Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030-3101, USA.
J Cell Sci. 2011 Apr 1;124(Pt 7):1007-16. doi: 10.1242/jcs.081406.
Mitotic spindle orientation can influence tissue organization and vice versa. Cells orient their spindles by rotating them parallel or perpendicular to the cell--and hence the tissue--axis. Spindle orientation in turn controls the placement of daughter cells within a tissue, influencing tissue morphology. Recent findings implicating tumor suppressor proteins in spindle orientation bring to the forefront a connection between spindle misorientation and cancer. In this Commentary, we focus on the role of three major human tumor suppressors--adenomatous polyposis coli (APC), E-cadherin and von Hippel-Lindau (VHL)--in spindle orientation. We discuss how, in addition to their better-known functions, these proteins affect microtubule stability and cell polarity, and how their loss of function causes spindles to become misoriented. We also consider how other cancer-associated features, such as oncogene mutations, centrosome amplification and the tumor microenvironment, might influence spindle orientation. Finally, we speculate on the role of spindle misorientation in cancer development and progression. We conclude that spindle misorientation alone is unlikely to be tumorigenic, but it has the potential to synergize with cancer-associated changes to facilitate genomic instability, tissue disorganization, metastasis and expansion of cancer stem cell compartments.
有丝分裂纺锤体的取向可以影响组织的结构，反之亦然。细胞通过将其平行或垂直于细胞——进而垂直于组织——轴旋转来调整纺锤体的方向。纺锤体的取向反过来控制了子细胞在组织中的位置，从而影响组织形态。最近的研究发现，肿瘤抑制蛋白参与纺锤体的定向，这将纺锤体定向错误与癌症之间的联系摆在了突出的位置。在这篇评论中，我们重点关注三种主要的人类肿瘤抑制蛋白——腺瘤性结肠息肉病（APC）、E-钙黏蛋白和von Hippel-Lindau（VHL）——在纺锤体定向中的作用。我们讨论了这些蛋白除了其更为人所知的功能外，如何影响微管稳定性和细胞极性，以及它们的功能丧失如何导致纺锤体定向错误。我们还考虑了其他与癌症相关的特征，如癌基因突变、中心体扩增和肿瘤微环境，如何影响纺锤体的定向。最后，我们推测纺锤体定向错误在癌症发展和进展中的作用。我们的结论是，纺锤体定向错误本身不太可能致癌，但它有可能与癌症相关的变化协同作用，促进基因组不稳定性、组织紊乱、转移和癌症干细胞区室的扩张。
