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Chemoresistant colorectal cancer cells and cancer stem cells mediate growth and survival of bystander cells.

Bose D, Zimmerman LJ, Pierobon M, Petricoin E, Tozzi F, Parikh A, Fan F, Dallas N, Xia L, Gaur P, Samuel S, Liebler DC, Ellis LM
Br J Cancer. 2011 105 (11): 1759-67

PMID: 22045189 · PMCID: PMC3242606 · DOI:10.1038/bjc.2011.449

BACKGROUND - Recent studies suggest that cancer stem cells (CSCs) mediate chemoresistance, but interestingly, only a small percentage of cells in a resistant tumour are CSCs; this suggests that non-CSCs survive by other means. We hypothesised that chemoresistant colorectal cancer (CRC) cells generate soluble factors that enhance survival of chemonaive tumour cells.

METHODS - Chemoresistant CRC cells were generated by serial passage in oxaliplatin (Ox cells). Conditioned media (CM) was collected from parental and oxaliplatin-resistant (OxR) cells. CRC cells were treated with CM and growth and survival were assessed. Tumour growth rates were determined in nude mice after cells were treated with CM. Mass spectrometry (MS) identified proteins in CM. Reverse phase protein microarray assays determined signalling effects of CM in parental cells.

RESULTS - Oxaliplatin-resistant CM increased survival of chemo-naive cells. CSC CM also increased growth of parental cells. Parental and OxR mixed tumours grew larger than tumours composed of parental or OxR cells alone. Mass spectrometry detected unique survival-promoting factors in OxR CM compared with parental CM. Cells treated with OxR CM demonstrated early phosphorylation of EGFR and MEK1, with later upregulation of total Akt .We identified progranulin as a potential mediator of chemoresistance.

CONCLUSION - Chemoresistant tumour cells and CSCs may promote resistance through soluble factors that mediate survival in otherwise chemosensitive tumour cells.

MeSH Terms (27)

Animals Antineoplastic Agents Bystander Effect Cell Line, Tumor Cell Survival Colorectal Neoplasms Culture Media Drug Resistance, Neoplasm ErbB Receptors HCT116 Cells HT29 Cells Humans Intercellular Signaling Peptides and Proteins Male MAP Kinase Kinase 1 Mass Spectrometry Mice Mice, Nude Microarray Analysis Neoplastic Stem Cells Organoplatinum Compounds Oxaliplatin Phosphorylation Progranulins Proto-Oncogene Proteins c-akt Signal Transduction Up-Regulation

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