1a as a prognostic marker in gastrointestinal stromal tumours of the stomach (Takahashi et al, 2003;Chen et al, 2005), conflicting data concerning patient prognosis for gastric adenocarcinoma exist Sumiyoshi et al, 2006;Urano et al, 2006;Cabuk et al, 2007;Griffiths et al, 2007). Inhibition of HIF-1a by means of RNA interference or chemical compounds has proven antitumoural activity in two murine gastric cancer models.…”

The JAK/STAT signaling cascade in gastric carcinoma (Review)

“…An increased expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFR1-4) is known to promote angiogenesis, and is therefore associated with more aggressive forms of gastric cancer (41)(42)(43). Despite promising in vitro results, clinical trials with the VEGF-A monoclonal antibody bevacizumab failed to show a significant improvement in patient survival rates when supplemented with first-line chemotherapy (44,45).…”

Expression of midkine and vascular endothelial growth factor in gastric cancer and the association of high levels with poor prognosis and survival

“…Midkine (MK) is a recently discovered heparin-binding growth factor with strong differentiation, mitotic and angiogenesis activity (7)(8)(9). Vascular endothelial growth factor (VEGF) promotes vascular endothelial cell proliferation and its high expression in tumors is significantly associated with advanced disease and poor prognosis (10)(11)(12). We investigated MK and VEGF expression levels in gastric cancer specimens by immunohistochemistry, and examined their relationship to prognostic factors of gastric cancer.…”