Endocanalicular transendothelial crossing (ETC): a novel intravasation mode used by HEK-EBNA293-VEGF-D cells during the metastatic process in a xenograft model

Armando, F. et al. (2020) Endocanalicular transendothelial crossing (ETC): a novel intravasation mode used by HEK-EBNA293-VEGF-D cells during the metastatic process in a xenograft model. PLoS ONE, 15(10), e0239932. (doi: 10.1371/journal.pone.0239932) (PMID:33085676) (PMCID:PMC7577447)

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Abstract

In cancer metastasis, intravasation of the invasive tumor cell (TCi) represents one of the most relevant events. During the last years, models regarding cancer cell intravasation have been proposed, such as the “endocanalicular transendothelial crossing” (ETC) theory. This theory describes the interplay between two adjacent endothelial cells and the TCi or a leukocyte during intravasation. Two endothelial cells create a channel with their cell membranes, in which the cell fits in without involving endothelial cell intercellular junctions, reaching the lumen through a transendothelial passage. In the present study, ten SCID mice were subcutaneously xenotransplanted with the HEK-EBNA293-VEGF-D cell line and euthanized after 35 days. Post-mortem examinations were performed and proper specimens from tumors were collected. Routine histology and immunohistochemistry for Ki-67, pAKT, pERK, ZEB-1, TWIST-1, F-actin, E-cadherin and LYVE-1 were performed followed by ultrastructural serial sections analysis. A novel experimental approach involving Computed Tomography (CT) combined with 3D digital model reconstruction was employed. The analysis of activated transcription factors supports that tumor cells at the periphery potentially underwent an epithelial-to-mesenchymal transition (EMT)-like process. Topographical analysis of LYVE-1 immunolabeled lymphatics revealed a peritumoral localisation. TEM investigations of the lymphatic vessels combined with 3D digital modelling enhanced the understanding of the endotheliocytes behavior during TCi intravasation, clarifying the ETC theory. Serial ultrastructural analysis performed within tumor periphery revealed numerous cells during the ETC process. Furthermore, this study demonstrates that ETC is an intravasation mode more frequently used by the TCi than by leukocytes during intravasation in the HEK-EBNA293-VEGF-D xenograft model and lays down the potential basis for promising future studies regarding intravasation blocking therapy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cameron, Professor Ewan
Creator Roles:
Cameron, E. R.Investigation, Supervision, Writing – review and editing
Authors: Armando, F., Ferrari, L., Arcari, M. L., Azzali, G., Dallatana, D., Ferrari, M., Lombardi, G., Zanfabro, M., Di Lecce, R., Lunghi, P., Cameron, E. R., Cantoni, A. M., and Corradi, A.
College/School:College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2020 Armando et al.
First Published:First published in PLoS ONE 15(10): e0239932
Publisher Policy:Reproduced under a Creative Commons License

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