β-catenin in epithelial tumorigenesis

catenin is a critical mediator of the Wnt canonical pathway for multiple cellular responses. Using transgenic mice, loss or activation of β-catenin has been studied in multiple tissues to elucidate its role in vivo. In this editorial, we focus on recent findings examining the involvement of β-catenin in cancer initiation and progression of epithelial tissues in thymus and prostate. β-catenin in the thymic epithelium and thymoma. In thymus, correct differentiation of cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs) is required for thymocyte development and selection. Ablation of β-catenin in Keratin 5 (K5)-expressing mTECs results in thymic atrophy, mainly due to a defective IL-7 niche in β-catenin-deficient mTEC derivatives that are unable to support early thymocyte development [1]. Using a lineage-tracing approach, we found that an increased number of K8-expressing cTECs are generated from β-catenin-deficient mTECs, and differentiation of Aire + and MHCII high mTECs from β-catenin-deficient mTECs is defective [1]. Additionally, we created transgenic mouse lines, which expressed an active form of β-catenin fused with the ligand-binding domain of the estrogen receptor (∆N64Ctnnb1/ER T2) in mTECs, that could functionally rescue defects in thymopoiesis caused by β-catenin-deficient mTEC derivatives [2]. These findings suggest that endogenous β-catenin is required for maintaining mTEC differentiation and may block cTEC differentiation (Figure 1A). In addition, expression of the ∆N64Ctnnb1/ER T2 transgene in mTECs can activate Wnt/β-catenin canonical signaling and drive thymoma initiation and progression [2]. Early thymoma lesions driven by the ∆N64Ctnnb1/ER T2 transgene are frequently identified at the cortical-medullary junction (CMJ) of the transgenic thymi. Interestingly, the CMJ of the thymus is hypothesized to be the anatomic location of bi-potential progenitors that can give rise to both cTECs and mTECs. Thus, this observation implies that the thymic epithelial progenitors at CMJ are susceptible to β-catenin oncogenic signaling during thymoma development. The thymoma lesions express K5, ∆Np63 (α and β isoforms), and β5t, which is a protease subunit used as a differential diagnostic marker of human type B3 thymomas. Consistent with expression patterns Editorial found in human thymomas, ∆N64Ctnnb1/ER T2-mediated thymomas showed loss of AIRE and downregulation of p21. Moreover, histologic characteristics of ∆N64Ctnnb1/ER T2 transgene-induced thymomas have a squamoid appearance and loose connective tissue in the perivascular space resembling that of human type B3 thymomas (or atypical thymomas). Thus, our recent findings demonstrate that β-catenin oncogenic signaling drives K5-expressing thymoma initiation and progression (Figure 1A). Figure 1. The proposed models for the …