Stepwise Progression of Centrosome Defects Associated with Local Tumor Growth and Metastatic Process of Human Pancreatic Carcinoma Cells Transplanted Orthotopically into Nude Mice

• Published in: Laboratory investigation 2001-07, Vol.81 (7), p.945-952
• Main Authors: Shono, Masaki, Sato, Norihiro, Mizumoto, Kazuhiro, Maehara, Naoki, Nakamura, Masafumi, Nagai, Eishi, Tanaka, Masao
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Cell Division; Centrosome; Experimental digestive system and abdominal tumors; Gastroenterology. Liver. Pancreas. Abdomen; Humans; In Situ Hybridization, Fluorescence; Laboratory Medicine; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Fluorescence; Neoplasm Metastasis; Neoplasm Transplantation; Pancreatic Neoplasms - pathology; Pathology; Spindle Apparatus; Tumor Cells, Cultured; Tumors
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.3780306

Recent evidence indicates that loss of centrosome integrity may be a major cause of genetic instability underlying various human cancers. The aim of this study was to define the role of centrosome defects during the in vivo tumor progression of pancreatic carcinoma using an orthotopic implantation model. Injection of Suit-2 human pancreatic cancer cells into the pancreata of nude mice reproduced the pattern of local tumor growth and distant metastasis observed in humans. Pancreatic xenografts, peritoneal disseminations, and hepatic metastases were harvested, and tumor cells were examined for centrosomes by immunofluorescence microscopy. Centrosome abnormalities, characterized by increased numbers of centrosomes, were detected in only a small fraction of parental Suit-2 cells in culture, whereas the frequency was markedly increased in cells isolated from the pancreatic xenografts. Abnormal centrosome numbers were found at higher frequencies in metastatic foci than in pancreatic xenografts. A significant positive correlation existed between the fraction of cells with multiple centrosomes and that with multipolar mitotic spindles, suggesting a functional involvement of aberrant centrosomes in spindle disorganization and chromosome missegregation. In addition, the increased frequency of abnormal centrosomes was associated with an enhanced degree of chromosomal instability. These findings suggest a novel model of pancreatic tumor progression whereby a stepwise increase in the magnitude of centrosomal abnormalities confers an increased chance for aberrant mitotic events, thus accelerating genetic instability and causing the tumor to progress to a more advanced stage.