ORTHOTOPIC XENOGRAFTS OF HUMAN PANCREATIC CARCINOMAS ACQUIRE GENETIC ABERRATIONS DURING DISSEMINATION IN NUDE-MICE

Orthotopic transplantation of human tumors in nude mice reproduces the pattern of local growth and distal dissemination, The aim of our stud y was to determine the pattern of genetic alterations in human carcino mas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice, Eight of the sixteen orthoimplanted human pancreatic car cinomas mere perpetuated through several passages. Four perpetuated tu mors followed distinct patterns of distal dissemination, Point mutatio ns in the K-ras gene, genetic aberrations in the p53 and p16 genes, an d allelic losses at retinoblastoma, adenomatous polyposis coli, and de leted in colorectal cancer loci were analyzed, Perpetuated tumors main tained the pattern of genetic alterations present in primary tumors, F ive perpetuated tumors contained K-ras mutations, and ail tumors conta ined p53 and/or p16 genetic aberrations, Allelic losses were present i n four of the perpetuated tumors. Additional genetic alterations were detected in 6 of 35 metastases analyzed, Five of 9 peritoneal metastas es or malignant ascitic cells acquired either K-ras or second p53 muta tions, In contrast, only I of 25 liver metastases and none of the lymp h node metastases acquired additional mutations, No additional p16 gen e aberrations or other allelic losses were evidenced during tumor diss emination. We conclude that orthotopically implanted pancreatic carcin omas xenografted in nude mice show a high degree of genetic stability, Mutations in K-ras and p53 genes can occur in this model system in th e more advanced stages of pancreatic tumor progression, mainly during peritoneal dissemination.