Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung
Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung
复制标题
DOI：
10.1093/carcin/bgq105
复制
发表时间：
2010-10-01
期刊：
影响因子：
4.7
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Satoh, Hironori;Moriguchi, Takashi;Yamamoto, Masayuki
Nrf2转录因子对于调节细胞对各种致癌物的防御至关重要。然而，宿主Nrf2与癌症转移之间的关系仍然未被探索。为了解决这个问题，我们研究了Nrf2缺陷小鼠在小鼠刘易斯肺癌（3LL）细胞系植入后对肺癌转移的易感性。Nrf2缺陷小鼠可重复地表现出比野生型小鼠更高数量的肺转移结节。携带癌症的Nrf2缺陷小鼠的肺和骨髓（BM）含有增加数量的炎性细胞，包括髓源性抑制细胞（MDSC），一种有效的免疫抑制细胞群。MDSC可以通过利用活性氧（ROS）修饰T细胞受体复合物来减弱CD8（+）T细胞免疫。相对于野生型小鼠，Nrf2缺陷小鼠的MDSC保留了升高的ROS水平。骨髓移植实验显示Nrf2缺陷小鼠的造血和免疫系统功能紊乱。Nrf2缺陷BM细胞的野生型受体小鼠在癌细胞接种后显示肺转移水平增加。这些小鼠在MDSC中表现出高水平的ROS积累，这与脾脏CD8（+）T细胞的减少非常吻合。相比之下，Keap1敲低突变小鼠携带高水平的Nrf2表达显示出对癌细胞转移到肺的抵抗力增加，伴随着MDSC组分中ROS的减少。因此，我们的研究结果揭示了Nrf2在预防癌症转移中的新功能，可能是通过其保持造血和免疫系统中氧化还原平衡的能力。
The Nrf2 transcription factor is crucial for regulating the cellular defense against various carcinogens. However, relationship between host Nrf2 and cancer metastasis remains unexplored. To address this issue, we examined susceptibility of Nrf2-deficient mice to pulmonary cancer metastasis following implantation of the mouse Lewis lung carcinoma (3LL) cell line. Nrf2-deficient mice reproducibly exhibited a higher number of pulmonary metastatic nodules than wild-type mice did. The lung and bone marrow (BM) of cancer-bearing Nrf2-deficient mice contained increased numbers of inflammatory cells, including myeloid-derived suppressor cells (MDSCs), a potent population of immunosuppressive cells. MDSCs can attenuate CD8(+) T-cell immunity through modification of the T-cell receptor complex exploiting reactive oxygen species (ROS). MDSCs of Nrf2-deficient mice retained elevated levels of ROS relative to wild-type mice. BM transplantation experiments revealed functional disturbance in the hematopoietic and immune systems of Nrf2-deficient mice. Wild-type recipient mice with Nrf2-deficient BM cells showed increased levels of lung metastasis after cancer cell inoculation. These mice exhibited high-level accumulation of ROS in MDSCs, which showed very good coincidence to the decrease of splenic CD8(+) T-cells. In contrast, Keap1-knockdown mutant mice harboring high-level Nrf2 expression displayed increased resistance against the cancer cell metastasis to the lung, accompanied by a decrease in ROS in the MDSCs fraction. Our results thus reveal a novel function for Nrf2 in the prevention of cancer metastasis, presumably by its ability to preserve the redox balance in the hematopoietic and immune systems.