Tissue necrosis and its role in cancer progression
Tissue necrosis and its role in cancer progression
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DOI：
10.1038/s41388-018-0555-y
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发表时间：
2019-03-14
期刊：
影响因子：
8
通讯作者：
Benny, Ofra
中科院分区：
文献类型：
--
作者：
Karsch-Bluman, Adi;Feiglin, Ariel;Benny, Ofra
人们在揭示癌症耐药和复发的机制方面做出了巨大努力。由缺氧和代谢应激引起的细胞死亡的原位效应在很大程度上与炎症相关。然而，在这项工作中，我们专注于坏死对癌症促进和肿瘤微环境的直接影响。导致细胞坏死的条件下，营养和氧气剥夺，概括在体外，并用于产生计算蛋白质组学分析的样品。在这些条件下，我们确定了可能参与肿瘤耐药性的富集途径簇，导致癌症复发。我们发现坏死细胞的含量增强血管生成和内皮细胞增殖，诱导血管形成，以及增加迁移，侵袭和细胞-细胞相互作用。在体内研究中，MDA-MB-231异种移植物暴露于坏死裂解物，导致增殖和血管生成增加。肿瘤组织的组织学分析揭示了通过蛋白质组学分析鉴定的关键介质的高表达水平。此外，当全身注射细胞时，再加上坏死的裂解物，在肺中检测到更高数量的大病变。最后，使用异种移植物，我们证明了将坏死信号的拮抗剂与抗癌治疗相结合可增强延长的治疗效果。这种方法表明了一种范式转变，其中靶向晚期坏死分泌因子可能会增加生存率并增强抗癌治疗的疗效。
Great efforts have been made in revealing the mechanisms governing cancer resistance and recurrence. The in-situ effects of cell death, caused by hypoxia and metabolic stress, were largely studied in association with inflammation. However, in this work, we focused on the direct effects of necrosis on cancer promotion and on the tumor microenvironment. The conditions leading to cell necrosis, upon nutrient and oxygen deprivation, were recapitulated in-vitro and were used to generate samples for computational proteomic analysis. Under these conditions, we identified clusters of enriched pathways that may be involved in tumor resistance, leading to cancer recurrence. We show that the content of necrotic cells enhances angiogenesis and proliferation of endothelial cells, induces vasculature, as well as increases migration, invasion, and cell-cell interactions. In-vivo studies, where MDA-MB-231 xenografts were exposed to necrotic lysates, resulted in an increase in both proliferation and angiogenesis. Histological analysis of tumor tissues revealed high expression levels of key mediators that were identified by proteomic analysis. Moreover, when cells were injected systemically, coupled with necrotic lysates, a higher number of large lesions was detected in the lung. Finally, using xenografts, we demonstrated that combining an antagonist of a necrotic signal with an anticancer treatment potentiates the prolonged therapeutic effect. This approach suggests a paradigm shift in which targeting late necrotic-secreted factors may increase survival and enhance the efficacy of anticancer therapy.