Despite the fact that the majority of cancer patients succumb to metastatic disease, most aspects of tumor metastasis are not understood in detail at present. Cell biologic steps of dissemination are dififcult to characterize in human tumors and research is in large part conifned to cell line and experimental animal studies. Epithelial-mesenchymal transition (EMT), intravasation of malignant cells, dissemination as circulating tumor cells (CTCs) and eventually mesenchymal-epithelial transition (MET) at distal sites are steps believed to be involved in metastasis. Small cell lung cancer (SCLC) is distinguished by early dissemination and excessive numbers of CTCs, which allowed for theex vivo expansion of six permanent CTC lines taken from relapsed patients. Cells exhibit an epithelial phenotype with partial EMT traits and are chemoresistant due to formation of large tumorospheres. Since cells may have invaded without undergoing EMT, the role of MET is uncertain. These SCLC CTC cell lines seem to represent the metastasis-inducing cancer cells; these are the minute subpopulation of CTCs capable of surviving in the circulation and transitioning to metastases, leading in turn to resistance and failure of therapy. Full characterization of these lines is expected to provide the markers to ifnd the relevant CTCs among the highly heterogeneous population observable in the context of tumor recurrence.
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