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首页> 外文期刊>Molecular cancer research: MCR >Paracrine Interaction of Cancer Stem Cell Populations Is Regulated by the Senescence-Associated Secretory Phenotype (SASP)
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Paracrine Interaction of Cancer Stem Cell Populations Is Regulated by the Senescence-Associated Secretory Phenotype (SASP)

机译：癌症干细胞群的旁静脉相互作用受到衰老相关的分泌表型（SASP）的调节

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Dyskeratosis congenita is a telomere DNA damage syndrome characterized by defective telomere maintenance, bone marrow failure, and increased head and neck cancer risk. The Pot1b(-/-); Terc(+/-) mouse exhibits some features of dyskeratosis congenita, but head and neck cancer was not reported in this model. To model the head and neck cancer phenotype, we created unique Pot1b- and p53-null-mutant models which allow genetic lineage tracing of two distinct stem cell populations. Loss of Pot1b expression depleted stem cells via ATR/Chk1/p53 signaling. Tumorigenesis was inhibited in Pot1b(-/-); p53(+/+) mice due to cellular senescence. Pot1b(-/-); p53(-/-) tumors also exhibited senescence, but proliferated and metastasized with expansion of Lgr6(+) stem cells indicative of senescence-associated secretory phenotype. Selective depletion of the small K15(+) stem cell fraction resulted in reduction of Lgr6(+) cells and inhibition of tumorigenesis via senescence. Gene expression studies revealed that K15(+) cancer stem cells regulate Lgr6(+) cancer stem cell expansion via chemokine signaling. Genetic ablation of the chemokine receptor Cxcr2 inhibited cancer stem cell expansion and tumorigenesis via senescence. The effects of chemokines were primarily mediated by PI3K signaling, which is a therapeutic target in head and neck cancer. Implications: Paracrine interactions of cancer stem cell populations impact therapeutic options and patient outcomes.
机译：Dyskeratosis incenita是一种端粒体DNA损伤综合征，其特征在于端粒维护，骨髓衰竭，头部和颈部癌症风险增加。 Pot1b（ - / - ）; TERC（+/-）鼠标表现出一些特征的伴有表达症同性恋者，但在该模型中没有报道头部和颈部癌症。为了模拟头部和颈部癌症表型，我们创建了独特的POT1B和P53-NULL突变模型，允许两个不同干细胞群的遗传谱系追踪。通过ATR / CHK1 / P53信号传导损失Pot1B表达耗尽干细胞。肿瘤发生在Pot1b（ - / - ）中受到抑制; P53（+ / +）小鼠由于细胞衰老。 Pot1b（ - / - ）; P53（ - / - ）肿瘤也表现出衰老，但增殖和转移，并扩大LGR6（+）干细胞，其指示衰老相关的分泌表型。小K15（+）干细胞级分的选择性耗竭导致LGR6（+）细胞的减少，并通过衰老抑制肿瘤率。基因表达研究表明，K15（+）癌症干细胞通过趋化因子信号调节LGR6（+）癌症干细胞膨胀。趋化因子受体CXCR2的遗传烧蚀通过衰老抑制癌症干细胞膨胀和肿瘤瘤。趋化因子的影响主要由PI3K信号传导介导，这是头部和颈部癌症中的治疗靶标。含义：癌症干细胞种群的帕拉卡碱相互作用会影响治疗选择和患者结果。

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