Colorectal cancer and genetic alterations in the Wnt pathway

Segditsas, Stefania; Tomlinson, Ian

doi:10.1038/sj.onc.1210059

Cited by 516 publications

(395 citation statements)

References 40 publications

(42 reference statements)

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“…Nuclear b-catenin functions as a transcription cofactor of the T-cell factor/lymphoid enhancer factor family and leads to the activation of Wnt signaling, which is associated with CRC progression (Segditsas and Tomlinson, 2006). Therefore, we next investigated the effect of mPGES-1 deficiency on b-catenin expression and localization by immunohistochemical analysis.…”

Section: Resultsmentioning

confidence: 99%

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E 2 is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE 2 -biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of b-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D 2 and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MUs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MUs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MUs failed to facilitate tumor growth. The adoptive transfer of WT BM-MUs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MUs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

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Section: Resultsmentioning

confidence: 99%

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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“…CTNNB1 alterations in sinonasal HPC have been consistently reported in exon 3, with missense mutations [4,5]; mutations affecting positions 32-45 of the amino-terminal region disrupt phosphorylation-dependent degradation of b-catenin [6]. Numerous other tumor types harbor CTNNB1 mutations, most frequently desmoid-type fibromatosis [7,8] as well as salivary basal cell adenoma [9], pilomatricoma and pilomatrix carcinoma [10], hepatocellular carcinoma [11], colorectal carcinoma [12], medulloblastoma [13], endometrial adenocarcinoma [14], Wilms tumor [15], and adrenocortical carcinoma [16]. Sinonasal HPC shares the features of a uniform spindle and ovoid cell population and HPC-like vessels with SFT, Fig.…”

Section: Discussionmentioning

confidence: 99%

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Fletcher

2016

Head and Neck Pathol

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Sinonasal hemangiopericytoma (HPC) is a tumor showing pericytic myoid differentiation and which arises in the nasal cavity and paranasal sinuses. CTNNB1 mutations appear to be a consistent aberration in sinonasal HPC, and nuclear expression of b-catenin has been reported. Our aim was to evaluate the frequency of b-catenin expression in sinonasal HPC and its histologic mimics in the upper aerodigestive tract. Cases were retrieved from the surgical pathology and consultation files. Immunohistochemical staining for b-catenin was performed on 50 soft tissue tumors arising in the sinonasal tract or oral cavity, and nuclear staining was recorded semiquantitatively by extent and intensity. Nuclear reactivity for b-catenin was present in 19/20 cases of sinonasal HPC; 17 showed moderate-to-strong multifocal or diffuse staining, and 2 had moderate focal nuclear reactivity. All solitary fibrous tumors (SFT) (10/10) showed focal-to-multifocal nuclear staining, varying from weak to strong in intensity. Most cases of synovial sarcoma (9/10) showed nuclear b-catenin expression in the spindle cell component, ranging from focal-weak to strong-multifocal. No cases of myopericytoma (0/10) showed any nuclear b-catenin expression. bcatenin expression is prevalent in sinonasal HPC, but is also frequent in SFT and synovial sarcoma. Our findings indicate that b-catenin is not a useful diagnostic tool in the evaluation of spindle cell tumors with a prominent hemangiopericytoma-like vasculature in the sinonasal tract and oral cavity, and that definitive diagnosis relies on the use of a broader immunohistochemical panel.

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“…Direct connection between E-cadherin and gastric carcinogenesis has been demonstrated through the finding that genetic mutations in CDH1, the gene encoding E-cadherin, are associated with hereditary diffuse gastric cancer (Guilford et al, 1998). It is also well established that deregulated b-catenin signaling has an important function in the development of colorectal carcinoma (Segditsas and Tomlinson, 2006).…”

Section: Disruption Of Tight Junction and The Loss Of Epithelial Polamentioning

confidence: 99%

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

Hatakeyama

2008

Oncogene

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Colorectal cancer and genetic alterations in the Wnt pathway

Cited by 516 publications

References 40 publications

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

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