Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids

Vincan, Elizabeth; Darcy, Phillip K.; Farrelly, Caroline A.; Faux, Maree C.; Brabletz, Thomas; Ramsay, Robert G.

doi:10.1038/sj.onc.1210026

Cited by 70 publications

(104 citation statements)

References 50 publications

(75 reference statements)

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“…Moreover, the down-regulation of FZD7 with Small-interfering RNA (siRNA) in colon cancer cells resulted in decreased in vitro invasion activity (Ueno et al, 2008), which is consistent with previous findings that inhibition of FZD7 expression with dominant-negative mutant construct or siRNA reduced the motility of hepatocellular carcinoma cells (Merle et al, 2004) or colon cancer cells (Vincan et al, 2007), respectively. These data suggest that FZD7 may be important in the invasion and metastasis of CRC.…”

supporting

confidence: 78%

“…As shown in Figure 2D, it was clearly decreased with FZD7_siRNA transfection, suggesting that FZD7 may be a receptor for the non-canonical Wnt/JNK signalling pathway in colon cancer cells. These data may provide a molecular explanation for the previous findings that inhibition of FZD7 expression decreased the migratory activity of colon cancer cells (Vincan et al, 2007) and hapatocellular carcinoma cells (Merle et al, 2004).…”

Section: Discussionsupporting

confidence: 53%

“…However, no association was found between FZD7 expression and clinico-pathological factors except for pathological stage. This may be related to the functional diversity of FZD7 including induction of mesenchymal -epithelial transition (Vincan et al, 2007), osteogenic differentiation of hMSCs (Song et al, 2006) and Wnt11 induction of differentiated cell phenotypes (Yamanaka and Nishida, 2007;Kim et al, 2008). We have detected Wnt11 mRNA in seven colon cancer cell lines (data not shown).…”

Section: Discussionmentioning

confidence: 88%

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Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

et al. 2009

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BACKGROUND: The canonical Wnt signalling pathway is activated in most sporadic colorectal cancers (CRCs). We previously reported that FZD7 functions as a receptor for the canonical Wnt signalling pathway in colon cancer cells. METHODS AND RESULTS: In this study, we examined the function of FZD7 in survival, invasion and metastatic capabilities of colon cancer cells. FZD7_siRNA transfection decreased cell viability of HT-29 and HCT-116 colon cancer cells. Expression of c-Jun, phosphorylation of JNK and c-Jun, and activation of RhoA were suppressed after FZD7_siRNA transfection into HCT-116 cells. In vitro invasion activity and Wnt target gene expression were also reduced in HCT-116 cells transfected with FZD7_siRNA. Liver metastasis of stable FZD7_siRNA HCT-116 cell transfectants in scid mice was decreased to 40 -50% compared to controls. The mRNA levels of FZD7 in 135 primary CRC tissues were examined by real-time PCR. FZD7 mRNA levels were significantly higher in stage II, III or IV tumours than in non-tumour tissues (Po0.005), and overall survival was shorter in those patients with higher FZD7 expression (Po0.001). CONCLUSION: These data suggest that FZD7 may be involved in enhancement of survival, invasion and metastatic capabilities of colon cancer cells through non-canonical Wnt signalling pathways as well as the canonical pathway.

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supporting

confidence: 78%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 88%

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Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

et al. 2009

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“…In support of these findings, it was observed that silencing b-catenin in hypoxic MHCC97 and Hep3B cells also reversed EMT (56). Using a variant of the human cell line LIM1863 (LIM1863-Mph), Vincan and colleagues (57,58) established a unique model of colorectal cancer morphogenesis and showed that FZD7 plays a pivotal role in phenotype transitions, suggesting that Wnt signaling participates in orchestrating colorectal cancer morphogenesis. Similarly, silencing of FZD4 was shown to induce the phenotypic transition and activate b1-integrin and E-cadherin expression (59).…”

Section: Mechanism Of Metmentioning

confidence: 56%

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

Yao

Dai

Peng

2011

Molecular Cancer Research

382

296

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Cancer metastasis consists of a sequential series of events, and the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are recognized as critical events for metastasis of carcinomas. A current area of focus is the histopathological similarity between primary and metastatic tumors, and MET at sites of metastases has been postulated to be part of the process of metastatic tumor formation. Here, we summarize accumulating evidence from experimental studies that directly supports the role of MET in cancer metastasis, and we analyze the main mechanisms that regulate MET or reverse EMT in carcinomas. Given the critical role of MET in metastatic tumor formation, the potential to effectively target the MET process at sites of metastasis offers new hope for inhibiting metastatic tumor formation.

