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.
Highlights
Esophageal cancer is one of the five most commonly diagnosed cancers in humans
Cells incubated in 10 μmol/L All-trans retinoic acid (ATRA) showed 29.5% and 40.3% reduction at 24 hours and 48 hours, relative to untreated cells. 100 mg/L Fluorouracil caused 29.9% and 41.2% reduction at 24 hours and 48 hours, relative to untreated cells, respectively (p < 0.05; Fig 1A)
Immunoblotting analysis showed that ATRA treatment increased the level of cleaved-PARP by 82% compared with the control (p < 0.05; Fig 1D), indicating that ATRA induces the apoptosis of EC1 cells
Summary
Esophageal cancer is one of the five most commonly diagnosed cancers in humans It is the third most common diagnosed malignancy and the fourth leading cause of death in China. In northern China, esophageal cancer has become the leading cause of cancer-related death due to the highly aggressive nature of the cells, high incidence in this region, and in diagnosis. These delays lead to later staging levels at diagnosis. There is no doubt that the patient accepted treatment early, proper drugs and appropriate adjuvant therapy, such as radiotherapy and endoscopic treatment, can reduce the mortality from esophageal cancer[4, 5]. It is important to discover and understand the molecular events underlying the initiation, proliferation, migration and metastasis of esophageal cancer
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