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BDNF/TrkB Content and Interaction with Gastrin-Releasing Peptide Receptor Blockade in Colorectal CancerBrunetto de Farias C.a, m, n · Rosemberg D.B.d · Heinen T.E.a · Koehler-Santos P.b · Abujamra A.L.a, m, n · Kapczinski F.c, f, n · Brunetto A.L.a, g, m, n · Ashton-Prolla P.b, j · Meurer L.k · Reis Bogo M.n, o · Damin D.C.h, l · Schwartsmann G.a, i, n · Roesler R.a, e, n
Laboratories of aCancer Research, bGenomic Medicine and cMolecular Psychiatry, University Hospital Research Center (CPE-HCPA), dDepartment of Biochemistry, and eLaboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Basic Health Sciences, Departments of fPsychiatry, gPediatrics, hSurgery and iInternal Medicine, School of Medicine, jDepartment of Genetics, Institute of Biosciences, and kDepartment of Pathology and lDivision of Coloproctology, University Hospital, Federal University of Rio Grande do Sul, mChildren’s Cancer Institute (ICI-RS), nNational Institute for Translational Medicine (INCT-TM), and oLaboratory of Genomic and Molecular Biology, School of Biosciences, Pontifical Catholic University, Porto Alegre, Brazil
Objective: 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). Methods: 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. Results: 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. Conclusions: BDNF and TrkB are present in colorectal cancer and might contribute to resistance to GRPR antagonists.
© 2011 S. Karger AG, Basel