Differential expression of angiogenesis-related genes in human gastric cancers with and those without high-frequency microsatellite instability

Abstract

Gastric cancers with and those without high-frequency microsatellite instability (MSI-H) represent distinctive pathways of carcinogenesis. The aim of this study was to clarify if expression of p53 related genes involved in angiogenesis is differentially regulated between these cancers. We systematically analyzed the expression of vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2), thrombospondin 1 (THBS1), and brain-specific angiogenesis inhibitor 1 (BAI1), and we correlated the results with microvessel count (MVC), MSI status, p53 mutations, and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in gastric cancers. Expression of VEGFA in carcinoma cells was immunohistochemically seen in 46% of 200 cases. VEGFA positivity was significantly associated with higher MVC, vascular invasion, lymph node and distant metastasis, and advanced tumor stage. FGF2 positivity was significantly associated with poor differentiation, depth of invasion, and higher MVC. VEGFA and FGF2 positivities and MVC were lower in MSI-H cancers than in MSI-L or MSS cancers. VEGFA expression was associated with both p53 mutations and PTGS2 expression. Methylation of the THBS1 gene was detected in 6 of 11 cancer cell lines and in 44% of 200 cases. THBS1 methylation was significantly associated with distal location, vascular invasion, distant metastasis, MSI-H, wild-type p53, and higher MVC. The prognosis was worst in patients with cancers that were VEGFA-positive and THBS1 methylation-positive. Gastric cancers with MSI-H were characterized by lower MVC, low frequency of VEGFA, FGF2, and PTGS2 overexpression, and high frequency of THBS1 methylation. Our results suggest that gastric cancers with and those without MSI-H represent distinctive pathways of carcinogenesis, including aberrant expression of factors regulating angiogenesis. The difference may be associated with less aggressive phenotype of these cancers with MSI-H and affect future molecular targeted therapeutics.