Chemotherapy Induces Tumor Clearance Independent of Apoptosis
Chemotherapy Induces Tumor Clearance Independent of Apoptosis
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DOI：
10.1158/0008-5472.can-08-2452
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Zong, Wei-Xing
中科院分区：
文献类型：
--
作者：
Guerriero, Jennifer L.;Ditsworth, Dara;Zong, Wei-Xing
细胞凋亡的失调与人类癌症的发展和对抗癌治疗的抗性有关。癌症治疗的最终目标是选择性地诱导癌细胞死亡并克服耐药性。需要更深入地了解特定化疗如何影响肿瘤细胞死亡，以开发战略性设计的抗癌药物。在这里，我们使用的异种移植小鼠肿瘤系统产生的遗传定义的细胞凋亡缺陷，检查参与多种形式的细胞死亡诱导的环磷酰胺（CP），DNA烷化剂化疗中常用的。我们发现，尽管细胞凋亡促进肿瘤消退，但由于细胞死亡的其他优势被激活，它对于肿瘤的完全消退是不可或缺的。通过肿瘤细胞形态学、高迁移率族蛋白1蛋白的细胞外释放和CP处理的肿瘤中先天免疫细胞的激活，在有增殖能力和缺陷的肿瘤中观察到散发性坏死。我们的研究结果表明，在肿瘤坏死缺陷型肿瘤中，坏死可能通过刺激先天免疫反应在肿瘤清除中发挥重要作用。[Cancer Res 2008;68（23）：9595-600]
Dysregulation of apoptosis is associated with the development of human cancer and resistance to anticancer therapy. The ultimate goal of cancer treatment is to selectively induce cancer cell death and overcome drug resistance. A deeper understanding of how a given chemotherapy affects tumor cell death is needed to develop strategically designed anticancer agents. Here, we use a xenograft mouse tumor system generated from genetically defined cells deficient in apoptosis to examine the involvement of multiple forms of cell death induced by cyclophosphamide (CP), a DNA alkylating agent commonly used in chemotherapy. We find that although apoptosis facilitates tumor regression, it is dispensable for complete tumor regression as other fortes of cell death are activated. Sporadic necrosis is observed in both apoptosis-competent and deficient tumors evident by tumor cell morphology, extracellular release of high mobility group box 1 protein, and activation of innate immune cells in CP-treated tumors. Our findings indicate that in apoptosis-deficient tumors, necrosis may play a fundamental role in tumor clearance by stimulating the innate immune response. [Cancer Res 2008;68(23):9595-600]