Biology and clinical significance of circulating tumor cell subpopulations in lung cancer

By identifying and tracking genetic changes in primary tumors and metastases, patients can be stratified for the most efficient therapeutic regimen by screening for known biomarkers. However, retrieving tissues biopsies is not always feasible due to tumor location or risk to patient. Therefore, a liquid biopsies approach offers an appealing solution to an otherwise invasive procedure. The rapid growth of the liquid biopsy field has been aided by improvements in the sensitivity and specificity of enrichment assays for isolating circulating tumor cells (CTCs) from normal surrounding blood cells. Furthermore, the identification and molecular characterization of CTCs has been shown in numerous studies to be of diagnostic and prognostic relevance in breast, prostate and colon cancer patients. Despite these advancements, and the highly metastatic nature of lung cancer, it remains a challenge to detect CTCs in advanced non-small cell lung cancer (NSCLC). It may be that loss of epithelial features, in favor of a mesenchymal phenotype, and the highly heterogeneous nature of NSCLC CTCs contribute to their evasion from current detection methods. By identifying a broader spectrum of biomarkers that could better differentiate the various NSCLC CTCs subpopulations, it may be possible to not only improve detection rates but also to shed light on which CTC clones are likely to drive metastatic initiation. Here we review the biology of CTCs and describe a number of proteins and genetic targets which could potentially be utilized for the dissemination of heterogenic subpopulations of CTCs in NSCLC.