Journal Article

All-trans retinoic acid suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and metastasis in esophageal squamous cell carcinoma

Zhang, Linda, Sang, Luqian, Cui, Huijuan, Li, Na, Wang, Ying, Lu, Taiying, Lian, Jingyao, Li, Daoming, Yu, Jane J., Lu, Yanjuan, Zheng, Xiangyu, Li, Shanshan

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 5-Fluorouracil / Acids / Adjuvant chemotherapy / Analysis / Angiogenesis / Angiopoietin / Angiopoietin-1 - biosynthesis / Animal models / Animals / Antineoplastic Agents - pharmacology / Apoptosis / Biological activity / Biology and Life Sciences / Cachexia / Cancer therapies / Carcinoma, Squamous Cell - drug therapy / Care and treatment / Cell Line, Tumor / Cell Movement - drug effects / Cell Proliferation - drug effects / Cellular biology / Chemical compounds / Chemotherapy / Diagnosis / Esophageal cancer / Esophageal carcinoma / Esophageal Neoplasms - drug therapy / Esophageal Squamous Cell Carcinoma / Esophagus / Female / Fluorouracil - pharmacology / Gene expression / Health aspects / Humans / Immune response / In vitro methods and tests / Lung cancer / Lungs / Medicine and Health Sciences / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Neoplasm Metastasis - drug therapy / Neovascularization, Pathologic - drug therapy / Pharmacology / Physical Sciences / Platelet Endothelial Cell Adhesion Molecule-1 - biosynthesis / Polymerase chain reaction / Prognosis / Radiation therapy / Radiotherapy / Receptor, TIE-2 - biosynthesis / Receptors / Receptors, Vascular Endothelial Growth Factor - biosynthesis / Reproduction (biology) / Retinoic acid / Squamous cell carcinoma / Survival / Transcription / Tretinoin / Tretinoin - pharmacology / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - biosynthesis / Vesicular Transport Proteins - biosynthesis / Viability / Vitamin A / Xenografts