title: Dopamine agonist resistance-related endocan promotes angiogenesis and cells viability of prolactinomas.
abstract: Dopamine agonists (DAs) are the first-line treatment of prolactinomas. They function through the dopamine 2 receptor (D2R) in the tumor cells. Endocan, also called endothelial cell-specific molecule-1 (ESM1), has been described as a marker of neoangiogenesis. However, whether ESM1 promotes the resistance of prolactinomas to DA therapy is largely unknown. In our study, 25 patients with prolactinomas were divided into resistant- and sensitive- groups according to the clinical response to bromocriptine. We found that ESM1-microvessel density of resistant prolactinomas was significantly higher than that of sensitive prolactinomas (47.9 ± 11.6, n = 8, vs 13.1 ± 2.8, n = 17, p = 0.0006), indicating that ESM1 was a DA resistance-related gene. Immunostaining showed that ESM1 was expressed in tumor vessels and sporadic tumor cells, and ESM1 was overlapped with the Smooth Muscle Actin (SMA) and von Willebrand Factor (VWF) in the tumor vessels. Silencing of ESM1 markedly suppressed the viability of GH3 and MMQ cells in vitro, and furthermore, significantly increased the sensitivity of GH3 and MMQ cells to DA treatment. Additionally, silencing of ESM1 down-regulated the angiogenesis-associated genes, such as VEGFR2, FGF2, CD34, CD31, VWF, and EGFR. Knockdown of ESM1 decreased endothelial tube formation of HUVECs, and significantly increased the sensitivity of HUVECs to Avastin treatment. Therefore, we first demonstrate that DA resistance-related ESM1 promotes the angiogenesis and tumor cells growth of prolactinomas, suggesting that ESM1 may be a novel therapeutic target for prolactinomas.
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Zhi Gen
authors.initials: ZG
authors.lastname: Leng
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Yu Hang
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Shao Jian
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Ze Rui
authors.initials: ZR
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Zhi Peng
authors.initials: ZP
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Jiang Long
authors.initials: JL
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Li Fei
authors.initials: LF
authors.lastname: Wei
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Qi Chuan
authors.initials: QC
authors.lastname: Zhuge
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. zhebaowu@aliyun.com.|Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. zhebaowu@aliyun.com.
authors.forename: Zhe Bao
authors.initials: ZB
authors.lastname: Wu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D015175:Prolactinoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D011509:Proteoglycans / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D055815:Young Adult
chemical_list: D018491:Dopamine Agonists; C101134:ESM1 protein, human; D009363:Neoplasm Proteins; D011509:Proteoglycans; D001971:Bromocriptine
keywords: Angiogenesis; Bromocriptine; Dopamine agonist; Endocan; Endothelial cell-specific molecule 1; Prolactinoma