Inverse correlation of the up‐regulation of FZD10 expression and the activation of β‐catenin in synchronous colorectal tumors

Abstract

T he Wnt signal pathway is an essential signal pathway for multicellular organisms with diverse biological consequences. A large number of components are involved in signal transduction, one of which is the Frizzled homolog protein (FZD) that serves as a seven-pass transmembrane receptor for Wnt ligands. So far 10 members of FZD family genes have been identified based on structural and functional homologies. Colorectal cancers (CRCs) are prototype tumors and the Wnt signal pathway is profoundly involved in CRC pathogenesis. There are two major intracellular pathways of Wnt signal transduction: canonical and non-canonical pathways. In the early stages of CRC progression, Wnt signal activation frequently appears due to genetic alterations of molecules in the Wnt canonical pathway including Adenomatous polyposis coli (APC) and β-catenin, resulting in the stabilization and nuclear translocation of β-catenin with the subsequent transcriptional activation of Wnt target genes.(1-6) In contrast to extensive studies related to downstream events of Wnt signal transduction, little attention has been paid to the specificity of FZD receptors in CRCs, although there have been a few reports demonstrating the up-regulation of FZD1 and FZD2 in poorly differentiated CRCs,and FZD7 expression in colon cancer cell lines with APC or β-catenin mutations. (8) We previously demonstrated that FZD10, the latest cloned member of the FZD family, was specifically up-regulated in synovial sarcomas based upon a genome-wide analysis of gene-expression profiles in soft-tissue sarcomas.(9) Since FZD10 is located in plasma membranes and its expression is very low or absent in vital organs, we focused on this molecule as a likely candidate for antibody-based therapy, and demonstrated the therapeutic potential of antibodies directed against FZD10 in synovial sarcomas.(10,11) Although FZD10 protein expression patterns in tumor tissues were not demonstrated, and the precise biological behavior of FZD10 with regard to tumorigenesis of CRCs remains obscure, the up-regulation of FZD10 mRNA was observed in two out of 11 cases with primary CRCs. (12) Using a specific monoclonal antibody directed against FZD10, we analyzed expression patterns of FZD10 in colonic polyps, primary CRCs, and metastatic liver lesions to elucidate the role of FZD10 in the progression of CRCs. In addition, we examined the relationship between expression patterns of FZD10 and β-catenin, which is the main signal transducer of the canonical Wnt pathway. Materials and MethodsTissue samples and cell lines. Tissue samples were obtained from 104 CRC patients that had undergone surgical curative resection at the Department of Surgery, Kyoto University Hospital during 1999-2001 (Table 1). All samples were approved for analysis by the ethics committee of the Faculty of Medicine of Kyoto University. Formalin-fixed and paraffin-embedded samples were obtained from all patients, and were subdivided into the three following groups: (1) only primary tumor samples were available in 57 cases; (2) p...

Wnt/β-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer’s vesicle

“…1H) (Jho et al, 2002;Huang and Schier, 2009). Conversely, a role of fzd10 in the Wnt/PCP pathway, as suggested by studies in synovial sarcomas and synchronous colorectal tumors Nagayama et al, 2009), was excluded because defects in convergent extension movement, such as widened somite and abnormal ntl, hgg1 (ctsl1b -Zebrafish Information Network) and/or dlx3 staining, were not detected in fzd10 morphants (supplementary material Fig. S2O-R).…”

BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10

“…Notably, BRMS1L 29 , EMT 30 and enhanced cancer invasiveness and metastasis [30][31][32] . Furthermore, qRT-PCR verified that WNT9B and WNT10B, two important Wnt ligands, were reduced by BRMS1L for 1.43-and 1.61-fold, respectively, whereas FZD10 (frrizled class receptor 10), a Wnt signalling receptor [33][34][35] , was reduced by 84% (Po0.001, t-test, Fig. 3b).…”

“…Wnt signalling pathway has been shown to control self-renewal and differentiation of cancer cells 29 , and aberrant activation of Wnt signalling leads to EMT in breast epithelial cells 41,42 . As a receptor for the Wnt pathway, FZD10 is expressed at high level in colorectal cancers, gastric cancers, as well as in synovial sarcomas, and is associated with the activation of Wnt signalling in these cancers 33,34,43 . For instance, FZD10 activates the non-canonical Wnt/JNK pathway in synovial sarcoma cell 34 and enhances their anchorage-independent growth.…”

Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity

“…Since the rapid internalization would be one of the important factors of 90 Y-MAb 92-13 efficacy as described previously [26], FZD10 would be a suitable target of RIT. It was reported that FZD10 was expressed highly in approximately onequarter of colon cancer [27], up-regulated in 7 cases of 37 informative cases of lung cancer [28] and in a subset of gastric cancer. Therefore, 90 Y-MAb 92-13 would be a potential therapeutic agent for application to a variety of cancers.…”