The ratio of membrane-bound form Flt-1 mRNA to VEGF mRNA was correlated with tumor angiogenesis and prognosis in non-small cell lung cancer

Abstract

9586 Background: Angiogenesis is an essential process in development and progression of malignant tumors, and vascular endothelial growth factor (VEGF) and its receptors such as fms-like tyrosine kinase 1 (Flt-1) play critical roles in tumor angiogenesis. There have been reported two isoforms of Flt-1, membrane-bound form (mFlt-1) and soluble form. Experimental studies have revealed that mFlt-1 can act as a dual angiogenesis regulator, an angiogenesis inhibitor by trapping VEGF and an angiogenesis promoter in certain pathological conditions. In accordance with such complex function of mFlt-1 in tumor angiogenesis, clinical significance of mFlt-1 remains unclear. Methods: Expression of mFlt-1 mRNA along with VEGF mRNA was quantitatively evaluated by real-time RT-PCR in 79 resected non-small cell lung cancer (NSCLC) patients. Intra-tumoral microvessel density (IMVD) and mFlt-1 protein expression were assessed immunohistochemically. Results: Expression of mFlt-1 mRNA was positively correlated with mFlt-1 expression detected by immunohistochemical staining (P=0.099). Expressions of mFlt-1 mRNA and mFlt-1 protein were significantly higher in adenocarcinoma than in squamous cell carcinoma. Expression of mFlt-1 mRNA was positively correlated with VEGF mRNA expression. There was no significant difference in the mean IMVD according to mFlt-1 mRNA expression status or VEGF mRNA expression status. Next, the ratio of mFlt-1 mRNA to VEGF mRNA (mFlt-1/VEGF) was calculated. The mean IMVD for high mFlt-1/VEGF tumor was 57.0, which was significantly lower than that for low mFlt-1/VEGF tumor (148.5, P=0.004). The 5-year survival rate of high mFlt-1/VEGF patients was 69.6%, which was significantly higher than that of low mFlt-1/VEGF patients (41.6%; P=0.037). In contrast, expression status of mFlt-1 mRNA, mFlt-1 protein, or VEGF mRNA, did not provide a prognostic value. A multivariate analysis confirmed that high mFlt-1/VEGF was a significant factor to predict a favorable prognosis (P=0.043). Conclusions: The ratio of mFlt-1 mRNA to VEGF mRNA, not mFlt-1 mRNA alone, was inversely correlated with tumor angiogenesis, and was a significant prognostic factor. No significant financial relationships to disclose.