title: Circulating tumor cells as a window on metastasis biology in lung cancer.
abstract: Circulating tumor cell (CTC) number in metastatic cancer patients yields prognostic information consistent with enhanced cell migration and invasion via loss of adhesion, a feature of epithelial-to-mesenchymal transition (EMT). Tumor cells also invade via collective migration with maintained cell-cell contacts and consistent with this is the circulating tumor microemboli (CTM; contiguous groups of tumor cells) that are observed in metastatic cancer patients. Using a blood filtration approach, we examined markers of EMT (cytokeratins, E-cadherin, vimentin, neural cadherin) and prevalence of apoptosis in CTCs and CTM to explore likely mechanism(s) of invasion in lung cancer patients and address the hypothesis that cells within CTM have a survival advantage. Intra-patient and inter-patient heterogeneity was observed for EMT markers in CTCs and CTM. Vimentin was only expressed in some CTCs, but in the majority of cells within CTM; E-cadherin expression was lost, cytoplasmic or nuclear, and rarely expressed at the surface of the cells within CTM. A subpopulation of CTCs was apoptotic, but apoptosis was absent within CTM. This pilot study suggests that EMT is not prosecuted homogeneously in tumor cells within the circulation of lung cancer patients and that collective migration and enhanced survival of cells within CTM might contribute to lung cancer metastasis. Multiplex analysis and further detailed exploration of metastatic potential and EMT in CTCs/CTM is now warranted in a larger patient cohort.
authors.affiliation: Clinical and Experimental Pharmacology Group, University of Manchester, Manchester, United Kingdom.
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Hou
authors.forename: Matthew
authors.initials: M
authors.lastname: Krebs
authors.forename: Tim
authors.initials: T
authors.lastname: Ward
authors.forename: Robert
authors.initials: R
authors.lastname: Sloane
authors.forename: Lynsey
authors.initials: L
authors.lastname: Priest
authors.forename: Andrew
authors.initials: A
authors.lastname: Hughes
authors.forename: Glen
authors.initials: G
authors.lastname: Clack
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002470:Cell Survival; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor