Bulk tumour cell migration in lung carcinomas might be more common than epithelial-mesenchymal transition and be differently regulated

Martin Zacharias,Helmut Popper,Luka Brcic,Sylvia Eidenhammer

doi:10.1186/s12885-018-4640-y

Abstract

BackgroundEpithelial-to-mesenchymal transition (EMT) is one mechanism of carcinoma migration, while complex tumour migration or bulk migration is another - best demontrated by tumour cells invading blood vessels.MethodsThirty cases of non-small cell lung carcinomas were used for identifying genes responsible for bulk cell migration, 232 squamous cell and adenocarcinomas to identify bulk migration rates. Genes expressed differently in the primary tumour and in the invasion front were regarded as relevant in migration and further validated in 528 NSCLC cases represented on tissue microarrays (TMAs) and metastasis TMAs.ResultsMarkers relevant for bulk cancer cell migration were regulated differently when compared with EMT: Twist expressed in primary tumour, invasion front, and metastasis was not associated with TGFβ1 and canonical Wnt, as Slug, Snail, and Smads were negative and β-Catenin expressed membraneously. In the majority of tumours, E-Cadherin was downregulated at the invasive front, but not absent, but, coexpressed with N-Cadherin. Vimentin was coexpressed with cytokeratins at the invasion site in few cases, whereas fascin expression was seen in a majority. Expression of ERK1/2 was downregulated, PLCγ was only expressed at the invasive front and in metastasis. Brk and Mad, genes identified in Drosophila border cell migration, might be important for bulk migration and metastasis, together with invadipodia proteins Tks5 and Rab40B, which were only upregulated at the invasive front and in metastasis. CXCR1 was expressed equally in all carcinomas, as opposed to CXCR2 and 4, which were only expressed in few tumours.ConclusionBulk cancer cell migration seems predominant in AC and SCC. Twist, vimentin, fascin, Mad, Brk, Tsk5, Rab40B, ERK1/2 and PLCγ are associated with bulk cancer cell migration. This type of migration requires an orchestrated activation of proteins to keep the cells bound to each other and to coordinate movement. This hypothesis needs to be proven experimentally.

Highlights

Epithelial-to-mesenchymal transition (EMT) is one mechanism of carcinoma migration, while complex tumour migration or bulk migration is another - best demontrated by tumour cells invading blood vessels
We aimed to explore the frequency of bulk migration in AC and squamous cell carcinomas (SCC), to evaluate molecules which might be associated with migration, invasion, and metastasis using immunohistochemistry
As the study set had a rather small number of cases, we aimed to validate the importance of the markers in a larger cohort of Nonsmall cell carcinoma (NSCLC): tissue microarrays (TMA) were chosen which contained a total of 325 AC, 142 SCC, and 61 large cell carcinomas (LC); out of these cases, whole tissue sections from 115 cases of SCC and 117 cases of AC were randomly chosen for the evaluation of bulk and/or EMT migration (SETval)

Summary

Introduction

Epithelial-to-mesenchymal transition (EMT) is one mechanism of carcinoma migration, while complex tumour migration or bulk migration is another - best demontrated by tumour cells invading blood vessels. In EMT, as primarily described in experimental studies, the tumour cells downregulate adherence proteins, lose contact to cells, and change to a mesenchymal phenotype, often by exchanging keratin for vimentin or α-actin [1, 2]. Recent findings have challenged this view and proposed complex tumour cell migration as an alternative Some have called this hybrid EMT, and it has even been experimentally shown that cells can metastasize without changing to a mesenchymal phenotype, called the epithelial migration type [12,13,14,15]. Especially spindle cell carcinomas, often occur in the primary tumour with a mesenchymal phenotype, expressing α-actin instead of keratin They may continue doing this during metastasis, or they may revert back to an epithelial phenotype at the metastatic site

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