Activation of the Canonical Wnt/β-Catenin Signalling Pathway is Rare in Canine Malignant Melanoma Tissue and Cell Lines

Chon, Esther; Thompson, Victoria; Schmid, Steven M.; Stein, Timothy J.

doi:10.1016/j.jcpa.2012.07.001

Cited by 12 publications

(12 citation statements)

References 39 publications

(59 reference statements)

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“…As we have previously reported, β-catenin-transcriptional activity is minimal in canine malignant melanoma (Chon et al, 2013). Importantly, a number of in vitro and in vivo studies have demonstrated that BIO, a selective and potent inhibitor of GSK-3β, has anti-oncogenic effects against breast and pancreatic carcinoma stem cells, osteosarcoma, and melanoma (Liu et al, 2011; Cao et al, 2012; Dastjerdi et al, 2012; Nicolaou et al, 2012).…”

Section: Discussionsupporting

confidence: 66%

“…However, its effect has not been assessed on canine malignant melanoma cell lines. Therefore BIO may represent a logical compound for evaluation as it has known anti-cancer effects both in vitro and in vivo and it targets a pathway known to be suppressed in canine malignant melanoma (Liu et al, 2011; Chon et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

“…However, for therapeutic targets to be effective, they should be selected based on a working knowledge of the signaling pathways that contribute to the behavioral characteristics of the disease. Our previous work, as well as the work of others, suggests that the canonical Wnt signaling pathway is suppressed in malignant melanoma as evidenced by minimal β-catenin-mediated transcriptional activity (Chon et al, 2013). Interestingly, in humans with melanoma the activation of the canonical Wnt signaling pathway has been associated with reduced cell proliferation and improved survival (Chien et al, 2009).…”

Section: Introductionmentioning

confidence: 89%

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6-Bromoindirubin-3′oxime (BIO) decreases proliferation and migration of canine melanoma cell lines

Chon

Flanagan

Rodrigues

et al. 2015

The Veterinary Journal

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Despite recent therapeutic advances, malignant melanoma is an aggressive tumor in dogs and is associated with a poor outcome. Novel, targeted agents are necessary to improve survival. In this study, 6-bromoindirubin-3′-oxime (BIO), a serine/threonine kinase inhibitor with reported specificity for glycogen synthase kinase-3 beta (GSK-3β) inhibition, was evaluated in vitro in three canine melanoma cell lines (CML-10C2, UCDK9M2, and UCDK9M3) for β-catenin-mediated transcriptional activity, Axin2 gene and protein expression levels, cell proliferation, chemotoxicity, migration and invasion assays. BIO treatment of canine malignant melanoma cell lines at 5 µM for 72 h enhanced β-catenin-mediated transcriptional activity, suggesting GSK-3β inhibition, and reduced cell proliferation and migration. There were no significant effects on invasion, chemotoxicity, or apoptosis. The results suggest that serine/ threonine kinases may be viable therapeutic targets for the treatment of canine malignant melanoma.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

See 1 more Smart Citation

6-Bromoindirubin-3′oxime (BIO) decreases proliferation and migration of canine melanoma cell lines

Chon

Flanagan

Rodrigues

et al. 2015

The Veterinary Journal

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“…Contrary to these low numbers, Bongiovanni et al observed 47% (8/17) of canine OS samples to display nuclear staining; however, in nuclear‐positive samples, less than 10% of nuclei/cells within the sample were positive, indicating that these positive nuclei were very weakly positive. The results of these studies are similar to those evaluating β ‐catenin in human and canine malignant melanoma, in which the presence of cytoplasmic β ‐catenin is frequent, though nuclear β ‐catenin is rare and there is low transcriptional activity in melanoma cell lines . Interestingly, Kuphal and Bosserhoff found serine 33 and 37 residues in β ‐catenin to be hypo‐phosphorylated, likely preventing β ‐catenin from being targeted for ubiquitin‐mediated degradation.…”

Section: Discussionmentioning

confidence: 99%

β‐Catenin transcriptional activity is minimal in canine osteosarcoma and its targeted inhibition results in minimal changes to cell line behaviour

Piskun

Stein

2013

Vet Comparative Oncology

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Canine osteosarcoma (OS) is an aggressive malignancy associated with poor outcomes. Therapeutic improvements are likely to develop from an improved understanding of signaling pathways contributing to osteosarcoma development and progression. The Wnt signaling pathway is of interest for its role in osteoblast differentiation, its dysregulation in numerous cancer types, and the relative frequency of cytoplasmic accumulation of β-catenin in canine OS. This study aimed to determine the biological impact of inhibiting canonical Wnt signaling in canine OS, by utilizing either β-catenin siRNA or a dominant-negative TCF construct. There were no consistent, significant changes in cell line behavior with either method compared to parental cell lines. Interestingly, β-catenin transcriptional activity was 3-fold higher in normal canine primary osteoblasts compared to canine osteosarcoma cell lines. These results suggest canonical Wnt signaling is minimally active in canine osteosarcoma and its targeted inhibition is not a relevant therapeutic strategy.

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“…All of the melanoma lines established in our lab were derived from oral melanoma tumor biopsies and were either Stage II (CMSDSc and CMSDTa) or Stage III (CMSDJe and CMSDSh) melanomas. The melanoma cell lines CML-10C2 and CML-6M were derived from a cutaneous primary tumor and a lymph node metastatic lesion, respectively (Chon et al, 2013). The Jones melanoma cell line was derived from a primary tumor.…”

Section: Methodsmentioning

confidence: 99%

Comparison of cancer stem cell antigen expression by tumor cell lines and by tumor biopsies from dogs with melanoma and osteosarcoma

Guth

Deogracias

Dow

2014

Veterinary Immunology and Immunopathology

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Cancer stem cells (CSCs) represent a small subpopulation of tumor cells that play a critical role in initiating and sustaining tumor growth. However, we currently have an incomplete understanding of the expression patterns of CSC antigens in tumors of dogs, nor do we understand how expression of these antigens vary between tumor cell lines and tumor biopsy specimens. Therefore, we used flow cytometry and commonly reported CSC surface and intracellular markers to evaluate the phenotype and overall frequency of CSC subpopulations in tumor cell lines and primary tumor biopsy samples from dogs with melanoma and osteosarcoma. We found that cells expressing common CSC antigens were rare in tumor cell lines, with the exception of tumor cells expressing CD44 and CD90. In contrast, tumor cells expressing conventional CSC antigens such as CD133, CD34, CD44, CD24 and Oct3/4 were much more common in tumor biopsy samples. Notably, the frequency and types of putative CSC subpopulations were very similar in biopsy samples from dogs with either melanoma or osteosarcoma. Our results suggest that the tumor microenvironment significantly influences CSC subpopulations within tumors and that tumor cell lines may not accurately reflect the actual frequency or types of CSC subpopulations present in tumor tissues in vivo.

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Activation of the Canonical Wnt/β-Catenin Signalling Pathway is Rare in Canine Malignant Melanoma Tissue and Cell Lines

Cited by 12 publications

References 39 publications

6-Bromoindirubin-3′oxime (BIO) decreases proliferation and migration of canine melanoma cell lines

6-Bromoindirubin-3′oxime (BIO) decreases proliferation and migration of canine melanoma cell lines

β‐Catenin transcriptional activity is minimal in canine osteosarcoma and its targeted inhibition results in minimal changes to cell line behaviour

Comparison of cancer stem cell antigen expression by tumor cell lines and by tumor biopsies from dogs with melanoma and osteosarcoma

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