Abstract
Mechanisms governing the metastasis of endometrial carcinoma (EC) are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05) and lymphovascular space involvement (p<0.05) in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT). RNA interference (RNAi)-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC.
Highlights
Endometrial carcinoma (EC) is the most common cancer of the female genital tract
tyrosine kinase B (TrkB) is Upregulated in EC Tissues Because increased TrkB expression has been associated with tumor progression of many human cancers, we sought to determine if this was true for EC
There was weak or no staining in normal endometrium, whereas moderate to strong TrkB immunostaining was observed in endometrial atypical hyperplasia and EC tissues (Figure 1A)
Summary
Endometrial carcinoma (EC) is the most common cancer of the female genital tract. In the United States, approximately 49,500 new cases of EC will be diagnosed in 2013, and 8,200 deaths are expected [1]. Most EC is diagnosed at an early stage, 30% of all cases are still diagnosed at later stages, which correlates with decreased survival rates [2]. Women with certain histological subtypes, high-grade lesions, deep invasion into the uterus, a tumor that extends into the cervix, or a tumor that has spread to the lymphatic system, the blood vessels or outside the uterus are at highest risk of recurrence [3]. The current treatments for EC include surgery and adjuvant radiotherapy or chemotherapy. Only a select number of patients respond to these adjuvant therapies [4]. It is critical to better understand the molecular mechanisms that drive EC
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