T-cadherin loss promotes experimental metastasis of squamous cell carcinoma.

Abstract

T-cadherin is gaining recognition as a determinant for the development of incipient invasive squamous cell carcinoma (SCC). However, effects of T-cadherin expression on the metastatic potential of SCC have not been studied. Here, using a murine model of experimental metastasis following tail vein injection of A431 SCC cells we report that loss of T-cadherin increased both the incidence and rate of appearance of lung metastases. T-cadherin-silenced SCC metastases were highly disordered with evidence of single cell dissemination away from main foci whereas SCC metastases overexpressing T-cadherin developed as compact, tightly organised sheets. SCC cell adhesion to vascular endothelial cells (EC) in culture was increased for T-cadherin-silenced SCC and decreased for T-cadherin-overexpressing SCC. Confocal microscopy showed that T-cadherin-silenced SCC adherent on EC display an elongated morphology with long thin extensions and a high degree of intercalation within the EC monolayer, whereas SCC overexpressing T-cadherin formed poorly-spread multicellular aggregates that remain on the outer surface of the EC monolayer. T-cadherin-deficient SCC or human keratinocyte cells exhibited increased transendothelial migration in vitro which could be attenuated in the presence of EGFR inhibitor gefitinib. Our data suggest that loss of T-cadherin can increase metastatic potential and aggressiveness of SCC, possibly due to facilitating arrest and extravasation through the vascular wall and/or more efficient establishment of metastases in the new microenvironment.

• Authors: Maria Philippova, Dennis Pfaff, Emmanouil Kyriakakis, Stanislaw A Buechner, Giandomenica Iezzi, Giulio C Spagnoli, Andreas W Schoenenberger, Paul Erne, Therese J Resink
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 49 Issue 8 Pg. 2048-58 (May 2013) ISSN: 1879-0852 [Electronic] England
• PMID: 23369463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Cadherins
• H-cadherin
• Protein Kinase Inhibitors
• Quinazolines
• ErbB Receptors
• Gefitinib

Topics

• Animals
• Cadherins (genetics, metabolism)
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Adhesion (genetics)
• Cell Line, Tumor
• Cells, Cultured
• Coculture Techniques
• Endothelial Cells (cytology, metabolism)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Gefitinib
• Human Umbilical Vein Endothelial Cells (cytology, metabolism)
• Humans
• Immunoblotting
• Keratinocytes (cytology, metabolism)
• Lung Neoplasms (genetics, metabolism, secondary)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Microscopy, Confocal
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• RNA Interference
• Skin Neoplasms (genetics, metabolism, pathology)
• Transendothelial and Transepithelial Migration (drug effects, genetics)
• Transplantation, Heterologous