Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish
Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish
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DOI：
10.1073/pnas.1920049117
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发表时间：
2020-06-30
影响因子：
11.1
通讯作者：
Ferreira, Miguel Godinho
中科院分区：
文献类型：
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作者：
Lex, Kirsten;Gil, Mariana Maia;Ferreira, Miguel Godinho
当人类端粒较短时，癌症发病率随年龄呈指数增长。类似地，端粒酶逆转录酶（tert）突变的斑马鱼有过早的短端粒，并预期癌症的发病率更年轻。然而，由于短端粒构成了细胞增殖的障碍，端粒缩短目前被视为肿瘤抑制机制，应该可以预防癌症。这个难题还没有完全弄清楚。在我们目前的研究中，我们报告端粒缩短促进癌症在非细胞自主的方式。使用斑马鱼嵌合体，我们发现当野生型（WT）肿瘤在tert突变斑马鱼中产生时，侵袭性黑色素瘤的发病率增加。在tert突变体中，黑色素瘤病变（皮肤）和远处器官（肠）附近的组织表现出更高水平的衰老和炎症。此外，我们将第二代（G2）tert囊胚细胞转移到WT中以产生胚胎嵌合体。端粒非常短的细胞以非细胞自主的方式诱导幼虫组织中肿瘤坏死因子1-α（TNF 1-α）表达增加和衰老，从而产生炎症环境。考虑到炎症是促肿瘤发生的，我们将黑素瘤衍生的细胞移植到G2 tert斑马鱼胚胎中，并观察到具有短端粒的组织环境导致肿瘤发展增加。为了测试炎症是否是这种效应所必需的，我们用非类固醇抗炎药治疗黑色素瘤移植物，并表明可以避免更高的黑色素瘤传播。因此，除了短端粒在促进基因组不稳定性中的细胞自主作用外，我们提出端粒随着年龄的增长而缩短会导致全身性慢性炎症，从而增加肿瘤发病率。
Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-alpha (TNF1-alpha) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.