|Wnt/β-catenin is an essential signaling pathway that functions in embryonic development. Signaling by proteins of the WNT family leads to an accumulation of β-catenin (produced by the gene CTNNB1) in the cytoplasm. This β-catenin is translocated to the nucleus and activates the transcription of other genes.
Location: CTNNB1, Chromosome 3p21
The Wnt/β-catenin Pathway in Chordoma
Brachyury, known to be important in chordoma, is a direct target of Wnt in mouse, so the possibility that the Wnt/β-catenin signaling pathway plays a role in regulating brachyury has drawn the attention of chordoma researchers.2 Activation of Wnt/beta-catenin signaling is shown to contribute to the initiation and progression of other cancers, and inhibiting this signaling is being explored to treat them.3 4 While researchers have shown that members of the Wnt/β-catenin signaling pathway are expressed in many chordomas, they have yet to fully elucidate the role of the pathway or to explore the consequences of administering drugs that inhibit Wnt/beta-catenin signaling to chordoma model systems or to chordoma patients. This page contains a summary of published research that has explored Wnt signaling in chordoma.
Copy Number Variation
Chromosomal Aberrations: Loss of a region of chromosome 3 harboring CTNNB1 was observed in more than half of chordoma samples analyzed.5
Le et al. detected no common point mutations in CTNNB1 mutation hotspots in 21 sporadic chordomas.6 Choy et al. later detected a mutation in CTNNB1 in one of 45 chordomas.7
CTNNB1 has been detected in more than half of chordoma analyzed by immunohistochemistry.8 9 10 A recent study found that more chordoma samples (16/17) expressed CTNNB1 than did chondrosarcoma samples or controls.11
- Analysis of the gene networks amplified in skull base chordomas revealed that five overlapping networks had a major node of interaction with CTNNB1.12 The Wnt signaling pathway was also implicated by analysis of the pathways corresponding to significantly upregulated, intersecting genes identified by miRNA analysis.13 14
- Gene loci that were found to be hypermethylated in cancer samples versus controls fell into a number of cancer-related pathways, including the Wnt/β-catenin pathway.15
In vitro evidence
- Activation of the melatonin receptor MTNR1B was shown to increase chordoma cell sensitivity to chemotherapy by suppressing β‐catenin signaling.16
In vivo evidence
- Treatment of Mug-CC1 tumors in mice with cisplatin plus ICG-001 (a compound that disrupts CREB binding protein/β‐catenin binding) or cisplatin plus dasatinib (a tyrosinase inhibitor targeting SRC kinase activity) strongly inhibited tumor growth compared to vehicle or cisplatin-only controls.16
- Treatment of Mug-CC1 tumors in mice with cisplatin plus melatonin inhibited tumor growth compared to treatment with cisplatin or melatonin alone.16