Laboratorie of Cancer Research, University Hospital Research Center (CPE-HCPA), Porto Alegre, Brazil.
Oncology. 2010;79(5-6):430-9. doi: 10.1159/000326564. Epub 2011 Apr 8.
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.
神经营养因子和神经肽途径是癌症治疗的新兴靶点。本研究显示脑源性神经营养因子（BDNF）及其受体 TrkB 存在于结直肠癌中，且肿瘤组织中 BDNF 水平高于非肿瘤组织。此外，我们还研究了 BDNF 影响结直肠癌细胞对胃泌素释放肽受体（GRPR）抑制剂反应的作用。
本研究使用了 30 例散发性结直肠腺癌患者的新鲜冷冻肿瘤组织和相邻非肿瘤组织标本，以及 21 例患者的石蜡包埋结直肠癌样本。用 GRPR 拮抗剂、人重组 BDNF（hrBDNF）、Trk 拮抗剂 K252a 或西妥昔单抗处理 HT-29 或 SW620 细胞后，检测细胞增殖以及 mRNA 和蛋白水平。
在肿瘤样本和细胞系中检测到 BDNF 和 TrkB 的表达。与非肿瘤组织相比，肿瘤样本中的 BDNF 水平更高。GRPR 阻断通过表皮生长因子受体依赖性机制增加 HT-29 细胞中 BDNF 的表达和分泌。hrBDNF 处理可阻止 GRPR 阻断对细胞增殖的影响，而 Trk 抑制剂则减少增殖。
BDNF 和 TrkB 存在于结直肠癌中，可能有助于抵抗 GRPR 拮抗剂。
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