Stepwise progression of centrosome defects associated with local tumor growth and metastatic process of human pancreatic carcinoma cells transplanted orthotopically into nude mice
Stepwise progression of centrosome defects associated with local tumor growth and metastatic process of human pancreatic carcinoma cells transplanted orthotopically into nude mice
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DOI：
10.1038/labinvest.3780306
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发表时间：
2001-07-01
影响因子：
5
通讯作者：
Tanaka, M
中科院分区：
文献类型：
--
作者：
Shono, M;Sato, N;Tanaka, M
最近的证据表明，中心体完整性的丧失可能是导致各种人类癌症的遗传不稳定性的主要原因。本研究的目的是使用原位移植模型来确定中心体缺陷在胰腺癌体内肿瘤进展过程中的作用。将Suit-2人胰腺癌细胞注射到裸鼠的胰腺中再现了在人类中观察到的局部肿瘤生长和远处转移的模式。收集胰腺异种移植物、腹膜播散和肝转移瘤，并通过免疫荧光显微镜检查肿瘤细胞的中心体。中心体异常，其特征是中心体数量增加，仅在培养的一小部分亲本Suit-2细胞中检测到，而在从胰腺异种移植物分离的细胞中频率显著增加。中心体数目异常在转移灶中的发生率高于胰腺异种移植物。具有多个中心体的细胞比例与具有多极有丝分裂纺锤体的细胞比例之间存在显著正相关，表明异常中心体在纺锤体解体和染色体错误分离中具有功能性参与。此外，异常中心体的频率增加与染色体不稳定性的程度增强有关。这些发现表明胰腺肿瘤进展的一种新模型，即中心体异常程度的逐步增加赋予异常有丝分裂事件增加的机会，从而加速遗传不稳定性并导致肿瘤进展到更晚期。
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.