Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer.

Abstract

The development of pancreatic cancer in transgenic mice expressing the simian virus 40 tumor antigen placed under controlling regions of the elastase I gene is characterized by the sequential appearance of tetraploid and then multiple aneuploid cell populations. Pancreatic tissues from such transgenic mice were studied between 8 and 32 days of age. Virtually 100% of acinar cell nuclei had immunohistochemically detectable tumor antigen by 18 days. Tetraploid cells were demonstrated by DNA content flow cytometry by 20 days and were associated with the appearance of interphase cells that had 5-11 centrioles per cell in single thin sections of pancreatic tissue examined by electron microscopy. Mitotic cells also were observed that had 5 or more centrioles per cell that were incorporated into the poles of bipolar or at least tripolar spindle apparatuses. These observations indicate that formation of the tetraploid intermediate in the diploid----tetraploid----aneuploid sequence of pancreatic tumor formation in elastase-simian virus 40 tumor antigen transgenic mice is accompanied by the development of cells with 5 or more centrioles that can be incorporated into the poles of abnormal mitotic spindles. We speculate that cells with more than 4 centrioles are predisposed to the formation of multipolar mitoses that may yield daughter cells with chromosomal gains and losses, resulting in the subsequent development of aneuploid tumors.