Tumor engraftment in nude mice and enrichment in stroma-related gene pathways predicts poor survival and resistance to gemcitabine in patients with pancreatic cancer
Menée sur 94 patients atteints d'un adénocarcinome canalaire du pancréas, cette étude montre que le taux d'enrichissement en cellules tumorales de xénogreffes dans la souris nue est associé à un pronostic défavorable et à une résistance à la gemcitabine
Purpose: 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. Experimental Design: 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 (IHC). Gene expression was performed using U133 Plus 2.0 array. Patients were followed for progression and survival. Results: 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, 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 progression for patients who received treatment with gemcitabine for metastatic disease (n=7) was double in patients with xenografts sensitive to gemcitabine. Conclusion: 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.
Clinical Cancer Research , résumé, 2011