Tumor Engraftment in Nude Mice and Enrichment in Stroma-Related Gene Pathways Predict Poor Survival and Resistance to Gemcitabine in Patients with Pancreatic Cancer

• Published in: Clinical cancer research 2011-09, Vol.17 (17), p.5793-5800
• Main Authors: GARRIDO-LAGUNA, Ignacio, USON, Maria, HRUBAN, Ralph H, MAITRA, Anirban, LAHERU, Daniel, RUBIO-VIQUEIRA, Belén, JIMENO, Antonio, HIDALGO, Manuel, RAJESHKUMAR, N. V, AIK CHOON TAN, DE OLIVEIRA, Elizabeth, KARIKARI, Collins, VILLAROEL, Maria C, SALOMON, Ana, TAYLOR, Gretchen, SHARMA, Rajni
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - mortality; Carcinoma, Pancreatic Ductal - surgery; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Drug Resistance, Neoplasm - genetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - surgery; Pharmacology. Drug treatments; Prognosis; Smad4 Protein - genetics; Transplantation, Heterologous; Treatment Outcome; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-0341

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. 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. 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. 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.