Expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and matrix metalloproteinase-2 in sacral chordomas

Abstract

Hypoxia-inducible factor-1α (HIF-1α) has been reported to transactivate the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2), which are frequently overexpressed in numerous types of cancer and are known to be significant regulators of angiogenesis. Few studies have investigated the role of these factors in solid tumors, particularly chordomas, which are rare tumors that are thought to originate from notochordal remnants. To clarify whether HIF-1α is involved in angiogenesis in chordoma tissues, we examined the expression of HIF-1α, VEGF and MMP-2 with immunohistochemistry using a tissue microarray containing 35 chordoma samples. The results indicated that HIF-1α, VEGF and MMP-2 are expressed in the majority of chordoma samples. VEGF expression was significantly correlated with HIF-1α and MMP-2 expression, as well as with microvessel density (MVD). However, the prognosis of the chordoma patients was not significantly associated with the expression of these factors, but was associated with MVD. The results therefore showed that there is a correlation between the expression of HIF-1α, VEGF and MMP-2 in chordomas and that the angiogenic process is a potential therapeutic target for chordomas.

Figure 1

Expression of HIF-1α, VEGF, MMP-2 and CD34 in primary chordoma samples is shown. (A) Strong HIF-1α immunoreactivity in the cytoplasm and nuclei of tumor cells. (B) Positive immunohistochemical staining of VEGF. VEGF immunoreactivity is present in the cytoplasm of tumor cells. (C) MMP-2 was observed in the cytoplasm of tumor cells. (D) CD34 staining of chordoma tissue. HIF-1α, hypoxia-inducible factor-1α; VEGF, vascular endothelial growth factor; MMP-2, matrix metalloproteinase-2.

Figure 2

Correlation between MVD and the expression of (A) HIF-1α, (B) VEGF and (C) MMP-2. The Mann-Whitney U test revealed that VEGF expression was significantly associated with MVD (B) (P=0.008). The expression levels of (A) HIF-1α and (C) MMP-2 were not associated with MVD (P=0.540 and P=0.092, respectively).^*Statistically significant difference. HIF-1α, hypoxia-inducible factor-1α; VEGF, vascular endothelial growth factor; MMP-2, matrix metalloproteinase-2; MVD, microvessel density.

Figure 3

Impact of MVD and HIF-1α, VEGF and MMP-2 expression on patient overall survival (log-rank test) is shown. (A) The log-rank test revealed a significantly shorter overall survival rate in patients with tumors with a high MVD (P=0.018). Kaplan-Meier analyses indicated that there were no significant differences in the survival rates between (B) the high and low HIF-1α expression groups, (C) the VEGF-positive and VEGF-negative groups or (D) the high and low MMP-2 expression groups (P=0.223, P=0.740 and P=0.451, respectively). HIF-1α, hypoxia-inducible factor-1α; VEGF, vascular endothelial growth factor; MMP-2, matrix metalloproteinase-2; MVD, microvessel density.