PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axis
Abstract Cancer‐associated fibroblasts (CAFs) are intrinsic components of the tumor microenvironment that promote cancer progression and metastasis. Through an unbiased integrated analysis of gastric tumor grade and stage, we identified a subset of proangiogenic CAFs characterized by high podoplanin...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.70037 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594206701387776 |
|---|---|
| author | Zhenxiong Zhao Hui Sun Yingxue Liu Yanqiu Zhang Xin Wang Xu Wang Cong Tan Shujuan Ni Weiwei Weng Meng Zhang Lei Wang Dan Huang Wenchao Gu Jinjia Chang Weiqi Sheng Mi‐die Xu |
| author_facet | Zhenxiong Zhao Hui Sun Yingxue Liu Yanqiu Zhang Xin Wang Xu Wang Cong Tan Shujuan Ni Weiwei Weng Meng Zhang Lei Wang Dan Huang Wenchao Gu Jinjia Chang Weiqi Sheng Mi‐die Xu |
| author_sort | Zhenxiong Zhao |
| collection | DOAJ |
| description | Abstract Cancer‐associated fibroblasts (CAFs) are intrinsic components of the tumor microenvironment that promote cancer progression and metastasis. Through an unbiased integrated analysis of gastric tumor grade and stage, we identified a subset of proangiogenic CAFs characterized by high podoplanin (PDPN) expression, which are significantly enriched in metastatic lesions and secrete chemokine (CC‐motif) ligand 2 (CCL2). Mechanistically, PDPN(+) CAFs enhance angiogenesis by activating the AKT/NF‐κB signaling pathway. The canonical NF‐κB signaling protein P65 binds to the promoter region of CCL2, inducing its expression. Additionally, we found that CCL2 interacts with its nonclassical receptor ACKR1 (expressed on endothelial cells) to exert its proangiogenic effects. Furthermore, the disruption of CCL2‐ACKR1 communication via a CCL2 neutralizing antibody or the inhibition of AKT signaling transduction using AKT inhibitors effectively suppressed tumor growth. Together, this study elucidates the mechanism by which PDPN(+) CAFs promote angiogenesis, providing a deeper understanding of the molecular processes underlying CAF‐mediated angiogenesis and suggesting potential therapeutic targets for gastric cancer treatment. |
| format | Article |
| id | doaj-art-4abbd892d8dd49a9bc0a26f71524263f |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-4abbd892d8dd49a9bc0a26f71524263f2025-01-20T01:45:44ZengWileyMedComm2688-26632025-01-0161n/an/a10.1002/mco2.70037PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axisZhenxiong Zhao0Hui Sun1Yingxue Liu2Yanqiu Zhang3Xin Wang4Xu Wang5Cong Tan6Shujuan Ni7Weiwei Weng8Meng Zhang9Lei Wang10Dan Huang11Wenchao Gu12Jinjia Chang13Weiqi Sheng14Mi‐die Xu15Department of Gastric Surgery Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Artificial Intelligence Medicine, Graduate School of Medicine Chiba University Chiba JapanDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaDepartment of Oncology Shanghai Medical College, Fudan University Shanghai ChinaAbstract Cancer‐associated fibroblasts (CAFs) are intrinsic components of the tumor microenvironment that promote cancer progression and metastasis. Through an unbiased integrated analysis of gastric tumor grade and stage, we identified a subset of proangiogenic CAFs characterized by high podoplanin (PDPN) expression, which are significantly enriched in metastatic lesions and secrete chemokine (CC‐motif) ligand 2 (CCL2). Mechanistically, PDPN(+) CAFs enhance angiogenesis by activating the AKT/NF‐κB signaling pathway. The canonical NF‐κB signaling protein P65 binds to the promoter region of CCL2, inducing its expression. Additionally, we found that CCL2 interacts with its nonclassical receptor ACKR1 (expressed on endothelial cells) to exert its proangiogenic effects. Furthermore, the disruption of CCL2‐ACKR1 communication via a CCL2 neutralizing antibody or the inhibition of AKT signaling transduction using AKT inhibitors effectively suppressed tumor growth. Together, this study elucidates the mechanism by which PDPN(+) CAFs promote angiogenesis, providing a deeper understanding of the molecular processes underlying CAF‐mediated angiogenesis and suggesting potential therapeutic targets for gastric cancer treatment.https://doi.org/10.1002/mco2.70037angiogenesiscancer‐associated fibroblastsCCL2gastric cancerPDPN |
| spellingShingle | Zhenxiong Zhao Hui Sun Yingxue Liu Yanqiu Zhang Xin Wang Xu Wang Cong Tan Shujuan Ni Weiwei Weng Meng Zhang Lei Wang Dan Huang Wenchao Gu Jinjia Chang Weiqi Sheng Mi‐die Xu PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axis MedComm angiogenesis cancer‐associated fibroblasts CCL2 gastric cancer PDPN |
| title | PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axis |
| title_full | PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axis |
| title_fullStr | PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axis |
| title_full_unstemmed | PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axis |
| title_short | PDPN+ cancer‐associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF‐κB activation and the CCL2‐ACKR1 axis |
| title_sort | pdpn cancer associated fibroblasts enhance gastric cancer angiogenesis via akt nf κb activation and the ccl2 ackr1 axis |
| topic | angiogenesis cancer‐associated fibroblasts CCL2 gastric cancer PDPN |
| url | https://doi.org/10.1002/mco2.70037 |
| work_keys_str_mv | AT zhenxiongzhao pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT huisun pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT yingxueliu pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT yanqiuzhang pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT xinwang pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT xuwang pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT congtan pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT shujuanni pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT weiweiweng pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT mengzhang pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT leiwang pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT danhuang pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT wenchaogu pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT jinjiachang pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT weiqisheng pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis AT midiexu pdpncancerassociatedfibroblastsenhancegastriccancerangiogenesisviaaktnfkbactivationandtheccl2ackr1axis |