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We have previously reported on vasohibin as a novel endotheliumderived vascular endothelial growth factor (VEGF)-inducible inhibitor of angiogenesis. The aim of our present study was to define the role of vasohibin in endometrioid endometrial adenocarcinoma. We collected 78 sections of endometrial carcinoma for assessment using immunohistochemistry. Twenty-seven were well differentiated (G1), 25 were moderately differentiated (G2), and 26 were poorly differentiated endometrioid adenocarcinomas (G3). We also included 12 sections of normal cyclic endometria, six of which were in the proliferative phase and six were in the secretory phase. We investigated the expression of vasohibin, and compared it to VEGF receptor-2 (VEGFR-2: KDR/flk-1), CD34, Ki-67, VEGF-A, and D2-40 (as a lymphatic vessel marker). We assessed the ratio of vasohibin-and VEGFR-2-positive vessels in the stroma of endometrial carcinoma. Immunohistochemical assessment was classified as negative or positive based on staining intensity. Vasohibin was selectively expressed on vascular endothelial cells in both cyclic endometria and endometrial carcinomas. Vasohibin was highly expressed in the normal functional endmetrium of the secretory phase, especially in the spiral artery, and was highly expressed in all grades of endometrioid adenocarcinomas. The stromal endothelial cells in G3 expressed vasohibin and VEGFR-2 more frequently than these in G1. In endometrioid adenocarcinomas, there was a significant correlation between the expression percentage of vasohibin and that of VEGFR-2 (P < 0.0001, r 2 = 0.591). This is the first study to elucidate the correlation between expression of vasohibin in the stromal endothelial cells and that of VEGFR-2 in human carcinomas. (Cancer Sci 2008; 99: 914-919)

The aim of the present study is to clarify the critical roles of vasohibin in cervical carcinomas. We investigated the expression ratios of vasohibin and vascular endothelial growth factor (VEGF) receptor-2 on endothelium and microvessel density, lymphatic vessel density (LVD) by immunohistochemistry. Sixty-one squamous cell carcinoma (SCC), 18 mucinous adenocarcinoma (Adenocarcinoma), 38 carcinoma in situ (CIS), and 35 normal cervical epithelium were collected. We investigated the expression of vasohibin and compared it with the expression of VEGF receptor-2 (VEGFR-2, KDR/flk-1), and CD34 in the stromal endothelium. Expression of VEGF was counted using the histological score (H score). D2-40 was used as a marker for lymphatic endothelial cells to investigate LVD. The microvessel density of the normal cervical epithelium was significantly lower than that of CIS, SCC, and Adenocarcinoma (P < 0.05). The expression ratio of vasohibin in the normal cervical epithelium was significantly lower than that of SCC and Adenocarcinoma (P < 0.05). The expression ratio of VEGFR-2 of the normal cervical epithelium was significantly lower than that of SCC and Adenocarcinoma (P < 0.05). The LVD of the normal cervical epithelium was significantly lower than that of CIS, SCC, and Adenocarcinoma (P < 0.05). For normal cervical epithelium, CIS, and SCC, there was a moderate correlation between the expression percentage of vasohibin and the expression percentage of VEGFR-2 (P < 0.05, r 2 = 0.3018). This is the first study to elucidate the correlation between the expression of vasohibin in the stromal endothelial cells and the expression of VEGFR-2 in human cervical carcinomas. (Cancer Sci 2011; 102: 446-451) C ervical carcinoma is a common gynecologic malignancy in women worldwide. In 2008 in the USA, an estimated 11 070 new cases of invasive cervical cancer were diagnosed and 3870 cancer-related deaths were expected to occur; this represents approximately 1% of cancer deaths in women.1 The morbidity of cervical cancer, especially in women younger than 40 years old, is rapidly increasing and is the worst in Japan.2 It is well recognized that angiogenesis (the process of forming new vessels) is required for tumor growth and enables the hematogenous spread of tumor cells throughout the cervical cancer. Several studies document the association between the MVD and ⁄ or the extent of endothelial proliferation, the pre-cancer and tumor stage, and the invasive disease of the cervical cancer. (3)(4)(5)(6) The expression of various angiogenesis stimulators, such as VEGFs, angiopoietins, and thymidine phosphorylase, has been reported in cervical cancer and dysplasia. (7,8) Several published reports similarly report stromal LVD in cervical neoplasia. (9)(10)(11) Angiogenesis is determined by the local balance between angiogenic stimulators and inhibitors. However, the significance of endogenous angiogenesis inhibitors in cervical cancer is poorly documented.We isolated a novel angiogenesis inhibitor, vasohibin, which is specifically expresse...

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