Wnt signalling and the mechanistic basis of tumour development

Abstract

Abnormalities in the Wnt signalling pathway are found in a wide range of cancers. The diverse origin of these malignancies implies that the contribution that disrupted Wnt signalling makes to tumourigenesis is not limited to specific tissue types and thus can be regarded as a step which is 'generic' to the process of carcinogenesis. In recent years, rapid progress has been made in the understanding of the Wnt signalling pathway, giving an insight into how inappropriate activation of this pathway may facilitate the neoplastic conversion of a normal cell. Furthermore, elucidation of the mechanisms that regulate Wnt signalling has led to the possibility of manipulating these mechanisms in order to downregulate Wnt signalling in established tumours. In this review, the Wnt signalling pathway is described. The role of aberrant Wnt signalling in tumour development is discussed together with its clinical implications for anti-tumour therapy.

Coincident expression of β-catenin and cyclin D1 in endometrial stromal tumors and related high-grade sarcomas

“…3 We could not detect any mutations of the b-catenin and APC genes among the cases showing overexpression of b-catenin. It is therefore possible that another mechanism of b-catenin accumulation may be present in these tumors.…”

“…We consider that further studies to support this speculation would be of value because the Wnt signaling pathway and cyclin D1 could potentially be a future target of anticancer drugs. 3,25 Expression of MMP-7, which is another target of b-catenin, was limited in this study to only one case of endometrial stromal nodule and three of lowgrade endometrial stromal sarcoma, and there was no significant correlation between b-catenin overexpression and MMP-7 expression. MMP-7 did not seem to have a crucial function in tissue invasion and metastasis in low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma in this study.…”

“…2 Aberrant activation of the Wnt signaling pathway is known to contribute to tumorigenesis of a wide range of tumors, including colorectal cancer. 3 The Wnt signaling pathway is regulated by many components such as APC and b-catenin, and genetic or epigenetic abnormalities of these components can cause dysregulated activation of the Wnt signaling pathway. These changes result in a maintained increase in the levels and transcriptional activity of b-catenin protein in the nucleus, with immunohistochemical results showing such an abnormal nuclear accumulation of b-catenin.…”

“…4,[7][8][9] Cyclin D1 is known to stimulate the cell cycle and contribute to the process of cell proliferation, which is a characteristic of the stem cell phenotype. 3 MMP-7 degrades extracellular matrices and is important in tumor invasion and metastasis. 10,11 We investigated the frequency of cyclin D1 and MMP-7 overexpression by immunohistochemistry and attempted to determine whether they correlate with nuclear overexpression of b-catenin.…”

Mitochondrial DNA genotyping efficiently reveals clonality of synchronous endometrial and ovarian cancers

“…3 Analogously, it ought to be considered that mutation screening of CTNNB1 may be a relatively reliable criterion to reach a synchrony diagnosis, as virtually all CTNNB1 mutations identified in human tumors, endometrial and ovarian cancer included, are located in exon 3, making this a hot spot for mutation activation of b-catenin. 21 The very nature of an oncogene implies that only a few protein residues need to be mutated for its constitutive activation, which is the case for b-catenin. Hence, the probability that two independent tumors within the same individual may harbor the same mutation by chance is more likely than what would occur for an inactivating mutation in a tumor suppressor gene, especially if activation of that oncogene is required to drive tumorigenesis.…”