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

Martin Zacharias, Luka Brcic, Sylvia Eidenhammer, Helmut Popper

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. Thirty 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. Markers 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. Bulk 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.