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1.
Oncogene ; 30(10): 1183-93, 2011 Mar 10.
Article in English | MEDLINE | ID: mdl-21057538

ABSTRACT

The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Drug Resistance, Neoplasm/genetics , Endothelial Cells/drug effects , Fibroblast Growth Factor 2/metabolism , Indoles/pharmacology , Pyrroles/pharmacology , Aged , Female , Fibroblast Growth Factor 2/genetics , Humans , Immunoblotting , Kidney Neoplasms/metabolism , Male , Middle Aged , Signal Transduction/drug effects , Signal Transduction/physiology , Sunitinib , Tissue Array Analysis
2.
Prostate Cancer Prostatic Dis ; 13(2): 117-25, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20177423

ABSTRACT

Our previous work identified a chromosomal translocation t(4;6) in prostate cancer cell lines and primary tumors. Using probes located on 4q22 and 6q15, the breakpoints identified in LNCaP cells, we performed fluorescence in situ hybridization analysis to detect this translocation in a large series of clinical localized prostate cancer samples treated conservatively. We found that t(4;6)(q22;q15) occurred in 78 of 667 cases (11.7%). The t(4;6)(q22;q15) was not independently associated with patient outcome. However, it occurs more frequently in high clinical T stage, high tumor volume specimens and in those with high baseline PSA (P=0.001, 0.001 and 0.01, respectively). The t(4;6)(q22;q15) occurred more frequently in samples with two or more TMPRSS2:ERG fusion genes caused by internal deletion than in samples without these genomic alterations, but this correlation is not statistically significant (P=0.0628). The potential role of this translocation in the development of human prostate cancer is discussed.


Subject(s)
Chromosomes, Human, Pair 4/genetics , Chromosomes, Human, Pair 6/genetics , Prostatic Neoplasms/genetics , Translocation, Genetic , Genomic Instability , Humans , In Situ Hybridization, Fluorescence , Male , Oncogene Proteins, Fusion/genetics , Prognosis , Prostatic Neoplasms/pathology
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