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“…CRC lines from the LIM series, which were established over a long period of time from primary colorectal cancers, have been previously characterized phenotypically [29][30][31] and have been used extensively as models for colorectal cancer, with emphasis on the responsiveness to growth factors, 32 epithelial-to-mesenchymal transition 33 and induction of differentiation. 34 We now report a detailed analysis of the mutations Cells were derived from biopsies of colorectal adenocarcinomas or adenomas, as described in Supporting Information.…”

Section: Uiccmentioning

confidence: 99%

Selective inhibition of proliferation in colorectal carcinoma cell lines expressing mutant APC or activated B‐Raf

Zhang

Walker

Kiflemariam

et al. 2009

Intl Journal of Cancer

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Tumor-derived cell lines are indispensable tools for understanding the contribution of activated signaling pathways to the cancer phenotype and for the design and testing of targeted signal therapies. In our study, we characterize 10 colorectal carcinoma cell lines for the presence of mutations in the wnt, Ras/MAPK, PI3K and p53 pathways. The mutational spectrum found in this panel of cell lines is similar to that detected in primary CRC, albeit with higher frequency of mutation in the b-catenin and B-Raf genes. We have monitored activation of the wnt and Ras/MAPK pathways in these cells and analyzed their sensitivity to selective signaling inhibitors. Using b-catenin subcellular distribution as a marker, we show that cells harboring APC mutations have low-level activated wnt signaling, which can be blocked by the extracellular wnt inhibitor DKK-1, suggesting autocrine activation of this pathway; proliferation of these cells is also blocked by DKK-1. In contrast, cells with b-catenin mutations are unresponsive to extracellular wnt inhibition. Constitutive phosphorylation of MAPK is present in the majority of the cell lines and correlates with B-Raf but not K-Ras mutations; correspondingly, the proliferation of cells harboring mutations in B-Raf, but not K-Ras, is exquisitely sensitive inhibition of the MAPK pathway. We find no correlation between PI3K mutation or loss of PTEN expression and increased sensitivity to PI3K inhibitors. Our study discloses clear-cut differences in responsiveness to signaling inhibitors between individual mutations within an activated signaling pathway and suggests likely targets for signal-directed therapy of colorectal carcinomas. ' UICCKey words: colorectal cancer; cell lines; mutations; wnt signaling; signal therapiesThe progression of colorectal cancer from adenomas to carcinomas is characterized by a series of genetic changes, which lead to the activation of oncogenes and to the inactivation of tumor suppressor genes, perturbing the self-renewal, proliferative, adhesive and survival characteristics of the cells. 1,2 Colorectal cancers are characterized by mutations in 4 major pathways: wnt, Ras/MAPK, p53 and DNA repair.The APC gene is a key regulator of the wnt pathway. APC mutations are detected early in the adenoma-carcinoma progression, 3 are the hallmark of Familial Adenomatous Polyposis (FAP) and also occur with high frequency (up to 80%) in sporadic CRC. Mutations of the APC gene cluster in the central region of the protein and result in truncations, which delete most of the b-catenin binding sites, the axin-binding domain and the microtubule-binding regions. These deletions have been associated with activation of the canonical wnt signaling pathway and cytosolic/nuclear accumulation of b-catenin 4 but may also play an important, b-catenin independent, role in the loss of cell polarity observed in many colorectal carcinomas. 5 Underlying the relevance of the wnt pathway in the aetiogenesis of CRC, mutations of other components in the canonical wnt pathway also occur with...

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Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids

Cited by 70 publications

References 50 publications

Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

Selective inhibition of proliferation in colorectal carcinoma cell lines expressing mutant APC or activated B‐Raf

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