Research Article Gremlin, a Bone Morphogenetic Protein Antagonist, Is a Crucial Angiogenic Factor in Pituitary Adenoma Kenta Koketsu, Daizo Yoshida, Kyongsong Kim, Yudo Ishii, Shigeyuki Tahara, Akira Teramoto, and Akio Morita Department of Neurosurgery, Nippon Medical School, Tokyo 113-8602, Japan Correspondence should be addressed to Kenta Koketsu; kenta7240031@nms.ac.jp Received 27 September 2014; Revised 10 February 2015; Accepted 16 February 2015 Academic Editor: Amelie Bonnefond Copyright © 2015 Kenta Koketsu et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gremlin is an antagonist of bone morphogenetic protein (BMP) and a major driving force in skeletal modeling in the fetal stage. Several recent reports have shown that Gremlin is also involved in angiogenesis of lung cancer and diabetic retinopathy. he purpose of this study was to investigate the role of Gremlin in tumor angiogenesis in pituitary adenoma. Double luorescence immunohistochemistry of Gremlin and CD34 was performed in pituitary adenoma tissues obtained during transsphenoidal surgery in 45 cases (7 PRLoma, 17 GHoma, 2 ACTHoma, and 2 TSHoma). Gremlin and microvascular density (MVD) were detected by double-immunoluorescence microscopy in CD34-positive vessels from tissue microarray analysis of 60 cases of pituitary adenomas (6 PRLoma, 23 GHoma, 22 NFoma, 5 ACTHoma, and 4 TSHoma). In tissue microarray analysis, MVD was signiicantly correlated with an increased Gremlin level (linear regression:  < 0.005,  2 = 0.4958). In contrast, Gremlin expression showed no correlation with tumor subtype or Knosp score. he high level of expression of Gremlin in pituitary adenoma tissue with many CD34-positive vessels and the strong coherence of these regions indicate that Gremlin is associated with angiogenesis in pituitary adenoma cells. 1. Introduction Angiogenesis is a complex multistep process that has a crucial role in tumor growth, invasion, and metastasis. Improved understanding of angiogenesis will provide insights into tumor stage and the response of tumor vessels to antian- giogenic therapy and may lead to more personalized cancer therapy [1, 2]. Current attempts to disrupt tumor blood vessel formation are predominantly focused on targeting the VEGF- VEGFR signaling pathway [2]. Pituitary tumors are highly vascular neoplasms, which suggests an important role of angiogenesis in pituitary tumor growth, but the mechanisms that underlie tumorigenesis in pituitary adenomas are uncer- tain [3, 4]. In particular, the mechanism that controls tumor angiogenesis and whether this process is required for tumor growth have been the subject of much discussion. Microvascular density (MVD) has been studied in a number of neoplasia and generally there is a close relationship between angiogenesis and tumor progression. hus, MVD may be a predictive factor for disease progression and response to treatment. Zhang et al. found that cervical cancer progression is correlated with MVD and VEGF [5], and Zhao et al. showed that VEGF and MVD are decreased by siRNA silencing of c-Src, a predictor of a poor prognosis in pancreas cancer [6]. Norcantharidin, an angiogenic inhibitor in gallbladder cancer, has been shown to inhibit cancer cell proliferation, migration, and invasion and to reduce angiogenesis based on decreased MVD and VEGF expression [7]. VEGF is likely to have a role in tumor angiogenesis in pituitary adenomas that is similar to that in other neo- plasms, and VEGF also regulates the growth of pituitary tumor cells through its receptors VEGFR-1, VEGFR-8, and VEGFR-9. Onofri et al. [8, 9] showed that ligands of VEGF receptors inluence angiogenesis in pituitary adenomas and afect growth of pituitary tumor cells through VEGFR-1, and that VEGF and VEGFR-3 immunostaining in pituitary tumors was higher than in normal pituitary tissue. hese results indicate that the VEGF-C/VEGFR-3 system might be involved in controlling tumor angiogenesis in pituitary Hindawi Publishing Corporation International Journal of Endocrinology Volume 2015, Article ID 834137, 7 pages http://dx.doi.org/10.1155/2015/834137