Protection of small-cell lung cancer circulating tumor cells by cellular fragmentation

Aim: Small-cell lung cancer (SCLC) disseminates aggressively and may exhibit high chemoresistance and poor survival rates. In this study, we aimed to investigate a new mechanism of drug resistance for SCLC circulating tumor cells (CTCs). Methods: SCLC CTC cell lines ( n = 4) which shed cellular fragments (MAT), as demonstrated by light and scanning electron microscopy, are compared to permanent SCLC lines. Selected proteins are detected by proteome arrays and the functional impact of MAT is studied using cytotoxicity tests involving cisplatin and Topotecan. Results: The SCLC CTC lines revealed layers of attached cellular fragments with a range of decreasing sizes from intact cells (approximately 12 mu m) down to small debris (approximately 2 mu m) which are not detectable in permanent SCLC lines. Intact SCLC CTC clusters represent cores of these fragment-coated spheroids. Proteome profiling of MAT revealed a protein pattern similar to intact cells. Chemosensitivity tests employing SCLC and SCLC CTC lines with chemotherapeutics used in therapy of SCLC demonstrated an inhibitory activity of MAT on the resulting cytotoxicity. Conclusion: Generation of cell-associated debris by SCLC CTCs offers protective effects against cytotoxic drugs, representing a novel mechanism allowing survival of SCLC CTCs in patients.