title: Chemoresistant colorectal cancer cells and cancer stem cells mediate growth and survival of bystander cells.
abstract: 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.
  
  
  CONCLUSIONS
  Chemoresistant tumour cells and CSCs may promote resistance through soluble factors that mediate survival in otherwise chemosensitive tumour cells.
authors: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA.
authors: D
authors: D
authors: Bose
authors: L J
authors: LJ
authors: Zimmerman
authors: M
authors: M
authors: Pierobon
authors: E
authors: E
authors: Petricoin
authors: F
authors: F
authors: Tozzi
authors: A
authors: A
authors: Parikh
authors: F
authors: F
authors: Fan
authors: N
authors: N
authors: Dallas
authors: L
authors: L
authors: Xia
authors: P
authors: P
authors: Gaur
authors: S
authors: S
authors: Samuel
authors: D C
authors: DC
authors: Liebler
authors: L M
authors: LM
authors: Ellis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D024201:Bystander Effect / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003470:Culture Media; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis / Q000379:methods; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation; D000077153:Progranulins; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D003470:Culture Media; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009944:Organoplatinum Compounds; D000077153:Progranulins; D000077150:Oxaliplatin; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human