期刊
BRITISH JOURNAL OF CANCER
卷 104, 期 6, 页码 941-947出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2011.55
关键词
renal cell carcinoma; sorafenib; molecular targeted therapy; xenograft; survivin
类别
资金
- National Kidney Foundation [NKFRC/2008/07/23]
- SingHealth [TDF/CS004/2008]
- National Medical Research Council [NIG/005/2008]
- Singapore Millennium Foundation and Singapore Cancer Syndicate [SCS-AS0032, SCS-HS0021, SCS-AMS0086]
BACKGROUND: It is widely recognised that sorafenib inhibits a range of molecular targets in renal cell carcinoma (RCC). In this study, we aim to use patient- derived RCC xenografts to delineate the angiogenic and non-angiogenic molecular targets of sorafenib therapy for advanced RCC (aRCC). METHODS: We successfully generated three patient RCC-derived xenografts in severe combined immunodeficient mice, consisting of three different RCC histological subtypes: conventional clear cell, poorly differentiated clear cell RCC with sarcomatoid changes, and papillary RCC. This study also used clear cell RCC cells (786-0/ EV) harbouring mutant VHL to investigate the clonogenic survival of cells transfected with survivin sense and antisense oligonucleotides. RESULTS: All three xenografts retain their original histological characteristics. We reported that sorafenib inhibited all three RCC xenograft lines regardless of histological subtypes in a dose-dependant manner. Sorafenib-induced growth suppression was associated with not only inhibition of angiogenic targets p-PDGFR-beta, p-VEGFR-2, and their downstream signalling pathways p-Akt and p-ERK, cell cycle, and anti-apoptotic proteins that include cyclin D1, cyclin B1, and survivin but also upregulation of proapoptotic Bim. Survivin knockdown by survivin-specific antisense-oligonucleotides inhibited colony formation and induced cell death in clear cell RCC cells. CONCLUSION: This study has shed light on the molecular mechanisms of sorafenib in RCC. Inhibition of non-angiogenic molecules by sorafenib could contribute in part to its anti-tumour activities observed in vivo, in addition to its anti-angiogenic effects. British Journal of Cancer (2011) 104, 941-947. doi: 10.1038/bjc.2011.55 www. bjcancer. com
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