2. Academic Validation
  3. S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients

S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients

  • Cancer Lett. 2024 Nov 28:605:217288. doi: 10.1016/j.canlet.2024.217288.
Ying Ning 1,  Yu Chen 2,  Tian Tian 3,  Xinyan Gao 2,  Xiaolan Liu 2,  Jia Wang 4,  Huijun Chu 3,  Chenyang Zhao 4,  Yufei Yang 2,  Ke Lei 5,  He Ren 6,  Zhumei Cui 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China; Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
  • 2 Department of Clinical Medicine, Qingdao University, Qingdao, 266003, China.
  • 3 Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
  • 4 Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
  • 5 Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China. Electronic address: leike@qdu.edu.cn.
  • 6 Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China. Electronic address: herenrh@163.com.
  • 7 Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China. Electronic address: cuizhumei1966@qdu.edu.cn.
PMID: 39384116 DOI: 10.1016/j.canlet.2024.217288
Abstract

Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical Cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating Autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.

Keywords

Cervical cancer; Lymph node metastasis; NETs; S100A7; Target therapy.

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