Article: Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: Implication in hepatocellular carcinoma
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- Publisher Website: 10.1158/1078-0432.CCR-10-2802
- Scopus: eid_2-s2.0-79955990588
- PMID: 21421859
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| Title | Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: Implication in hepatocellular carcinoma | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Lam, CT1 Yang, ZF1 Lau, CK1 Tam, KH1 Fan, ST1 Poon, RTP1 | ||||||
| Keywords | Brain derived neurotrophic factor Angiogenesis Animal cell Cell invasion Cell migration | ||||||
| Issue Date | 2011 | ||||||
| Publisher | American Association for Cancer Research. | ||||||
| Citation | Clinical Cancer Research, 2011, v. 17 n. 10, p. 3123-3133 [How to Cite?] DOI: http://dx.doi.org/10.1158/1078-0432.CCR-10-2802 | ||||||
| Abstract | Purpose: Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development. Experimental Design: BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance. Results: Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival. Conclusions: BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC. ©2011 AACR. | ||||||
| ISSN | 1078-0432 2011 Impact Factor: 7.742 2011 SCImago Journal Rankings: 1.066 | ||||||
| DOI | http://dx.doi.org/10.1158/1078-0432.CCR-10-2802 | ||||||
| ISI Accession Number ID | WOS:000290610000008
Funding Information: This study was supported by Small Project Funding of the University of Hong Kong and by the Collaborative Research Fund (HKU5/CRF/08) of the Research Grant Council Hong Kong. | ||||||
| References | References in Scopus | ||||||
| Grants | Liver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury |
| dc.contributor.author | Lam, CT | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Yang, ZF | ||||||
| dc.contributor.author | Lau, CK | ||||||
| dc.contributor.author | Tam, KH | ||||||
| dc.contributor.author | Fan, ST | ||||||
| dc.contributor.author | Poon, RTP | ||||||
| dc.date.accessioned | 2011-07-27T01:36:44Z | ||||||
| dc.date.available | 2011-07-27T01:36:44Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.description.abstract | Purpose: Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development. Experimental Design: BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance. Results: Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival. Conclusions: BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC. ©2011 AACR. | ||||||
| dc.description.grant | Liver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury | ||||||
| dc.description.grantcode | 99532 | ||||||
| dc.description.nature | Link_to_subscribed_fulltext | ||||||
| dc.identifier.citation | Clinical Cancer Research, 2011, v. 17 n. 10, p. 3123-3133 [How to Cite?] DOI: http://dx.doi.org/10.1158/1078-0432.CCR-10-2802 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1158/1078-0432.CCR-10-2802 | ||||||
| dc.identifier.epage | 3133 | ||||||
| dc.identifier.hkuros | 187636 | ||||||
| dc.identifier.isi | WOS:000290610000008
Funding Information: This study was supported by Small Project Funding of the University of Hong Kong and by the Collaborative Research Fund (HKU5/CRF/08) of the Research Grant Council Hong Kong. | ||||||
| dc.identifier.issn | 1078-0432 2011 Impact Factor: 7.742 2011 SCImago Journal Rankings: 1.066 | ||||||
| dc.identifier.issue | 10 | ||||||
| dc.identifier.openurl | | ||||||
| dc.identifier.pmid | 21421859 | ||||||
| dc.identifier.scopus | eid_2-s2.0-79955990588 | ||||||
| dc.identifier.spage | 3123 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/135540 | ||||||
| dc.identifier.volume | 17 | ||||||
| dc.language | eng | ||||||
| dc.publisher | American Association for Cancer Research. | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | Clinical Cancer Research | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.subject | Brain derived neurotrophic factor | ||||||
| dc.subject | Angiogenesis | ||||||
| dc.subject | Animal cell | ||||||
| dc.subject | Cell invasion | ||||||
| dc.subject | Cell migration | ||||||
| dc.title | Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: Implication in hepatocellular carcinoma | ||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong