Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma
Abstract Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor‐derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willib...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202302677 |
| _version_ | 1797684961768112128 |
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| author | Samuel Wan Ki Wong Sze Keong Tey Xiaowen Mao Hiu Ling Fung Zhi‐Jie Xiao Danny Ka Ho Wong Lung‐Yi Mak Man‐Fung Yuen Irene Oi‐Lin Ng Jing Ping Yun Yi Gao Judy Wai Ping Yam |
| author_facet | Samuel Wan Ki Wong Sze Keong Tey Xiaowen Mao Hiu Ling Fung Zhi‐Jie Xiao Danny Ka Ho Wong Lung‐Yi Mak Man‐Fung Yuen Irene Oi‐Lin Ng Jing Ping Yun Yi Gao Judy Wai Ping Yam |
| author_sort | Samuel Wan Ki Wong |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor‐derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV–vWF levels are found in a larger cohort of HCC–sEV samples and metastatic HCC cell lines compared to their respective normal counterparts. Circulating sEVs of late‐stage HCC patients markedly augment angiogenesis, tumor–endothelial adhesion, pulmonary vascular leakiness, and metastasis, which are significantly compromised by anti‐vWF antibody. The role of vWF is further corroborated by the enhanced promoting effect of sEVs collected from vWF‐overexpressing cells. sEV–vWF modulates endothelial cells through an elevated level of vascular endothelial growth factor A (VEGF‐A) and fibroblast growth factor 2 (FGF2). Mechanistically, secreted FGF2 elicits a positive feedback response in HCC via the FGFR4/ERK1 signaling pathway. The co‐administration of anti‐vWF antibody or FGFR inhibitor significantly improves the treatment outcome of sorafenib in a patient‐derived xenograft mouse model. This study reveals mutual stimulation between HCC and endothelial cells by tumor‐derived sEVs and endothelial angiogenic factors, facilitating angiogenesis and metastasis. It also provides insights into a new therapeutic strategy involving blocking tumor–endothelial intercellular communication. |
| first_indexed | 2024-03-12T00:37:25Z |
| format | Article |
| id | doaj.art-b2ced8f4b6de42bdb147c293f71797b1 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-12T00:37:25Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-b2ced8f4b6de42bdb147c293f71797b12023-09-15T09:28:59ZengWileyAdvanced Science2198-38442023-09-011026n/an/a10.1002/advs.202302677Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular CarcinomaSamuel Wan Ki Wong0Sze Keong Tey1Xiaowen Mao2Hiu Ling Fung3Zhi‐Jie Xiao4Danny Ka Ho Wong5Lung‐Yi Mak6Man‐Fung Yuen7Irene Oi‐Lin Ng8Jing Ping Yun9Yi Gao10Judy Wai Ping Yam11Department of Pathology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongDepartment of Pathology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongDepartment of Pathology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongDepartment of Pathology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongResearch Centre The Seventh Affiliated Hospital Sun Yat‐sen University 518107 Shenzhen P. R. ChinaDepartment of Medicine School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongDepartment of Medicine School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongDepartment of Medicine School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongState Key Laboratory of Liver Research, The University of Hong Kong Hong KongDepartment of Pathology Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510060 P. R. ChinaDepartment of Hepatobiliary Surgery II ZhuJiang Hospital Southern Medical University Guangzhou Guangdong 510280 P. R. ChinaDepartment of Pathology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong KongAbstract Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor‐derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV–vWF levels are found in a larger cohort of HCC–sEV samples and metastatic HCC cell lines compared to their respective normal counterparts. Circulating sEVs of late‐stage HCC patients markedly augment angiogenesis, tumor–endothelial adhesion, pulmonary vascular leakiness, and metastasis, which are significantly compromised by anti‐vWF antibody. The role of vWF is further corroborated by the enhanced promoting effect of sEVs collected from vWF‐overexpressing cells. sEV–vWF modulates endothelial cells through an elevated level of vascular endothelial growth factor A (VEGF‐A) and fibroblast growth factor 2 (FGF2). Mechanistically, secreted FGF2 elicits a positive feedback response in HCC via the FGFR4/ERK1 signaling pathway. The co‐administration of anti‐vWF antibody or FGFR inhibitor significantly improves the treatment outcome of sorafenib in a patient‐derived xenograft mouse model. This study reveals mutual stimulation between HCC and endothelial cells by tumor‐derived sEVs and endothelial angiogenic factors, facilitating angiogenesis and metastasis. It also provides insights into a new therapeutic strategy involving blocking tumor–endothelial intercellular communication.https://doi.org/10.1002/advs.202302677feedback signalinghepatocellular carcinomaintercellular communicationsmall extracellular vesiclesvon Willebrand factor |
| spellingShingle | Samuel Wan Ki Wong Sze Keong Tey Xiaowen Mao Hiu Ling Fung Zhi‐Jie Xiao Danny Ka Ho Wong Lung‐Yi Mak Man‐Fung Yuen Irene Oi‐Lin Ng Jing Ping Yun Yi Gao Judy Wai Ping Yam Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma Advanced Science feedback signaling hepatocellular carcinoma intercellular communication small extracellular vesicles von Willebrand factor |
| title | Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma |
| title_full | Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma |
| title_fullStr | Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma |
| title_full_unstemmed | Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma |
| title_short | Small Extracellular Vesicle‐Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma |
| title_sort | small extracellular vesicle derived vwf induces a positive feedback loop between tumor and endothelial cells to promote angiogenesis and metastasis in hepatocellular carcinoma |
| topic | feedback signaling hepatocellular carcinoma intercellular communication small extracellular vesicles von Willebrand factor |
| url | https://doi.org/10.1002/advs.202302677 |
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