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.

Retinoic acid receptor γ activation promotes differentiation of human induced pluripotent stem cells into esophageal epithelium

“…Of note, several reports argued that RA signaling had a suppressive effect on esophageal cancer [35] as well as skin cancer [36]. In addition, the decreased expression of DSG3 [37], SPRR3 [38] and MAL [39], which were all also decreased under conditions of ATRA absence in our experiment ( Fig.…”

β‐Cryptoxanthin Inhibits Angiogenesis in Human Umbilical Vein Endothelial Cells Through Retinoic Acid Receptor

“…Additionally, such carotenoid downregulated VEGFA , ANGPT1 , and TEK angiogenic genes in HUVEC. Interestingly, inhibition of angiopoietin–TEK pathway by all‐ trans retinoic acid has been described in EC1 human cellular line of esophagus cancer, which is in agreement with our results, taking into account that β‐cryptoxanthin is a provitamin A carotenoid. Such antiangiogenic capacity against development of several diseases has been previously proposed for several carotenoids, including β‐cryptoxanthin, based on chemoprotection studies .…”

All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes

“…In addition, retinoids have been considered for the treatment of several types of cancer and autoimmune diseases. In cancer cells, retinoids induce differentiation, cell cycle arrest, apoptosis, and inhibition of cell migration and invasiveness (Flamini et al, 2014;Young et al, 2015;Cui et al, 2016;Li et al, 2017). In autoimmune diseases, retinoids have shown improvement of animal models of multiple sclerosis (Massacesi et al, 1991), systemic lupus erythematosus (Perez de Lema et al, 2004), type 1 diabetes , and RA (Kuwabara et al, 1996;Kwok et al, 2012).…”