Calderwood Stuart K, Ciocca Daniel R
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Int J Hyperthermia. 2008 Feb;24(1):31-9. doi: 10.1080/02656730701858305.
Heat shock proteins (HSPs) were first identified as stress proteins that confer resistance to physical stresses such as elevated temperatures in all cellular organisms. HSPs are rapidly elevated after stress and confer a temperature resistant phenotype. Temperature resistance is dependent on the ability of HSPs to function as molecular chaperones and prevent aggregation and on the capacity of Hsp27 and Hsp70 to act as wide spectrum inhibitors of the cell death pathways. HSP expression becomes deregulated in cancer leading to elevated expression. Elevated HSP expression promotes cancer by inhibiting programmed cell death (Hsp27, Hsp70) and by promoting autonomous growth (Hsp90) and leads to resistance to chemotherapy and hyperthermia. Tumor HSPs have another property that can be exploited in therapy. They are immunogenic and can be used to form the basis of anticancer vaccines. Elevation in HSP levels may thus have competing effects in tumor growth, being required for tumor cell survival but conferring a hazard for cancer cells due to their immunogenic properties. This dichotomy is also reflected by the approaches used to target HSP in therapy. Pharmacological approaches are being employed to inhibit activity or expression of tumor HSP. Immunological approaches aim at increasing HSP levels in cells and tissues with the aim of increasing tumor antigen presentation to the immune system.
热休克蛋白（HSPs）最初被鉴定为应激蛋白，在所有细胞生物体中赋予对诸如高温等物理应激的抗性。应激后热休克蛋白迅速升高，并赋予耐热表型。耐热性取决于热休克蛋白作为分子伴侣发挥功能并防止聚集的能力，以及热休克蛋白27（Hsp27）和热休克蛋白70（Hsp70）作为细胞死亡途径广谱抑制剂的能力。在癌症中，热休克蛋白的表达失调导致其表达升高。热休克蛋白表达升高通过抑制程序性细胞死亡（Hsp27、Hsp70）和促进自主生长（Hsp90）来促进癌症发展，并导致对化疗和热疗产生抗性。肿瘤热休克蛋白具有另一种可用于治疗的特性。它们具有免疫原性，可用于形成抗癌疫苗的基础。因此，热休克蛋白水平升高在肿瘤生长中可能具有相互矛盾的作用，既是肿瘤细胞存活所必需的，但由于其免疫原性特性又给癌细胞带来风险。这种二分法也反映在治疗中针对热休克蛋白所采用的方法上。正在采用药理学方法来抑制肿瘤热休克蛋白的活性或表达。免疫学方法旨在提高细胞和组织中的热休克蛋白水平，以增加肿瘤抗原向免疫系统的呈递。
