The onset of angiogenesis in a multistep process of esophageal squamous cell carcinoma.

Microvessel density (MVD) is an excellent predictive biomarker regarding tumor stage and survival in esophageal squamous cell carcinomas (ESCCs). However, it is obscure when tissues initiate angiogenesis in the malignant transformation of human esophageal squamous epithelium. To investigate the onset of angiogenesis in the multistep progressive process of ESCCs, immunohistochemical staining for CD31, CD105, and vascular endothelial growth factor receptor 2 (VEGFR-2) was performed in normal epithelium, Lugol-unstained lesions with non-dysplastic epithelium (LULs-NDE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD) samples. There were significant differences in the mean MVD for CD31 and CD105 between LULs-NDE and LGD (p<0.001, p<0.001), and between LGD and HGD (p<0.001, p=0.006), respectively. Furthermore, a significant difference in MVD for CD105 was seen in normal controls and LULs-NDE (p=0.002), while thick vessels (>10 mu m) stained with anti-CD105 were not present in normal controls and LULs-NDE despite the presence of these thickened vessels in dysplasia. Our results suggest that CD105 is an efficient marker protein to determine MVD, suggesting that the angiogenic switch occurs at the earliest stage of dysplastic transformation in ESCC.