Critical Role Of Notch Signaling In Chordoma Proliferation And Invasion

PurposeNotch signaling plays an important role in developmental processes andadult tissue homeostasis. Altered Notch signaling has been associated withvarious diseases including cancer. Notch signaling is an important mediator ofgrowth and survival in several cancer types, with Notch pathway genesfunctioning as oncogenes or tumor suppressors in different cancers. While theimportance of altered Notch signaling in cancers of hematopoietic and epithelialorigins has been established, its role in tumors of mesenchymal origin is lessclear. The role of Notch in chordoma is unknown.MethodsWe assessed the expression of Notch pathway genes in human chordomacell lines CM-319and patient samples. We then used pharmacologic andretroviral manipulation of the Notch pathway and studied the effect onchordoma cell proliferation, survival, and invasion. ResultsNotch pathway genes, including Notch ligand DLL1, DLL3, Notch1-4, andthe Notch Target gene HES1, were expressed in chordoma cells, and humanchordoma cell lines and primary human chordoma tumor samples showsignifcant up-regulation of Notch, its target genes and Osterix. Blockade ofNotch pathway signaling restrain invasion of chordoma cell by affecting cellsplit cycle.ConclusionThese studies identify a new proliferation and invasion-regulating pathwayin chordoma and define a novel function for the Notch pathway: regulation ofinvasion. Because the Notch pathway can be inhibited pharmacologically, thesefindings point toward possible new treatments to reduce proliferation andinvasion in chordoma. These data suggest that activation of Notch signalingcontributes to the proliferation and invasion of human chordoma and itsinhibition may be a therapeutic approach for the treatment of this mesenchymaltumor.