Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease

Abstract

Mutations in apc which lead to activation of the Wnt signaling pathway are a hallmark of sporadic colon cancers but occur infrequently in colon cancers arising in patients with inflammatory bowel disease (IBD). There is evidence, however, that other components of the Wnt pathway may be altered in IBD-related colon cancer. In this study, we examined the expression the Wnt pathway components frizzled (Fz), the cell surface receptor, and disheveled (DVL), a family of cytoplasmic signal transduction molecules, in IBD and IBDrelated colon cancer. Paraffin sections of normal and malignant colon tissues were obtained from patients with a history of ulcerative colitis and from controls with sporadic colon cancer. Tissue sections were stained with antibodies directed against Fz1/2 receptors and DVL1, DVL2 and DVL3 and antigen expression visualized by immunohistochemistry. Fz1/2 receptors were minimally expressed in normal IBD mucosa, were not expressed in IBD colon cancer, but exhibited strong expression in dysplastic tissues adjacent to the cancers. DVL1 was not expressed in IBD normal mucosa or normal mucosa from non-IBD patients, but was expressed in all cancers. DVL2 and DVL3 were expressed in all normal mucosa samples tested, and in sporadic colon cancer, but were not expressed in colon cancers arising in IBD patients. The characteristics of Fz and DVL expression in IBD tissues reported herein provides evidence of the importance of Wnt signaling in IBD and IBD-related colon cancer and, specifically, the significance of non-APC components of this pathway. Fz may serve as a marker for dyspasia in IBD patients and DVL1 is a potential therapeutic target for IBD-related colon cancer.

Wnt Pathway-Related Gene Expression in Inflammatory Bowel Disease

“…Colonic mucosal proliferation is increased in UC, especially in the setting of high-grade dysplasia [26]. However, whereas some studies have suggested that Wnt signaling is involved in UC-related colon cancer [23], others suggest that UC-associated colon cancers arise along a different pathway than sporadic, Wnt/ APC driven, colon cancers [27]. Characteristics of Wnt signaling in UC mucosa compared with colonic mucosa of non-UC patients has not been previously defined.…”

“…Nucleotide array analysis comparing inflamed intestinal mucosa of patients with ulcerative colitis to inflamed mucosa of patients with Crohn's disease revealed increased expression of three Wnt pathway genes, SARP1 (SFRP2), frizzled (FZD), and disheveled (DVL), in samples from patients at highest risk for colon cancer-those with longstanding ulcerative colitis [22]. Recent work from our laboratory indicates that the pattern of DVL family-member expression is distinct in IBDassociated colon cancers in comparison with sporadic colon cancer [23]. Differential expression of FZD, DVL, and SFRP2 suggests that Wnt signaling may contribute to colon carcinogenesis in patients with IBD.…”

Morphological Classification of Corrupted Colonic Crypts in Ulcerative Colitis

“…In closing, while cellular descriptions and molecular signals that control cell proliferation and cell mutations during carcinogenesis in UC have received much attention ( [35][36][37][38][39][40], the signals that might be instrumental in designing morphogenesis (41) resulting in the "etching" of various CCC phenotypes in UC, have remained unattended.…”

Antimicrobial and antiviral effects of human defensins: pathogenetic value and prospective application to medicinal therapy

“…В исследо-вании пути сигнала Wnt, который был опосредован через β-катенин/Tcf-4, было показано, что он может быть ключевым регулирующим каналом для диффе-ренцировки клеток Панета и вызвать их созревание в криптах кишечника [174,233]. В сравнительных ис-следованиях было продемонстрировано, что генная программа клеток Панета критически зависит от ак-тивности эмбрионального фактора Tcf-4 кишечни-ка [213]. Этот сигнальный путь нарушен у пациентов IBD.…”