Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.
Cell Stress Chaperones. 2012 Nov;17(6):765-78. doi: 10.1007/s12192-012-0349-z. Epub 2012 Jul 13.
Current cancer therapies including cytotoxic chemotherapy, radiation and hyperthermic therapy induce acute proteotoxic stress in tumour cells. A major challenge to cancer therapeutic efficacy is the recurrence of therapy-resistant tumours and how to overcome their emergence. The current study examines the concept that tumour cell exposure to acute proteotoxic stress results in the acquisition of a more advanced and aggressive cancer cell phenotype. Specifically, we determined whether heat stress resulted in an epithelial-to-mesenchymal transition (EMT) and/or the enhancement of cell migration, components of an advanced and therapeutically resistant cancer phenotype. We identified that heat stress enhanced cell migration in both the lung A549, and breast MDA-MB-468 human adenocarcinoma cell lines, with A549 cells also undergoing a partial EMT. Moreover, in an in vivo model of thermally ablated liver metastases of the mouse colorectal MoCR cell line, immunohistological analysis of classical EMT markers demonstrated a shift to a more mesenchymal phenotype in the surviving tumour fraction, further demonstrating that thermal stress can induce epithelial plasticity. To identify a mechanism by which thermal stress modulates epithelial plasticity, we examined whether the major transcriptional regulator of the heat shock response, heat shock factor 1 (HSF1), was a required component. Knockdown of HSF1 in the A549 model did not prevent the associated morphological changes or enhanced migratory profile of heat stressed cells. Therefore, this study provides evidence that heat stress significantly impacts upon cancer cell epithelial plasticity and the migratory phenotype independent of HSF1. These findings further our understanding of novel biological downstream effects of heat stress and their potential independence from the classical heat shock pathway.
目前的癌症治疗方法包括细胞毒性化疗、放疗和热疗，都会在肿瘤细胞中引起急性蛋白毒性应激。癌症治疗效果的一个主要挑战是治疗耐药肿瘤的复发，以及如何克服它们的出现。本研究探讨了肿瘤细胞暴露于急性蛋白毒性应激会导致获得更先进和侵袭性的癌细胞表型的概念。具体来说，我们确定了热应激是否会导致上皮-间充质转化（EMT）和/或增强细胞迁移，这是一种先进的、治疗耐药的癌症表型的组成部分。我们发现，热应激增强了肺 A549 和乳腺 MDA-MB-468 人腺癌细胞系中的细胞迁移，A549 细胞也经历了部分 EMT。此外，在小鼠结直肠 MoCR 细胞系热消融肝转移的体内模型中，对经典 EMT 标志物的免疫组织化学分析表明，存活肿瘤部分向更间质表型转移，进一步表明热应激可诱导上皮可塑性。为了确定热应激调节上皮可塑性的机制，我们研究了热休克反应的主要转录调节剂热休克因子 1（HSF1）是否是必需的组成部分。在 A549 模型中敲低 HSF1 并不能阻止热应激细胞相关的形态变化或增强的迁移表型。因此，本研究提供了证据表明，热应激显著影响癌细胞上皮可塑性和迁移表型，而不依赖于 HSF1。这些发现进一步加深了我们对热应激的新型生物学下游效应及其与经典热休克途径的潜在独立性的理解。
