Park Juwon, Wysocki Robert W, Amoozgar Zohreh, Maiorino Laura, Fein Miriam R, Jorns Julie, Schott Anne F, Kinugasa-Katayama Yumi, Lee Youngseok, Won Nam Hee, Nakasone Elizabeth S, Hearn Stephen A, Küttner Victoria, Qiu Jing, Almeida Ana S, Perurena Naiara, Kessenbrock Kai, Goldberg Michael S, Egeblad Mikala
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Medical Scientist Training Program, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Sci Transl Med. 2016 Oct 19;8(361):361ra138. doi: 10.1126/scitranslmed.aag1711.
Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target.
中性粒细胞是血液中最丰富的白细胞类型，能够形成中性粒细胞胞外陷阱（NETs）。这些是通过中性粒细胞的DNA与相关蛋白水解酶排出而产生的病原体捕获结构。感染产生的NETs可促进癌症转移。我们发现，转移性乳腺癌细胞在没有感染的情况下可诱导中性粒细胞形成支持转移的NETs。利用活体成像技术，我们在已到达小鼠肺部的转移性4T1癌细胞周围观察到了类似NET的结构。我们还在三阴性人类乳腺癌的临床样本中发现了NETs。NETs的形成在体外刺激了乳腺癌细胞的侵袭和迁移。抑制NET的形成或用脱氧核糖核酸酶I（DNase I）消化NETs可阻断这些过程。用消化NET的、包被有DNase I的纳米颗粒进行治疗可显著减少小鼠的肺转移。我们的数据表明，癌细胞诱导NETs是一种此前未被识别的促进转移的肿瘤-宿主相互作用，也是一个潜在的治疗靶点。
