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

Abstract

Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor and VASH2 is its homolog. Our previous analysis revealed that VASH1 is expressed in endothelial cells to terminate angiogenesis, whereas VASH2 is expressed in infiltrating mononuclear cells mobilized from bone marrow to promote angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis. To test the possible involvement of VASH2 in the tumor, we examined human ovarian cancer cells for the presence of VASH2. Immunohistochemical analysis revealed that VASH2 protein was preferentially detected in cancer cells of serous ovarian adenocarcinoma. We then used SKOV-3 and DISS, two representative human serous adenocarcinoma cell lines, and examined the role of VASH2 in the tumor. The knockdown of VASH2 showed little effect on the proliferation of cancer cells in vitro but notably inhibited tumor growth, peritoneal dissemination, and tumor angiogenesis in a murine xenograft model. Next, we stably transfected the human VASH2 gene into two types of murine tumor cells, EL-4 and MLTC-1, in which endogenous VASH2 was absent. When either EL-4 or MLTC-1 cells were inoculated into VASH2 (À/À) mice, the VASH2 transfectants formed bigger tumors when compared with the controls, and the tumor microvessel density was significantly increased. VASH2 stimulated the migration of endothelial cells, and its increased expression in cancer cells is related to the decrease of mir-200b. These results indicate that VASH2 expressed in serous ovarian carcinoma cells promoted tumor growth and peritoneal dissemination by promoting angiogenesis. Mol Cancer Res; 10(9); 1135-46. Ó2012 AACR.

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

“…VASH2 has been implicated in tumor progression [5][6][7][8][9][10][11][12]. In this study, we investigated the expression of VASH2 in human pancreatic cancer, and found significantly higher levels of VASH2 in pancreatic cancer tissues than in paired cancer-adjacent normal tissue.…”

“…We have demonstrated that VASH2 protein expression can be detected in both the nuclear and cytoplasmic compartments [4]. Recently, VASH2 has been demonstrated to be involved in the malignant behavior of a number of malignancies, including hepatic cancer [5,6], ovarian cancer [7,8], endometrial cancer [9], gastrointestinal cancers [10], breast cancer [11], and pancreatic cancer [12]. Kim JC et al have reported that VASH2 promotes tumor progression and is associated with a poor clinical outcome in pancreatic ductal adenocarcinoma [12].…”

miR-200b and Cancer/Testis Antigen CAGE Form a Feedback Loop to Regulate the Invasion and Tumorigenic and Angiogenic Responses of a Cancer Cell Line to Microtubule-targeting Drugs

“…For example, miR-210 (20) and miR-29a (21) promotes angiogenesis whereas miR-200b inhibits angiogenesis (22). Vasohibin-2 promotes angiogenesis by exerting a negative regulation on the expression of miR-200b (23). miR-200b mimic prevents diabetes-induced increased VEGF expression, glucose-induced increased permeability, and angiogenesis (24).…”

Association between TAp73, p53 and VASH1 expression in lung adenocarcinoma

“…A secretory protein, VASH1 can be induced as a negative feedback regulator in endothelial cells by stimulators of angiogenesis such as VEGF and fibroblast growth factor 2 (FGF-2) (27). Many reports have indicated that VASH1 expression is high in malignant solid tumors, and that its expression is closely related to tumor angiogenesis, such as in breast (28), liver (29), renal (19), ovarian (30), colorectal (18), and lung cancer (31). Similar to these reports, we found the higher VASH1 expression in LAC tissue than in the adjacent normal Table III.…”