BDNF mediated TrkB activation is a survival signal for transitional cell carcinoma cells

Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien 970, Taiwan, R.O.C.
International Journal of Oncology (Impact Factor: 3.03). 06/2010; 36(6):1469-76. DOI: 10.3892/ijo_00000633
Source: PubMed


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.

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    • "In previous years it has been shown that BDNF expression is associated with different functions in non-neuronal solid tumors. BDNF expression controls cellular proliferation and survival, and is also connected to cell invasion via the secretion of matrix metalloproteinase (8–12). The PI3K/AKT and ERK pathways in tumor cells activated by BDNF may result in cells that are not sensitive to chemotherapeutic drugs (13,14). "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) has been observed to be elevated in solid tumors including colorectal cancer. The present study aimed to investigate the effect of modulation of BDNF at the transcription level on the cellular function of colorectal cells and to increase our understanding of its biological role in human colon cancer. An investigation of a cohort of human colorectal tissues (tumor n=66; normal n=88) using quantitative PCR and immunohistochemistry demonstrated that BDNF is aberrantly expressed in human colon cancer and a significantly raised level of BDNF is associated with its stage at diagnosis. The expression profile of BDNF in human colon cancer cell lines was evaluated using RT-PCR. A set of anti-BDNF ribozymes were used to transfect colon cancer cells in order to generate BDNF knockdown cells to evaluate the effect on growth and apoptosis. BDNF gene transcripts were successfully detected in the colon cancer cell lines, Caco-2 and HRT18. BDNF knockdown in Caco-2 and HRT18 cell lines resulted in decreased rates of growth and proliferation. Analysis of apoptosis showed that cell apoptosis was increased. It is concluded that BDNF, a neurotrophic growth factor aberrantly expressed in cancers such as colon cancer, has a profound impact on the cellular behavior of colon cancer cells and that BDNF is associated with a reduction in the apoptosis of colon cancer. BDNF is therefore a potential therapeutic target in colon cancer and its effect in human colon cancer requires further investigation.
    Experimental and therapeutic medicine 12/2013; 6(6):1475-1481. DOI:10.3892/etm.2013.1330 · 1.27 Impact Factor
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    • "Several studies indicated that BDNF and/or its receptor, TrkB, might be involved in cancer growth and metastasis in several malignant tissues, such as neuroblastoma (Aoyama et al, 2001), pancreatic ductal carcinoma (Miknyoczki et al, 1999), prostate cancer (Montano and Djamgoz, 2004), lung cancer (Ricci et al, 2001), and hepatocellular carcinoma (Yang et al, 2005). The TrkB activation by BDNF was shown to enhance the proliferation and survival of transitional cell carcinoma cell lines, whereas a TrkB antagonist suppressed their migration and invasion (Huang et al, 2010a, 2010b). Previously, we used RNA interference in colorectal cancer (CRC) cells to demonstrate that high levels of TrkB transcript expression is associated with poor prognosis in CRC patients and enhanced malignant potential in terms of proliferation, migration, invasion, and anoikis inhibition (Fujikawa et al, 2012). "
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    ABSTRACT: Background: Brain-derived neutrophic factor (BDNF) is a member of the neutrophin family that is known to activate the high-affinity tropomyosin-related receptor kinase B (TrkB). This study aimed to clarify the clinical and biological significance of the BDNF/TrkB pathway in gastric cancer. Methods: We analysed BDNF and TrkB expression in gastric cancer samples by real-time reverse transcription PCR and immunohistochemistry. To investigate the biological role of BDNF/TrkB axis, recombinant human BDNF (rhBDNF) and the Trk antagonist K252a were used for in vitro and in vivo analysis. Results: The BDNF expression at the invasive front of primary tumours was significantly elevated compared with that in the tumour core and adjacent normal mucosa. Increased BDNF expression at the invasive front was significantly correlated with factors reflecting disease progression, and poor prognosis. Increased co-expression of the BDNF/TrkB axis was significantly correlated with poor prognosis. Gastric cancer cells expressed BDNF, and administration of rhBDNF promoted proliferation, migration, invasion, and inhibition of anoikis. These effects were generally inhibited by K252a. In an in vivo assay, BDNF(+)/TrkB(+) gastric cancer cells injected into nude mice established peritoneal dissemination, whereas K252a inhibited tumour growth. Conclusion: The BDNF/TrkB pathway might be deeply involved in gastric cancer disease progression.
    British Journal of Cancer 11/2012; 108(1). DOI:10.1038/bjc.2012.499 · 4.84 Impact Factor
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    • "TrkB activated by exogenous BDNF confers resistance to anoikis [28]–[30], [50], and induces EMT through transcriptional activation of several EMT-inducing transcription factors [21], [22], [32]. We present the first evidence that, in breast cancer, endogenous NTF3 is secreted upon suspension to enable TrkB-mediated anoikis resistance. "
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    ABSTRACT: Anoikis is apoptosis initiated upon cell detachment from the native extracellular matrix. Since survival upon detachment from basement membrane is required for metastasis, the ability to resist anoikis contributes to the metastatic potential of breast tumors. miR-200c, a potent repressor of epithelial to mesenchymal transition, is expressed in luminal breast cancers, but is lost in more aggressive basal-like, or triple negative breast cancers (TNBC). We previously demonstrated that miR-200c restores anoikis sensitivity to TNBC cells by directly targeting the neurotrophic receptor tyrosine kinase, TrkB. In this study, we identify a TrkB ligand, neurotrophin 3 (NTF3), as capable of activating TrkB to induce anoikis resistance, and show that NTF3 is also a direct target of miR-200c. We present the first evidence that anoikis resistant TNBC cells up-regulate both TrkB and NTF3 when suspended, and show that this up-regulation is necessary for survival in suspension. We further demonstrate that NF-κB activity increases 6 fold in suspended TNBC cells, and identify RelA and NF-κB1 as the transcription factors responsible for suspension-induced up-regulation of TrkB and NTF3. Consequently, inhibition of NF-κB activity represses anoikis resistance. Taken together, our findings define a critical mechanism for transcriptional and post-transcriptional control of suspension-induced up-regulation of TrkB and NTF3 in anoikis resistant breast cancer cells.
    PLoS ONE 11/2012; 7(11):e49987. DOI:10.1371/journal.pone.0049987 · 3.23 Impact Factor
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