An orthotopic nude mouse model for evaluating pathophysiology and therapy of pancreatic cancer.

Abstract

Orthotopic, clinically relevant animal models are necessary for the study of pathophysiology and therapy for pancreatic cancer. To develop a minimally traumatic technique of orthotopic tumor induction, to develop a scoring system to quantify local and systemic tumor spread, and to provide a model with a broad range of well-differentiated to undifferentiated pancreatic cancers. Orthotopic tumors were induced in nude mice by atraumatic pancreatic implantation of two fragments from subcutaneous donor tumors or intrapancreatic injection of human tumor cells (MIAPaCa-2, AsPC-1, HPAF-2, Capan-1). Animals were monitored for 14 weeks or until death. Primary tumor volume, local infiltration, and systemic metastasis were assessed and analyzed at autopsy. Macroscopic findings were confirmed by histologic evaluation. Tumor take rate in the implantation group was 100% for all four cell lines. Marked differences with regard to tumor size, metastatic spread, and survival were found depending on the grade of differentiation. Less differentiated cells (MIAPaCa-2, AsPC-1) caused higher dissemination scores and mortality than better-differentiated cells (HPAF-2, Capan-1). Clinical features included cachexia, jaundice, and malignant ascites. Orthotopic tumor cell injection resulted in an incomplete tumor take rate. Moreover, early artificial abdominal tumor spread was found in injected animals due to microscopic cell loss during the injection procedure. Orthotopic implantation of donor tumor fragments into nude mice is technically feasible and is superior to the cell injection technique. It results in reproducible local and systemic development of pancreatic cancer that mimics the human disease. A dissemination score may help to better quantify therapeutic effects in future studies.