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Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis.

ABSTRACT: BACKGROUND:Wnt signalling dysregulation has been implicated in cancer, including colon and gastric cancer. Initiation of Wnt signalling is modulated by soluble Wnt antagonists (sWAs), including soluble frizzled related proteins, dickkopf (Dkk) proteins, and Wnt inhibitory factor-1 (Wif1). AIMS:To evaluate the role of sWAs in upper (gastric) and lower (colon) gastrointestinal tract tumorigenesis. METHODS:Dkk1-3, Wif1, and FrzB expression was evaluated by in situ RNA hybridisation on normal and malignant human gastric and colon tissues. Expression was graded semiquantitatively. RESULTS:Wif1, Dkk1, and Dkk2 were not expressed in normal gastric tissue. Dkk3 was expressed in some samples, with stronger expression in deep gastric glands. FrzB was expressed in several normal gastric samples, but not in matched tumour specimens. In contrast, Dkk1 and FrzB were not expressed in normal colon. Wif1 was expressed in most colon samples, with stronger expression at crypt bases. Dkk3 and Dkk2 expression was also concentrated at crypt bases. There were no differences between sWA expression in malignant colon and matched normal tissue. CONCLUSIONS:sWA expression differed between upper and lower gastrointestinal tract. The loss of FrzB in gastric cancer suggests that it acts as a tumour suppressor. The graded expression of Dkk3 in gastric tissue, and Dkk2, Dkk3, and Wif1 in colon tissue, with increased expression in the deep gastric glands/colonic crypt bases, where gastrointestinal stem cells reside, suggests that sWAs may be crucial Wnt signalling regulators in these tissues, and may contribute to stem cell pool maintenance. sWAs are important components of the gastrointestinal proliferative regulatory network.

SUBMITTER: Byun T

PROVIDER: S-EPMC1770654 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis.

Byun T T Karimi M M Marsh J L JL Milovanovic T T Lin F F Holcombe R F RF

Journal of clinical pathology 20050501 5

<h4>Background</h4>Wnt signalling dysregulation has been implicated in cancer, including colon and gastric cancer. Initiation of Wnt signalling is modulated by soluble Wnt antagonists (sWAs), including soluble frizzled related proteins, dickkopf (Dkk) proteins, and Wnt inhibitory factor-1 (Wif1).<h4>Aims</h4>To evaluate the role of sWAs in upper (gastric) and lower (colon) gastrointestinal tract tumorigenesis.<h4>Methods</h4>Dkk1-3, Wif1, and FrzB expression was evaluated by in situ RNA hybridis ...[more]

PMID: 15858124

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Project description:BACKGROUND:Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). However, the aberrant level of Wnt ligands in serum have not been explored. Here, we aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC. METHODS:The Oncomine database was used to analyze the relationship between WNT4 and the prognosis of CRC. ELISA was performed to measure WNT4 levels in serum and conditioned medium from fresh CRC tissues and adjacent normal tissues. Western blot and immunohistochemistry were carried out to measure the expression of WNT4 in human CRC tissues and adjacent normal tissues. The migration and invasion of CRC cells were determined by trans-well assay, and the effects of WNT4 on CRC invasion and metastasis in vivo were verified by tumor xenograft in nude mice. Cancer-associated fibroblasts (CAFs) and angiogenesis in subcutaneous nodules were detected by immunofluorescence (IF). In addition, the suspended spheres formation and tube formation assay were performed to explore the effects of WNT4 on CAFs and angiogenesis respectively. RESULTS:WNT4 was significantly upregulated in serum of CRC patients, and CRC tissues were identified as an important source of elevated WNT4 levels in CRC patients. Interestingly, elevated levels of WNT4 in serum were downregulated after tumor resection. Furthermore, we found that WNT4 contributed to epithelial-to-mesenchymal transition (EMT) and activated fibroblasts by activating the WNT4/?-catenin pathway in vitro and in vivo. Moreover, angiogenesis was induced via the WNT4/?-catenin/Ang2 pathway. Those effects could be reversed by ICG-001, a ?-catenin/TCF inhibitor. CONCLUSION:Our findings indicated that serum levels of WNT4 may be a potential biomarker for CRC. WNT4 secreted by colorectal cancer tissues promote the progression of CRC by inducing EMT, activate fibroblasts and promote angiogenesis through the canonical Wnt/?-catenin signalling pathway.

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Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis.

Publications

Expression of secreted Wnt antagonists in gastrointestinal tissues: potential role in stem cell homeostasis.

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