Abstract 1142: Tropomyosin-related receptor kinase B at the invasive front of gastric cancer and tumor cell dedifferentiation

Abstract

Abstract Background: Tropomyosin-related receptor kinase B (TrkB) promotes proliferation and invasion related to poor prognoses of various malignancies. TrkB is also involved in resistance to anoikis (a form of detachment-induced apoptosis) and epithelial-to-mesenchymal transition (EMT). Gastric cancer (GC) with mixed histology frequently shows both a well/moderately differentiated (low or intermediate grade) at the surface to the center and a poorly differentiated (high grade) at the invasive front. Dedifferentiation is the progression of cells towards a less differentiated state. Here, we examined the role of TrkB at the invasive front of gastric cancer and its association with tumor cell dedifferentiation. Methods: Immunoreactive TrkB at the invasive front and dedifferentiation, which shows a higher histological grade than that at the surface or center, was evaluated and clarified its clinical and prognostic significance in 320 GC specimens. In vitro study, expression of TrkB, E-cadherin, vimentin, Oct4, and Sox2 at a wound healing edge, which mimics the tumor invasive front, was evaluated in the human GC cell line MKN7. Results: Fifty patients (16%) showed high TrkB expression at the invasive front. Twenty-one patients (6.6%) showed tumor cell dedifferentiation. High TrkB expression at the invasive front and tumor cell dedifferentiation were significantly associated with aggressive phenotypes of GC such as a larger tumor size, depressive macroscopic morphology, lymphovascular invasion, advanced T stage, lymph node involvement, synchronous liver and peritoneal metastasis, and advanced stage. Six patients had high TrkB expression in dedifferentiated GC cells. High TrkB expression at the invasive front was an independent prognostic factor of GC in multivariate analysis (hazard ratio; 1.69, p=0.039). MKN7 cells at the wound healing edge showed increased TrkB, vimentin, Oct4, and Sox2 expression and decreased E-cadherin expression. Tumor cells at the wound edge also showed an increased size and morphological changes in the nucleus or cytoplasm, suggesting that MKN-7 cells at the wound edge may undergo EMT or tumor cell dedifferentiation similar to that of tumor cells at the invasive front of primary tumors. Conclusion: Assessment of immunoreactive TrkB at the tumor invasive front in whole tissue sections provides prognostic information for GC patients. Citation Format: Koji Tanaka, Tadanobu Shimura, Takahito Kitajima, Satoru Kondo, Shozo Ide, Hiroki Imaoka, Yoshinaga Okugawa, Susumu Saigusa, Yuji Toiyama, Yasuhiro Inoue, Tshimitsu Araki, Keiichi Uchida, Yasuhiko Mohri, Masato Kusunoki. Tropomyosin-related receptor kinase B at the invasive front of gastric cancer and tumor cell dedifferentiation. [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 1142. doi:10.1158/1538-7445.AM2014-1142