Abstract 3451: Blockade of BDNF-induced Trk B signaling inhibits peritoneal carcinomatosis arising arising from colorectal cancer

Abstract

Abstract Background: Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain-derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. Studies in our laboratory revealed: an association between TrkB levels and tumor progression and patient prognosis in gastric cancer; the association of TrkB with chemotherapy resistance in esophageal cancer; and TrkB's involvement in the epithelial-mesenchymal transition in colorectal cancer. We have also demonstrated the involvement of the BDNF/TrkB pathway in tumor progression in gastric cancer. Aim: We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Methods: Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a Trk inhibitor) were used for in vitro proliferation, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Results: Tissue BDNF mRNA levels were significantly associated with an undifferentiated histology as well as lymph node and liver metastasis. The co-expression of BDNF and TrkB mRNA was significantly associated with lymph node, and liver metastasis and peritoneal carcinomatosis. Patients with high BDNF mRNA had a significantly poor prognosis, and those that co-expressed both BDNF and TrkB mRNA showed a trend toward poor prognosis. BDNF promoted tumor cell proliferation and migration, facilitated invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB, and subsequently treated with K252a, peritoneal tumor metastasis was found to be significantly reduced, as compared with control mice. Conclusion: Blockade of BDNF-induced Trk B signaling inhibits peritoneal carcinomatosis arising arising from colorectal cancer. BDNF/TrkB signaling may thus be a potential target for treating the peritoneal carcinomatosis arising from colorectal cancer. Citation Format: Hiroki Imaoka, Koji Tanaka, Yoshinaga Okugawa, Tadanobu Shimura, Takahito Kitajima, Satoru Kondo, Shozo Ide, Susumu Saigusa, Yuji Toiyama, Yasuhiro Inoue, Toshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Kenichiro Ishii, Masato Kusunoki. Blockade of BDNF-induced Trk B signaling inhibits peritoneal carcinomatosis arising arising from colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3451. doi:10.1158/1538-7445.AM2014-3451