An LCN2‐Dependent Positive‐Feedback Loop Between Gastric Cancer Cells and Tumor‐Associated‐Macrophages Mediates Lymphangiogenesis and Lymphatic Metastasis Article Swipe
Zhixin Huang
,
Ying Li
,
Qian Yan
,
Linying Ye
,
Tianhao Zhang
,
Cheng Yang
,
Jialin Wu
,
Peng Duan
,
Tiantian Zhang
,
Zihan Yu
,
Zeyu Zhao
,
Risheng Zhao
,
Zhi Liang
,
Ertao Zhai
,
Shirong Cai
,
Jianhui Chen
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1002/advs.202508352
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1002/advs.202508352
Lymph node (LN) metastasis is a major determinant of poor prognosis in patients with gastric cancer (GC). Tumor‐associated macrophages (TAMs) play a crucial role in promoting tumor metastasis and progression; however, the underlying mechanisms through which TAMs induce LN metastasis in GC remain poorly understood. This study demonstrates that low lipocalin‐2 (LCN2) expression is associated with increased LN metastasis and shorter survival in GC. Functionally, LCN2 silencing significantly increases M2‐type TAM infiltration, lymphangiogenesis, and LN metastasis. Mechanistically, LCN2 downregulates the NF‐κB pathway‐mediated CCL5 expression by interacting with Annexin A1, which inhibits K63‐ and M1‐linked ubiquitination of NEMO. Furthermore, LCN2‐regulated CCL5 recruits and repolarizes TAMs through the CCR5/PI3K/AKT/GSK3β axis, which subsequently promotes lymphangiogenesis and LN metastasis via vascular endothelial growth factor C (VEGFC) secretion. Additionally, interleukin‐10 (IL‐10) derived from M2‐type TAMs suppresses IκBζ and its target gene, LCN2 , in GC cells by promoting IκBζ degradation, thereby establishing an IL‐10/IκBζ/LCN2 positive‐feedback loop that sustains LCN2 suppression. These findings suggest that reduced LCN2 expression drives a positive feedback loop between tumor cells and TAMs that continuously enhances lymphangiogenesis and LN metastasis in GC. Therefore, targeting these related pathways may represent a promising therapeutic strategy for GC patients and LN metastasis.
Related Topics
Concepts
Lymphangiogenesis
Lymphatic system
Metastasis
Cancer research
Cancer
Cancer cell
Medicine
Biology
Chemistry
Internal medicine
Pathology
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1002/advs.202508352
- https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202508352
- OA Status
- gold
- Cited By
- 1
- References
- 54
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4413852475
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4413852475Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1002/advs.202508352Digital Object Identifier
- Title
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An LCN2‐Dependent Positive‐Feedback Loop Between Gastric Cancer Cells and Tumor‐Associated‐Macrophages Mediates Lymphangiogenesis and Lymphatic MetastasisWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
-
2025-08-30Full publication date if available
- Authors
-
Zhixin Huang, Ying Li, Qian Yan, Linying Ye, Tianhao Zhang, Cheng Yang, Jialin Wu, Peng Duan, Tiantian Zhang, Zihan Yu, Zeyu Zhao, Risheng Zhao, Zhi Liang, Ertao Zhai, Shirong Cai, Jianhui ChenList of authors in order
- Landing page
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https://doi.org/10.1002/advs.202508352Publisher landing page
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https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202508352Direct link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
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goldOpen access status per OpenAlex
- OA URL
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https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202508352Direct OA link when available
- Concepts
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Lymphangiogenesis, Lymphatic system, Metastasis, Cancer research, Cancer, Cancer cell, Medicine, Biology, Chemistry, Internal medicine, PathologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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1Total citation count in OpenAlex
- Citations by year (recent)
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2025: 1Per-year citation counts (last 5 years)
- References (count)
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54Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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