Roles of intrinsic angiogenesis inhibitor, vasohibin, in cervical carcinomas

Abstract

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...

Vasohibin-2 Expressed in Human Serous Ovarian Adenocarcinoma Accelerates Tumor Growth by Promoting Angiogenesis

“…Previously, we investigated the expression of VASH1 under conditions accompanied by conducive to pathologic angiogenesis and showed its presence in endothelial cells of various cancers (17)(18)(19)(20)(21), atherosclerotic lesions (22), agedependent macular degeneration (23), and diabetic retinopathy (24). However, the expression of VASH2 is ill-defined.…”

Vasohibin-1 Is a Poor Prognostic Factor of Ovarian Carcinoma

“…In uterine corpus carcinoma, the VASH1 expression was reported to be higher as the differentiation is poorer, but its correlation has not been analyzed yet (Yoshinaga et al 2008). In uterine cervix carcinoma, higher VASH1 expression was reported in infiltrating carcinoma than in in-situ carcinoma, and in adenocarcinoma than in squamous cell carcinoma, without regard to the correlation with prognosis (Yoshinaga et al 2011). In renal cell carcinoma, a finding different from the above was reported where the high VASH1 expression group demonstrated a better PFS, but correlation with OS was not proven (Kanomata et al 2013).…”

“…Additionally, VASH1 expression not only in ECs of normal tissue but also ECs surrounding malignant tissue has been reported. Until the current time, VASH1 expression has been reported in carcinomas in the mammary gland (Tamaki et al 2009), large intestine (Liu et al 2015), lung (Zhang et al 2014), uterine corpus (Yoshinaga et al 2008), uterine cervix (Yoshinaga et al 2011), upper urinary tract (Miyazaki et al 2012), prostate (Kosaka et al 2013), and renal cell carcinoma (Kanomata et al 2013) in humans. These reports suggest that the expression level of VASH1 differs between cancer invasion of the same organ depending on degree and histological type.…”

Expression of Vasohibin-1 in Human Carotid Atherosclerotic Plaque

“…Interestingly, VASH1 exists in microvessel endothelial cells in a variety of solid tumors, and the VASH1 expression levels correlate with the prognosis and grade of malignancy [27][28][29][30][31][32][33][34] . Moreover, endogenous VASH1 is expressed in adventitial microvessels of the aortic wall, and exogenous VASH1 prevents neointimal formation by inhibiting adventitial angiogenesis 24) .…”