Chordoma Foundation

Sonic Hedgehog

SHH in Chordoma

Sonic Hedgehog (SHH) encodes a morphogen that is secreted by the fetal notochord and plays a role in patterning the neural tube during vertebrate embryonic development when it binds to a receptor site on its ligand PTCH1.

Location: Chromosome 7p12

SHH is expressed in highly proliferative epidermal keratinocytes, suggesting that activation of the pathway allows cells to maintain progression through the cell cycle and avoid apoptosis; disrupting normal function of this pathway could therefore contribute to tumorigenesis.1

Researchers have shown that, in mice, Shh-expressing notochord cells remain in the vertebral column after embryonic development has ceased. These resemble the “notochordal remnants” from which human chordomas are proposed to arise.2 Since Shh signaling plays a role in the development of the notochord in mice but appears to be inactive in later stages, it is hypothesized that the reactivation of SHH could cause benign notochordal remnants to transform into malignant neoplasms.3

The existence of notochordal remnants in mice suggest that Shh expression could be manipulated to create an in vivo model system for chordoma research. Attempts to develop this model and to understand the role of SHH in chordoma are ongoing.

Molecular Evidence

Copy Number Variation

  • Chromosomal Aberrations: Chromosome 7 gains and partial polysomies are among the most common chromosomal aberrations observed in chordomas.4 5 6 7 8 9

Gene Expression

  • Ptch1 and Gli1 were detected by in situ hybridization in a subset of primary chordoma patients but not detected in recurrent cases.10

Protein Expression

  • 19 cranial and spinal primary tumors from 14 chordoma patients showed expression of Shh and GLI1 by immunohistochemistry.10
  • SHH and its receptor PTCH1 are expressed in early notochordal development but are less so in later stages of fetal development; however, the pair is expressed in most chordomas to a greater extent than in benign notochordal tissue, intervertebral disc, and chondrosarcoma controls.3

Chari N, McDonnell T. The sonic hedgehog signaling network in development and neoplasia. Adv Anat Pathol. 2007;14(5):344-352. [PubMed]
Choi K, Cohn M, Harfe B. Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation. Dev Dyn. 2008;237(12):3953-3958. [PubMed]
Cates J, Itani D, Coffin C, Harfe B. The sonic hedgehog pathway in chordoid tumours. Histopathology. 2010;56(7):978-979. [PubMed]
Scheil S, Brüderlein S, Liehr T, et al. Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1. Genes Chromosomes Cancer. 2001;32(3):203-211. [PubMed]
Brandal P, Bjerkehagen B, Danielsen H, Heim S. Chromosome 7 abnormalities are common in chordomas. Cancer Genet Cytogenet. 2005;160(1):15-21. [PubMed]
Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res. 2011;1(1):4. [PubMed]
Sawyer J, Husain M, Al-Mefty O. Identification of isochromosome 1q as a recurring chromosome aberration in skull base chordomas: a new marker for aggressive tumors? Neurosurg Focus. 2001;10(3):E6. [PubMed]
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]
Walter B, Begnami M, Valera V, Santi M, Rushing E, Quezado M. Gain of chromosome 7 by chromogenic in situ hybridization (CISH) in chordomas is correlated to c-MET expression. J Neurooncol. 2011;101(2):199-206. [PubMed]
Akhavan-Sigari R, Schulz-Schaeffer W, Angelika H, Rohde V. The Importance of the Hedgehog Signaling Pathway in Tumorigenesis of Spinal and Cranial Chordoma. J Clin Med. 2019;8(2).

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