Brown University, Department of Molecular Pharmacology, Physiology, & Biotechnology, Providence, 02912, USA.
Brown University, Department of Molecular Pharmacology, Physiology, & Biotechnology, Providence, 02912, USA; Brown University, Center for Biomedical Engineering, Providence, 02912, USA; Brown University, School of Engineering, Providence, 02912, USA.
Semin Cancer Biol. 2022 Jun;81:64-72. doi: 10.1016/j.semcancer.2021.05.014. Epub 2021 May 13.
Polyploid giant cancer cells (PGCCs) are a commonly observed histological feature of human tumors and are particularly prominent in late stage and drug resistant cancers. The chromosomal duplication conferred by their aneuploidy gives rise to DNA damage resistance and complex tumor cell karyotypes, a driving factor in chemotherapy resistance and disease relapse. Furthermore, PGCCs also exhibit key cytoskeletal features that give rise to a distinct biophysical phenotype, including increased density of polymerized actin and vimentin intermediate filaments, nuclear and cytoskeletal stiffening, increased traction force, and migratory persistence. Despite recent research highlighting the role PGCCs play in cancer progression, this population of tumor cells remains poorly characterized in terms of their biophysical properties. In this review, we will discuss the various aspects of their biomolecular phenotype, such as increased stemness as well as a mixed EMT signature. These features have been extensively associated with tumorigenesis and recurrence, and aggressive cancers. Additionally, we will also examine the distinct PGCC cytoskeletal features of actin and filamentous vimentin. Specifically, how the differential organization of these networks serve to support their increased size and drive migratory persistence. These findings could shed light on potential therapeutic strategies that allow for specific elimination or mitigation of the invasive potential of these polyploid cancer cells. Lastly, we will examine how the biophysical and molecular phenotype of PGCCs combine to tip the scale in favor of promoting cancer progression, presenting an important target in the clinical treatment of cancer.
多倍体巨癌细胞 (PGCCs) 是人类肿瘤中常见的组织学特征，尤其在晚期和耐药性癌症中更为突出。其非整倍体赋予的染色体复制导致 DNA 损伤抗性和复杂的肿瘤细胞核型，这是化疗耐药和疾病复发的驱动因素。此外，PGCC 还表现出关键的细胞骨架特征，导致独特的生物物理表型，包括聚合肌动蛋白和中间丝波形蛋白密度增加、核和细胞骨架变硬、牵引力增加以及迁移持续存在。尽管最近的研究强调了 PGCC 在癌症进展中的作用，但这些肿瘤细胞群体在其生物物理特性方面仍未得到充分描述。在这篇综述中，我们将讨论它们的生物分子表型的各个方面，例如增加的干性以及混合的 EMT 特征。这些特征与肿瘤发生和复发以及侵袭性癌症密切相关。此外，我们还将研究 PGCC 肌动蛋白和丝状波形蛋白的独特细胞骨架特征。具体来说，这些网络的不同组织如何支持它们的增大并推动迁移持续存在。这些发现可能为特定消除或减轻这些多倍体癌细胞的侵袭潜力提供潜在的治疗策略提供线索。最后，我们将研究 PGCC 的生物物理和分子表型如何结合起来，有利于促进癌症进展，为癌症的临床治疗提供一个重要的靶点。
