Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila.
Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila.
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通过涉及果蝇中的ROS，巨噬细胞和JNK的扩增环，凋亡caspase的肿瘤促进功能。
DOI：
10.7554/elife.26747
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发表时间：
2017-08-30
期刊：
影响因子：
7.7
通讯作者：
Bergmann A
中科院分区：
文献类型：
--
作者：
Pérez E;Lindblad JL;Bergmann A
细胞凋亡及其分子介质半胱天冬酶长期以来被认为是肿瘤抑制因子，并且癌症的一个标志是“逃避细胞凋亡”。然而，最近的工作表明，凋亡半胱天冬酶也可以促进增殖和肿瘤生长在某些条件下。半胱天冬酶如何促进增殖以及如何保护细胞免受凋亡半胱天冬酶的潜在有害作用在很大程度上是未知的。在这里，我们表明，虽然半胱天冬酶被激活在一个充分研究的肿瘤模型在果蝇，致癌突变的原癌基因Ras（RasV12）保持肿瘤细胞在一个'undead'样的条件和转化半胱天冬酶从肿瘤抑制到肿瘤促进剂。而不是杀死细胞，半胱天冬酶现在促进细胞内和细胞外活性氧（ROS）的产生。ROS的一个功能是募集和激活巨噬细胞样免疫细胞，其反过来向肿瘤上皮细胞发出信号以激活致癌JNK信号传导。JNK进一步促进和放大胱天蛋白酶活性，从而构成反馈放大环。干扰扩增环可以大大降低这些细胞的肿瘤行为，并显着提高生物体的生存。总之，RasV12修饰的半胱天冬酶启动了一个涉及肿瘤上皮细胞和巨噬细胞样免疫细胞的反馈放大环，这是不受控制的肿瘤生长和侵袭行为所必需的。在动物的整个发育和生命过程中，许多细胞死亡并被移除以为新组织腾出空间。一组称为半胱天冬酶的蛋白质在细胞死亡过程中起着关键作用。化学疗法和放射疗法作为癌症治疗起作用，因为它们破坏分裂的癌细胞，以至于半胱天冬酶被打开并杀死这些细胞。不幸的是，肿瘤在治疗后偶尔会重新生长，部分原因是半胱天冬酶也有助于产生促进任何存活癌细胞生长的信号。Pérez，Lindblad和Bergmann现在使用果蝇Drosophila来研究半胱天冬酶如何促进肿瘤细胞生长和扩散。这些果蝇都携带一种名为Ras的基因突变，这种基因在人类癌症中经常发生突变。Pérez、Lindblad和Bergmann通过结合遗传和生化实验发现，突变的Ras可以阻止具有活性半胱天冬酶的细胞死亡。相反，半胱天冬酶重新定向它们的活性，帮助癌细胞产生称为活性氧的小化学物质。这些化学物质可以在癌症中发挥许多不同的作用，但在这种情况下，它们会将免疫细胞吸引到肿瘤部位。免疫细胞反过来将其他信号发送回癌细胞，癌细胞进一步激活半胱天冬酶。总的来说，癌细胞和周围免疫细胞之间的这种自我维持的信号循环有助于肿瘤生长。未来开发新的癌症治疗方法的工作将需要研究如何增强半胱天冬酶的细胞杀伤特性，同时抑制其帮助肿瘤生长的能力。还需要进一步的实验来确定突变的Ras基因如何保护肿瘤细胞免于死亡。
Apoptosis and its molecular mediators, the caspases, have long been regarded as tumor suppressors and one hallmark of cancer is ‘Evading Apoptosis’. However, recent work has suggested that apoptotic caspases can also promote proliferation and tumor growth under certain conditions. How caspases promote proliferation and how cells are protected from the potentially harmful action of apoptotic caspases is largely unknown. Here, we show that although caspases are activated in a well-studied neoplastic tumor model in Drosophila, oncogenic mutations of the proto-oncogene Ras (RasV12) maintain tumorous cells in an ‘undead’-like condition and transform caspases from tumor suppressors into tumor promotors. Instead of killing cells, caspases now promote the generation of intra- and extracellular reactive oxygen species (ROS). One function of the ROS is the recruitment and activation of macrophage-like immune cells which in turn signal back to tumorous epithelial cells to activate oncogenic JNK signaling. JNK further promotes and amplifies caspase activity, thereby constituting a feedback amplification loop. Interfering with the amplification loop strongly reduces the neoplastic behavior of these cells and significantly improves organismal survival. In conclusion, RasV12-modified caspases initiate a feedback amplification loop involving tumorous epithelial cells and macrophage-like immune cells that is necessary for uncontrolled tumor growth and invasive behavior. Throughout the development and life of an animal, many of its cells die and are removed to make space for new tissues. A group of proteins called caspases play a key role in this cell death process. Chemotherapy and radiotherapy work as cancer treatments because they damage dividing cancer cells to such an extent that caspases are turned on and kill those cells. Unfortunately the tumor occasionally grows back after the treatment, partly because caspases also help to produce signals that boost the growth of any surviving cancer cells. Pérez, Lindblad and Bergmann have now used the fruit fly Drosophila to investigate how caspases encourage tumor cells to grow and spread. The fruit flies all carried a mutation in a gene called Ras, which is often mutated in human cancers. Using a combination of genetic and biochemical experiments Pérez, Lindblad and Bergmann found that mutant Ras prevents cells with active caspases from dying. Instead, the caspases redirect their activity and help cancer cells to produce small chemicals called reactive oxygen species. These chemicals can play many different roles in cancers, but in this setting they attract immune cells to the site of the tumor. The immune cells in turn send other signals back to the cancer cells, which further activate the caspases. Overall, this self-perpetuating signaling loop between the cancer cells and the surrounding immune cells helps the tumors to grow. Future work toward developing new cancer treatments will need to work on ways of enhancing the cell-killing properties of caspases while inhibiting their ability to help tumors to grow. Further experiments will also be needed to find out exactly how the mutant Ras gene protects tumor cells from death.