Centrosome amplification arises before neoplasia and increases upon p53 loss in tumorigenesis

Centrosome abnormalities are a typical hallmark of human cancers. However, the origin and dynamics of such abnormalities in human cancer are not known. In this study, we examined centrosomes in Barrett's esophagus tumorigenesis, a well-characterized multistep pathway of progression, from the pr...

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Published in:	The Journal of cell biology 2018-07, Vol.217 (7), p.2353-2363
Main Authors:	Lopes, Carla A M, Mesquita, Marta, Cunha, Ana Isabel, Cardoso, Joana, Carapeta, Sara, Laranjeira, Cátia, Pinto, António E, Pereira-Leal, José B, Dias-Pereira, António, Bettencourt-Dias, Mónica, Chaves, Paula
Format:	Article
Language:	eng
Subjects:	Abnormalities Adenocarcinoma Adenocarcinoma - genetics Adenocarcinoma - metabolism Adenocarcinoma - pathology Amplification Barrett Esophagus - genetics Barrett Esophagus - metabolism Barrett Esophagus - pathology Cancer Carcinogenesis - genetics Cell Line, Tumor Centrosome - metabolism Centrosome - pathology Centrosomes Dysplasia Esophagus Female Gene amplification Gene Expression Regulation, Neoplastic Humans Male Metastases Metastasis Mutation Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology p53 Protein Single-Cell Analysis Transformation Tumor suppressor genes Tumor Suppressor Protein p53 - genetics Tumorigenesis Tumors
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Summary:	Centrosome abnormalities are a typical hallmark of human cancers. However, the origin and dynamics of such abnormalities in human cancer are not known. In this study, we examined centrosomes in Barrett's esophagus tumorigenesis, a well-characterized multistep pathway of progression, from the premalignant condition to the metastatic disease. This human cancer model allows the study of sequential steps of progression within the same patient and has representative cell lines from all stages of disease. Remarkably, centrosome amplification was detected as early as the premalignant condition and was significantly expanded in dysplasia. It was then present throughout malignant transformation both in adenocarcinoma and metastasis. The early expansion of centrosome amplification correlated with and was dependent on loss of function of the tumor suppressor p53 both through loss of wild-type expression and hotspot mutations. Our work shows that centrosome amplification in human tumorigenesis can occur before transformation, being repressed by p53. These findings suggest centrosome amplification in humans can contribute to tumor initiation and progression.
ISSN:	0021-9525 1540-8140