BDNF mediated TrkB activation is a survival signal for transitional cell carcinoma cells
ABSTRACT Pathologically, >90% of bladder cancer is transitional cell carcinoma (TCC). Previously, brain-derived neurotrophic factor (BDNF) but not tropomyosin-related kinase B (TrkB) was found in normal urothelium. TrkB activation by BDNF has been shown to promote the progression of several cancers, however, the existence and functional roles of both BDNF and TrkB in TCC have not been elucidated. In this study, three human TCC cell lines, BFTC905, TSGH8301, and T24 were used for the investigation. Both BDNF and TrkB but not TrkA or TrkC identified by RT-PCR and Western blotting were found in these cell lines. Immunostaining demonstrated the cytosolic expression of BDNF and TrkB, as well as membranous expression of TrkB in these cells. BDNF released from three cell lines was also detected in culture medium by ELISA. The proliferation of BFTC905 cells was enhanced by recombinant human BDNF (rhBDNF) in vitro, which was associated with increased phospho-TrkB and phospho-ERK levels. In contrast, TrkB-Fc chimeric protein served as BDNF scavenger eliciting cytotoxicity. Addition of rhBDNF in these cell lines cultured in poly-HEMA [Poly(2-hydroxyethyl methacrylate)] coated dishes for 48 h did not confer resistance to anoikis. Increased phospho-Akt expression was observed transiently within an hour after rhBDNF administration but disappeared 24 h later. Weekly injections of 100 ng rhBDNF into the cancer cell-loading site for 6 weeks promoted BFTC905 xenograft growth in SCID mice. Daily injection of 5 microg TrkB-Fc chimeric protein into the tumor 2 weeks after tumor cell implantation delayed tumor growth concomitant with phospho-TrkB suppression in xenografts. These results indicate that BDNF binding to TrkB receptor is a survival signal for TCC cells. Drugs that block BDNF or TrkB may provide a new and potential approach for TCC therapy.
- SourceAvailable from: Yavuz Dodurga
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- "In the United States, bladder cancer is the fourth most common cancer in men (Jemal et al., 2009), whereas incidence is lowest in Asia and South America, where it is about 70% lower than in the United States. Pathologically, >90% of bladder cancers are transitional cell carcinoma (TCC) (Huang et al., 2010). Eighty percent of the transitional cell carcinomas are confined to epithelium for initial diagnosis (pTa, pT1), and 20% of that are invaded in the muscular layer (muscularis propria-pT2-3-4) (Dinney et al., 2004). "
ABSTRACT: This study was undertaken to evaluate the expression of DMBT1 in bladder cancer and its correlation with clinico-pathological parameters analyzed in bladder carcinoma patients. We investigated DMBT1 in 56 paraffin embedded specimens of transitional cell carcinoma of the urinary bladder. We assessed DMBT1 gene expression at mRNA level by RT-PCR. Our results show 100% expression of DMBT1 in bladder carcinoma samples. Due to this preliminary results; gene expression was compared to tumor grade, and a significant difference was detected between grade 1 and 3 (p = 0.028). The down-regulation of DMBT1 gene expression in carcinomas suggests the possible role in bladder cancer.Biomarkers 11/2011; 16(7):610-5. DOI:10.3109/1354750X.2011.620627 · 2.52 Impact Factor
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ABSTRACT: Neurotrophin and neuropeptide pathways are emerging targets in cancer. Here we show that brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are present in colorectal cancer and that BDNF levels are increased in tumors compared to nontumor tissue. In addition, we investigate the role of BDNF in influencing the response of colorectal cancer cells to inhibition of gastrin-releasing peptide receptors (GRPR). Fresh-frozen sporadic colorectal adenocarcinoma specimens and adjacent nonneoplastic tissue from 30 patients, as well as paraffin-embedded colorectal cancer samples from 21 patients, were used in this study. Cell proliferation and mRNA and protein levels were examined in HT-29 or SW620 cells treated with a GRPR antagonist, human recombinant BDNF (hrBDNF), a Trk antagonist K252a, or cetuximab. Expression of BDNF and TrkB was detected in tumor samples and cell lines. BDNF levels were higher in tumor samples compared to nonneoplastic tissue. BDNF expression and secretion were increased by GRPR blockade in HT-29 cells through a mechanism dependent on epidermal growth factor receptors. Treatment with hrBDNF prevented the effect of GRPR blockade on cell proliferation, whereas a Trk inhibitor reduced proliferation. BDNF and TrkB are present in colorectal cancer and might contribute to resistance to GRPR antagonists.Oncology 01/2010; 79(5-6):430-9. DOI:10.1159/000326564 · 2.61 Impact Factor
- Expert Review of Anti-infective Therapy 10/2011; 11(10):1473-5. DOI:10.1586/era.11.150 · 2.28 Impact Factor