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J Cell Biol. 2018 Jul 2;217(7):2353-2363. doi: 10.1083/jcb.201711191. Epub 2018 May 8.

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

Author information

1
Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal lopes.carla.am@gmail.com.
2
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
3
Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal.
4
Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal.
5
Ophiomics-Precision Medicine, Lisbon, Portugal.
6
Instituto Gulbenkian de Ciência, Oeiras, Portugal mdias@igc.gulbenkian.pt.
7
Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal pchaves@ipolisboa.min-saude.pt.

Abstract

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.

PMID:
29739803
PMCID:
PMC6028540
DOI:
10.1083/jcb.201711191
[Indexed for MEDLINE]
Free PMC Article

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