Hypoxia-inducible factor-1α and semaphorin4D genes involved with tumor-associated macrophage-induced metastatic behavior and clinical significance in colon cancer

Abstract

Background Hypoxia promotes tumor angiogenesis and hypoxia-inducible factor-1 alpha (HIF-1α) plays a pivotal role in this process. Recently identified pro-angiogenic factor, semaphorin4D (Sema4D) also promotes angiogenesis and enhances invasive proliferation in some tumors. Furthermore, tumor-associated macrophages (TAMs) can increase the expression of HIF-1α and Sema4D in cancer cells and thus influence tumor growth and progression. The purpose of this study was to evaluate the effect of TAMs on the expression of Sema4D and HIF-1α and the impact of biologic behavior in colon cancer cells. Methods Immunohistochemistry was used to analyze HIF-1α and Sema4D expression in 86 curatively resected colon cancer samples and 52 normal colon tissues samples. The relationship between their expression and clinicopathological factors was analyzed. Furthermore, macrophage-tumor cell interactions, such as metastasis, angiogenesis, were also studied using in vitro co-culture systems. Statistical analysis was performed using SPSS 17.0 software (SPSS Inc., USA). Differences between two groups were analyzed with Student's t test. Results HIF-1α (58%) and Sema4D (60%) were expressed at a significantly higher level in tumors than in normal tissues (P <0.01, for both). Furthermore, HIF-1α and Sema4D expression was significantly correlated with lymphatic metastasis, specific histological types and TNM stages (P <0.05), but not with age and tumor size (P >0.05). Sema4D expression was correlated with that of HIF-1α (r=0.567, P <0.01). TAMs markedly induced HIF-1α and Sema4D expression in colon cancer cells and subsequently increased their migration and invasion. Conclusions HIF-1α and Sema4D expression are closely related to lymphatic metastasis, specific histological types and TNM stages in colon cancer. Furthermore, TAMs promote migration and invasion of colon cancer cells and endothelial tube formation, possibly through up-regulation of HIF-1α and Sema4D.