The role of Tyk2 in regulation of breast cancer growth.
The role of Tyk2 in regulation of breast cancer growth.
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DOI：
10.1089/jir.2011.0023
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发表时间：
2011-09
期刊：
影响因子：
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通讯作者：
Qifang Zhang;J. Sturgill;M. Kmieciak;Karol Szczepanek;Marta Derecka;Catherine M. Koebel;L. Graham;Yun Dai;Shuang Chen;S. Grant;J. Cichy;K. Shimoda;A. Gamero;M. Manjili;H. Bear;D. Conrad;A. Larner
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文献类型：
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作者：
Qifang Zhang;J. Sturgill;M. Kmieciak;Karol Szczepanek;Marta Derecka;Catherine M. Koebel;L. Graham;Yun Dai;Shuang Chen;S. Grant;J. Cichy;K. Shimoda;A. Gamero;M. Manjili;H. Bear;D. Conrad;A. Larner
干扰素 (IFN) 的抗生长和免疫调节作用使这些细胞因子能够用于治疗多种血液和实体恶性肿瘤。 IFN 通过激活 Jak/Stat 信号通路发挥作用。 IFNγ 刺激酪氨酸激酶 Jak1 和 Jak2，导致 Stat1 转录因子激活，而 1 型 IFN (IFNα/β) 激活 Jak1 和 Tyk2，后者通过 Stat1 和 Stat2 介导其作用。 IFNγ、IFNα受体或 Stat1 表达的破坏会抑制小鼠的抗肿瘤反应并削弱癌症免疫监视。 Jak2 的突变或 Jak1 或 Jak2 的组成型激活也会促进多种恶性肿瘤的发展。尽管有数据表明Tyk2在淋巴瘤的发病机制中发挥作用，但Tyk2表达对肿瘤发生的影响尚不清楚。我们在此报告，与 Tyk2(+/+) 动物相比，接种 4T1 乳腺癌细胞的 Tyk2(-/-) 小鼠显示出增强的肿瘤生长和转移。 Tyk2(-/-) 动物中 4T1 细胞的加速生长似乎并不是由于 CD4(+)、CD8(+) T 细胞或 NK 细胞功能下降所致。相反，Tyk2 的肿瘤抑制作用至少部分是由骨髓来源的抑制细胞介导的，这些细胞似乎更有效地抑制 Tyk2(-/-) 小鼠的 T 细胞反应。我们的结果为 Tyk2 在抑制乳腺癌生长和转移中的作用提供了第一个证据。
The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFNγ stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFNα/β) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFNγ, IFNα receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2(-/-) mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2(+/+) animals. Accelerated growth of 4T1 cells in Tyk2(-/-) animals does not appear to be due to decreased function of CD4(+), CD8(+) T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2(-/-) mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer.