title: All-trans retinoic acid suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and metastasis in esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) is the second common cancer in Henan province and is well-known for aggressiveness and dismal prognosis. Adjuvant therapies, chemotherapy, radiotherapy and endoscopic treatment have not improved survival rates in patients with late stage esophageal carcinoma. All-trans retinoic acid (ATRA) is the active ingredient of Vitamin A and affects a wide spectrum of biological processes including development, growth, neural function, immune function, reproduction, and vision. It is one of the most potent therapeutic agents used for treating cancers, especially lung adenocarcinomas. ATRA inhibits metastatic potential and angiogenesis in several tumor models. We investigated the effects of ATRA on the expression of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2) and receptor Tie-2 in EC1 cells in vitro. We also assessed the growth and migration of EC1 cells in vitro. ATRA treatment caused 29.5% and 40.3% reduction of the growth of EC1 cells after 24 hours and 48 hours, relative to the control. ATRA plus fluorouracil treatment reduced the viability more strongly than either drug alone, indicating an additive effect. Moreover, ATRA decreased EC1 migration by 87%. Furthermore, ATRA treatment led to a marked decrease of the transcript levels of Ang-1, Ang-2, Tie-2, VEGF, and VEGF receptors, as assessed by real-time RT-PCR. Importantly, the protein levels of Ang-1, Ang-2 and Tie-2 were reduced by ATRA treatment. In vivo, we found ATRA treatment suppressed the tumor growth and improved the cachexia of mice. Importantly, ATRA treatment decreased the expression of CD31, Ang-1, Ang-2 and Tie-2 in subcutaneous tumors of EC1 cells. Collectively, our findings demonstrate that ATRA exhibits a dose- and temporal-dependent effect on the metastatic behavior, suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and the progression of xenograft tumors of EC1 cells.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Daoming
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zheng
authors.affiliation: School of Life Sciences, Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Lian
authors.affiliation: Department of Oncology, Zhengzhou First People's Hospital, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Oncology, The Chinese People's Liberation Army 150 Central Hospital, Luoyang, Henan Province, People's Republic of China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Behavioral Neuroscience, Northeastern University, Boston, MA, United States of America.
authors.forename: Linda
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Luqian
authors.initials: L
authors.lastname: Sang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.|Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People's Republic of China.
authors.forename: Taiying
authors.initials: T
authors.lastname: Lu
mesh_terms: D042683:Angiopoietin-1 / Q000096:biosynthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D042787:Receptor, TIE-2 / Q000096:biosynthesis*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D033921:Vesicular Transport Proteins / Q000096:biosynthesis*
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D000970:Antineoplastic Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; C555023:VPS51 protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; D014212:Tretinoin; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; D005472:Fluorouracil