The Wnt Signalling Cascade and the Adherens Junction Complex in Craniopharyngioma Tumorigenesis
The Wnt Signalling Cascade and the Adherens Junction Complex in Craniopharyngioma Tumorigenesis
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DOI：
10.1007/s12022-014-9341-8
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发表时间：
2015-03-01
影响因子：
4.4
通讯作者：
Grossman, Ashley B.
中科院分区：
文献类型：
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作者：
Preda, Veronica;Larkin, Sarah J.;Grossman, Ashley B.
颅咽管瘤是上皮性鞍区肿瘤，有造釉细胞瘤（aCP）和乳头状（pCP）亚型。aCP类型通常发生在儿童时期，pCP发生在中年人; aCP通常含有CTNNB 1突变，编码β-连环蛋白，是粘附连接的一种成分和Wnt信号传导的介导剂。没有这样的突变事件与pCP相关，其中BRAF基因似乎更重要。在95个颅咽管瘤的大系列中，我们发现52%的病例中aCP亚型携带CTNNB 1突变，而pCP亚型则没有，大多数病例中免疫组织化学和测序方法之间一致。当存在时，CTNNB 1突变在整个aCP肿瘤中发现，而β-连环蛋白从膜到胞质溶胶和细胞核的易位仅限于侵入肿瘤前沿附近的小细胞簇。我们在100%的aCP中观察到易位的β-连环蛋白，不仅发生在细胞簇中，而且发生在分散在整个肿瘤中的单个细胞中。我们表征了涉及α-连环蛋白、β-连环蛋白、γ-连环蛋白、p120和E-钙粘蛋白（细胞溶质和膜组分）的粘附连接。虽然在其他鞍区肿瘤发生途径中被认为是重要的，但在这些肿瘤中没有粘附连接的破坏，表明连接完整性的丧失与β-连环蛋白易位或突变无关。我们的结论是CTNNB 1突变的基础上的肿瘤发生在大多数的aCP，这是不同的形态和在分子水平上从pCP。
Craniopharyngiomas are epithelial, sellar tumours with adamantinomatous (aCP) and papillary (pCP) subtypes. The aCP type usually occurs during childhood and pCP in middle-aged adults; aCPs often contain mutations in CTNNB1, encoding beta-catenin, a component of the adherens junction and a mediator of Wnt signalling. No such mutational event has been associated with pCPs, where the BRAF gene appears to be more important. In a large series of 95 craniopharyngiomas, we show that the aCP subtype harbours mutations in CTNNB1 in 52 % of cases, while the pCP subtype does not, with agreement between immunohistochemistry and sequencing methods in the majority of cases. When present, the CTNNB1 mutation is found throughout the aCP tumour, while translocation of beta-catenin from membrane to cytosol and nucleus is restricted to small cell clusters near the invading tumour front. We observed translocated beta-catenin in 100 % of aCPs, occurring not only in cell clusters but also in individual cells scattered throughout the tumour. We characterised the adherens junction involving alpha-catenin, beta-catenin, gamma-catenin, p120 and E-cadherin (cytosolic and membranous components). Although suggested to be important in other sellar mass tumourigenesis pathways, there was no disruption of the adherens junction in these tumours, indicating that a loss of junctional integrity is not associated with beta-catenin translocation or mutation. We conclude that mutations in CTNNB1 underlie tumourigenesis in the majority of aCPs, which are distinct morphologically and at the molecular level from pCPs.