Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

Abstract

BackgroundEsophageal squamous cell carcinoma (ESCC) is a global public health issue, as it is the eighth most common cancer worldwide. The mechanisms behind ESCC invasion and progression are still poorly understood, and warrant further investigation into these processes and their drivers. In recent years, the ligand Activin A has been implicated as a player in the progression of a number of cancers. The objective of this study was to investigate the role of Activin A signaling in ESCC.MethodsTo investigate the role Activin A plays in ESCC biology, tissue microarrays containing 200 cores from 120 ESCC patients were analyzed upon immunofluorescence staining. We utilized three-dimensional organotypic reconstruct cultures of dysplastic and esophageal squamous tumor cells lines, in the context of fibroblast-secreted Activin A, to identify the effects of Activin A on cell invasion and determine protein expression and localization in epithelial and stromal compartments by immunofluorescence. To identify the functional consequences of stromal-derived Activin A on angiogenesis, we performed endothelial tube formation assays.ResultsAnalysis of ESCC patient samples indicated that patients with high stromal Activin A expression had low epithelial ACVRIB, the Activin type I receptor. We found that overexpression of stromal-derived Activin A inhibited invasion of esophageal dysplastic squamous cells, ECdnT, and TE-2 ESCC cells, both positive for ACVRIB. This inhibition was accompanied by a decrease in expression of the extracellular matrix (ECM) protein fibronectin and podoplanin, which is often expressed at the leading edge during invasion. Endothelial tube formation was disrupted in the presence of conditioned media from fibroblasts overexpressing Activin A. Interestingly, ACVRIB-negative TE-11 cells did not show the prior observed effects in the context of Activin A overexpression, indicating a dependence on the presence of ACVRIB.ConclusionsWe describe the first observation of an inhibitory role for Activin A in ESCC progression that is dependent on the expression of ACVRIB.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2920-y) contains supplementary material, which is available to authorized users.

Successful Establishment of Primary Type II Alveolar Epithelium with 3D Organotypic Coculture

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“…Building on prior work in other organ systems (17), we have developed a system of 3D organotypic coculture that can be used with primary human AT2 cells and pulmonary fibroblasts. In contrast to 2D cultures of primary AT2 cells, which lose many of their defining characteristics, we demonstrate that primary lung epithelial cells cultured in this 3D organotypic coculture retain their AT2 physiology and molecular characteristics.…”

FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways

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Tumour infiltrating lymphocytes correlate with improved survival in patients with esophageal squamous cell carcinoma

“…Esophageal carcinoma (EC) is one of the most prevalent life threatening malignancies 1 , which ranks as the eighth most frequently diagnosed cancer, and the sixth leading cause of cancer death worldwide 2 3 . China alone accounts for more than 70% of global EC, and 95% is esophageal squamous cell carcinoma (ESCC), with an estimated 478,000 new cases and 375,000 new deaths in 2015 4 5 .…”