Charters Geoffrey A, Stones Clare J, Shelling Andrew N, Baguley Bruce C, Finlay Graeme J
Auckland Cancer Society Research Centre, The University of Auckland, New Zealand.
Cancer Genet. 2011 Sep;204(9):477-85. doi: 10.1016/j.cancergen.2011.07.001.
Correct partitioning of the replicated genome during mitosis is orchestrated by centrosomes, and chromosomal instability is a commonly reported feature of human cancer. Melanomas are notorious for their genetic instability and rapid clonal evolution that may be manifested as aggressive growth and facile generation of therapy-resistant variants. We characterized the centrosomal status, ploidy, and gene status (TP53, CDKN2A/B, BRAF, and NRAS) of 15 human metastatic melanoma cell lines. Cells were labelled for pericentrin (a centrosomal marker), DNA and α-tubulin, and scored for centrosome morphology, supernumerary centrosomes, and mitotic symmetry. The incidence of supernumerary centrosomes correlated with that of gross centrosomal abnormalities (r = 0.90), mitotic asymmetry (r = 0.90), and, surprisingly, increased content of G/M cells (r = 0.79). Centrosomal numerical dysregulation, observed in all cell lines, was found not to be specifically related to the status of any of the characterized gene mutations that were found in 13/15 cell lines. We conclude that centrosomal dysregulation may arise from multiple mechanisms and may drive the generation of genetic and phenotypic diversity in melanoma.
有丝分裂过程中复制基因组的正确分配由中心体精心安排，而染色体不稳定性是人类癌症常见的特征。黑色素瘤以其遗传不稳定性和快速克隆进化而臭名昭著，这可能表现为侵袭性生长和容易产生抗治疗变体。我们对15个人类转移性黑色素瘤细胞系的中心体状态、倍性和基因状态（TP53、CDKN2A/B、BRAF和NRAS）进行了表征。细胞用中心体蛋白（一种中心体标记物）、DNA和α-微管蛋白进行标记，并对中心体形态、多余中心体和有丝分裂对称性进行评分。多余中心体的发生率与总体中心体异常的发生率（r = 0.90）、有丝分裂不对称性（r = 0.90）相关，令人惊讶的是，还与G/M期细胞含量增加相关（r = 0.79）。在所有细胞系中观察到的中心体数量失调与13/15个细胞系中发现的任何特征基因突变状态均无特异性关联。我们得出结论，中心体失调可能源于多种机制，并可能推动黑色素瘤中遗传和表型多样性的产生。
