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



To 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.



Analysis 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.



We describe the first observation of an inhibitory role for Activin A in ESCC progression that is dependent on the expression of ACVRIB.
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
Holli A
HA
Loomans
Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.|Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Shanna A
SA
Arnold
Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Laura L
LL
Quast
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra Drive, Building 20, BMS 223, Orlando, FL, 32816, USA. claudia.andl@ucf.edu.
Claudia D
CD
Andl
D030201:Activin Receptors, Type I / Q000378:metabolism*; D028341:Activins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004938:Esophageal Neoplasms / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015398:Signal Transduction; D046888:Tissue Array Analysis / Q000379:methods*
D016326:Extracellular Matrix Proteins; C422405:activin A; D028341:Activins; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I
Angiogenesis; Cell signaling; Dysplasia; Esophageal cell invasion; Fibronectin; Podoplanin