title: Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer.
abstract: OBJECTIVE
  The goal of this study was to evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts.
  
  
  METHODS
  Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells were determined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array. Patients were followed for progression and survival.
  
  
  RESULTS
  A total of 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression for patients who received treatment with gemcitabine for metastatic disease (n = 7) was double in patients with xenografts sensitive to gemcitabine.
  
  
  CONCLUSIONS
  A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate. Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways.
authors: The Sidney Kimmel Comprehensive Cancer Center and the Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Ignacio
authors: I
authors: Garrido-Laguna
authors: Maria
authors: M
authors: Uson
authors: N V
authors: NV
authors: Rajeshkumar
authors: Aik Choon
authors: AC
authors: Tan
authors: Elizabeth
authors: E
authors: de Oliveira
authors: Collins
authors: C
authors: Karikari
authors: Maria C
authors: MC
authors: Villaroel
authors: Ana
authors: A
authors: Salomon
authors: Gretchen
authors: G
authors: Taylor
authors: Rajni
authors: R
authors: Sharma
authors: Ralph H
authors: RH
authors: Hruban
authors: Anirban
authors: A
authors: Maitra
authors: Daniel
authors: D
authors: Laheru
authors: Belén
authors: B
authors: Rubio-Viqueira
authors: Antonio
authors: A
authors: Jimeno
authors: Manuel
authors: M
authors: Hidalgo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D011379:Prognosis; D051901:Smad4 Protein / Q000235:genetics*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein; D003841:Deoxycytidine; D000093542:Gemcitabine