Chordoma Foundation

Wnt

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

Aside from their role in early development, WNTs and their downstream effectors are involved various processes that can be important for cancer cell progression, including tumor initiation, tumor growth, cell senescence, cell death, differentiation, and metastasis. Overexpression of constitutively activated β-catenin can lead to tumorigenesis.1

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.

Molecular Evidence


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

Somatic Mutation

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

Protein Expression

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

Pathway Activation

  • 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


References

1.
Anastas J, Moon R. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13(1):11-26. [PubMed]
2.
Arnold S, Stappert J, Bauer A, Kispert A, Herrmann B, Kemler R. Brachyury is a target gene of the Wnt/beta-catenin signaling pathway. Mech Dev. 2000;91(1-2):249-258. [PubMed]
3.
Herbst A, Kolligs F. Wnt signaling as a therapeutic target for cancer. Methods Mol Biol. 2007;361:63-91. [PubMed]
4.
Sarkar D, Shields B, Davies M, Müller J, Wakeman J. BRACHYURY confers cancer stem cell characteristics on colorectal cancer cells. Int J Cancer. 2012;130(2):328-337. [PubMed]
5.
Rinner B, Weinhaeusel A, Lohberger B, et al. Chordoma characterization of significant changes of the DNA methylation pattern. PLoS One. 2013;8(3):e56609. [PubMed]
6.
Le L, Nielsen G, Rosenberg A, et al. Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846. [PubMed]
7.
Choy E, MacConaill L, Cote G, et al. Genotyping cancer-associated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1. PLoS One. 2014;9(7):e101283. [PubMed]
8.
Naka T, Oda Y, Iwamoto Y, et al. Immunohistochemical analysis of E-cadherin, alpha-catenin, beta-catenin, gamma-catenin, and neural cell adhesion molecule (NCAM) in chordoma. J Clin Pathol. 2001;54(12):945-950. [PubMed]
9.
Horiguchi H, Sano T, Qian Z, et al. Expression of cell adhesion molecules in chordomas: an immunohistochemical study of 16 cases. Acta Neuropathol. 2004;107(2):91-96. [PubMed]
10.
Triana A, Sen C, Wolfe D, Hazan R. Cadherins and catenins in clival chordomas: correlation of expression with tumor aggressiveness. Am J Surg Pathol. 2005;29(11):1422-1434. [PubMed]
11.
Aviel-Ronen S, Zadok O, Vituri A, et al. α-methylacyl-CoA racemase (AMACR) expression in chordomas differentiates them from chondrosarcomas. Sci Rep. 2016;6:21277. [PubMed]
12.
Diaz R, Guduk M, Romagnuolo R, et al. High-resolution whole-genome analysis of skull base chordomas implicates FHIT loss in chordoma pathogenesis. Neoplasia. 2012;14(9):788-798. [PubMed]
13.
Long C, Jiang L, Wei F, et al. Integrated miRNA-mRNA analysis revealing the potential roles of miRNAs in chordomas. PLoS One. 2013;8(6):e66676. [PubMed]
14.
Chen K, Chen H, Zhang K, et al. MicroRNA profiling and bioinformatics analyses reveal the potential roles of microRNAs in chordoma. Oncol Lett. 2017;14(5):5533-5539. [PMC]
15.
Alholle A, Brini A, Bauer J, et al. Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas. Epigenetics. 2015;10(3):213-220. [PubMed]