文章：

死亡与抗死亡：肿瘤对细胞凋亡的抵抗

Death and anti-death: tumour resistance to apoptosis

原文发布日期：2002-04-01

DOI: 10.1038/nrc776

类型: Review Article

开放获取: 否

要点：

1. Apoptosis is a multi-step, multi-pathway cell-death programme that is inherent in every cell of the body. In cancer, the apoptosis:cell-division ratio is altered, which results in a net gain of malignant tissue.
2. Apoptosis can be initiated either through the death-receptor or the mitochondrial pathway. Caspases that cleave cellular substrates leading to characteristic biochemical and morphological changes are activated in both pathways. The apoptotic process is tightly controlled by various proteins. There are also other caspase-independent types of cell death.
3. Many physiological growth-control mechanisms that govern cell proliferation and tissue homeostasis are linked to apoptosis. Therefore, resistance of tumour cells to apoptosis might be an essential feature of cancer development.
4. Immune cells (T cells and natural killer cells) can kill tumour cells using the granule exocytosis pathway or the death-receptor pathway. Apoptosis resistance of tumour cells might lead to escape from immunosurveillance and might influence the efficacy of immunotherapy.
5. Cancer treatment by chemotherapy and γ-irradiation kills target cells primarily by inducing apoptosis. Therefore, modulation of the key elements of apoptosis signalling directly influences therapy-induced tumour-cell death.
6. Tumour cells can acquire resistance to apoptosis by the expression of anti-apoptotic proteins or by the downregulation or mutation of pro-apoptotic proteins.
7. Alterations of the p53 pathway also influence the sensitivity of tumour cells to apoptosis. Moreover, most tumours are independent of survival signals because they have upregulated the phosphatidylinositol 3-kinase (PI3K)/AKT pathway.
8. The present aim of research in this area is to understand further the molecular mechanisms of tumour resistance and sensitivity, and to use this insight to resensitize tumour cells to apoptosis and, accordingly, to tumour therapy.

要点翻译：

1. 细胞凋亡是机体所有细胞固有的一种多步骤、多通路的细胞死亡程序。在癌症中，凋亡与细胞分裂的比例发生改变，导致恶性组织出现净增长。
2. 细胞凋亡可通过死亡受体途径或线粒体途径启动。这两种途径都会激活可切割细胞底物的半胱天冬酶（Caspases），引发特征性生化与形态学改变。该过程受到多种蛋白质的精密调控，同时还存在其他不依赖半胱天冬酶的细胞死亡方式。
3. 众多调控细胞增殖和组织稳态的生理性生长控制机制都与凋亡密切相关。因此，肿瘤细胞对凋亡的抵抗可能是癌症发生的重要特征。
4. 免疫细胞（T细胞和自然杀伤细胞）可通过颗粒胞吐途径或死亡受体途径杀伤肿瘤细胞。肿瘤细胞的凋亡抵抗可能导致其逃避免疫监视，并影响免疫疗法的疗效。
5. 化疗和γ射线放疗主要通过诱导凋亡来杀死靶向肿瘤细胞。因此，对凋亡信号通路关键元件的调控直接影响治疗诱导的肿瘤细胞死亡。
6. 肿瘤细胞可通过表达抗凋亡蛋白，或下调/突变促凋亡蛋白来获得凋亡抗性。
7. p53通路的改变也会影响肿瘤细胞对凋亡的敏感性。此外，由于上调了磷脂酰肌醇3-激酶（PI3K）/AKT通路，大多数肿瘤细胞不再依赖生存信号。
8. 该领域当前的研究目标是进一步理解肿瘤耐药性和敏感性的分子机制，并利用这些发现使肿瘤细胞重新对凋亡敏感，从而提升肿瘤治疗效果。

英文摘要：

Every cell in a multicellular organism has the potential to die by apoptosis, but tumour cells often have faulty apoptotic pathways. These defects not only increase tumour mass, but also render the tumour resistant to therapy. So, what are the molecular mechanisms of tumour resistance to apoptosis and how can we use this knowledge to resensitize tumour cells to cancer therapy?

摘要翻译： 

多细胞生物的每一个细胞都可能通过凋亡而死亡，但肿瘤细胞的凋亡通路常常存在缺陷。这些缺陷不仅促进肿瘤体积增大，还使肿瘤对治疗产生抵抗。那么，肿瘤抵抗凋亡的分子机制是什么？我们又该如何利用这些知识，使肿瘤细胞重新对癌症治疗敏感？

原文链接：

Death and anti-death: tumour resistance to apoptosis