BDNF/TrkB Content and Interaction with Gastrin-Releasing Peptide Receptor Blockade in Colorectal Cancer

Abstract

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.

Serum concentrations of brain-derived neurotrophic factor (BDNF) are decreased in colorectal cancer patients

“…BDNF has been shown to be expressed in 93.3% of CRC tumours [17] and expression levels were observed to be higher in tumour tissue than non-neoplastic tissue [17,18]. Furthermore, multiple CRC cell lines have been shown to produce endogenous BDNF and together with TrkB an autocrine signalling loop exists in these cells that promotes cell proliferation and survival [18].…”

RNA interference-mediated knockdown of brain-derived neurotrophic factor (BDNF) promotes cell cycle arrest and apoptosis in B-cell lymphoma cells

“…The high expression level of BDNF is of great concern in cancer research. BDNF is found to be elevated in diverse tumors, including in hepatocellular carcimona [13], melanoma [14], and colorectal cancer [15], but not in nontumorous tissues or normal cell lines. Such previous researches suggest that BDNF may be involved in the development and progression of these malignancies.…”

Resistance to Anti-EGFR Therapy and Strategies to Overcome it: Possible Role of BDNF/TrkBma

“…We and others have reported that BDNF and TrkB levels are increased in CRC tumors [6,7]. Treating human CRC cells with an experimental anticancer peptide increases the mRNA expression, protein content, and secretion of BDNF, through a mechanism that depends on EGFR activity.…”

“…Treating human CRC cells with an experimental anticancer peptide increases the mRNA expression, protein content, and secretion of BDNF, through a mechanism that depends on EGFR activity. The increase in BDNF results in a compensatory response that rescues CRC cell proliferation and survival [6]. Importantly, BDNF protects against the anti-proliferative effect of cetuximab in a human CRC cell line, whereas a TrkB inhibitor can sensitize the cells to a low dose of cetuximab [8].…”