The autophagic tumor stroma model of cancer or "battery-operated tumor growth" A simple solution to the autophagy paradox
The autophagic tumor stroma model of cancer or "battery-operated tumor growth" A simple solution to the autophagy paradox
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DOI：
10.4161/cc.9.21.13817
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发表时间：
2010-11-01
期刊：
影响因子：
4.3
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
--
作者：
Martinez-Outschoorn, Ubaldo E.;Whitaker-Menezes, Diana;Lisanti, Michael P.
自噬在肿瘤发生中的作用存在争议。自噬抑制剂（氯喹）和自噬促进剂（雷帕霉素）均通过未知机制阻止肿瘤发生。这被称为“自噬悖论”。我们最近报告了解决这个悖论的一个简单方法。我们证明上皮癌细胞利用氧化应激在肿瘤微环境中诱导自噬。因此，自噬性肿瘤基质产生可循环的营养物质，然后可以被合成代谢上皮癌细胞用作化学构件。该模型导致从肿瘤基质到上皮癌细胞的净能量转移（能量不平衡），从而促进肿瘤生长。这种从肿瘤基质到上皮癌细胞的净能量转移既是单向的也是矢量的，代表了真正的宿主-寄生虫关系。我们将这种新范式称为“癌细胞代谢的自噬肿瘤基质模型”或“电池供电的肿瘤生长”。从这个意义上说，肿瘤基质中的自噬充当“电池”来促进肿瘤的生长、进展和转移，独立于血管生成。利用这种模型，系统性诱导自噬将阻止上皮癌细胞利用回收的营养物质，而系统性抑制自噬将阻止基质细胞产生回收的营养物质——两者都有效地“挨饿”癌细胞。我们讨论了这样的想法：通过癌细胞中天然内源自噬抑制剂的上调，肿瘤细胞可能对自噬的全身诱导产生抵抗。或者，肿瘤细胞也可能通过促自噬分子（例如 Beclin1）的基因沉默/删除，对全身诱导自噬产生抵抗力。如果癌细胞中出现自噬抗性，那么自噬的全身抑制将为此类耐药性提供治疗解决方案，因为它仍然会针对肿瘤基质中的自噬。因此，交替使用自噬促进剂和自噬抑制剂的抗癌疗法有望预防耐药性的发生。我们还讨论了为什么抗血管生成治疗被发现会促进肿瘤复发、进展和转移。更具体地，抗血管生成疗法将通过诱导基质缺氧来诱导肿瘤基质中的自噬，从而将非侵袭性肿瘤类型转化为“致命的”侵袭性肿瘤表型。因此，解开癌细胞和自噬性肿瘤基质之间的代谢寄生关系可能为抗癌治疗带来巨大希望。最后，我们认为肿瘤基质中的自噬是全身性消耗（癌症相关恶病质）的局部微观对应物，而全身性消耗与晚期和转移性癌症相关。癌症患者的恶病质并不是由于能量摄入减少，而是基础代谢率升高，能量消耗增加，导致能量负平衡。重要的是，当肿瘤被手术切除后，这种增加的代谢率恢复到正常水平。这种恶病质导致能量转移到肿瘤的观点与我们的假设一致。因此，与癌症相关的恶病质可能以基质自噬的形式局部开始，然后全身扩散。因此，基质自噬可能是全身性癌症相关恶病质的必要前兆。
The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a "lethal" aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia.