Notch signaling is not essential in sonic hedgehog-activated medulloblastoma.
Dysregulated signal transduction through the notch pathway has been noted in human and mouse medulloblastoma studies. Gamma secretase inhibitors (GSIs) impair notch signaling by preventing the cleavage of transmembrane notch proteins into their active intracellular domain fragments. Previous studies have shown that GSI treatment caused apoptosis and impaired medulloblastoma cell engraftment in xenograft systems. In this study, we used in vivo genetic and pharmacologic approaches to quantify the contribution of notch signaling to sonic hedgehog (shh)-activated mouse medulloblastoma models. In contrast to prior in vitro studies, pharmacologic inhibition of notch pathways did not reduce the efficiency of medulloblastoma xenotransplantation nor did systemic therapy impact tumor size, proliferation, or apoptosis in genetically engineered mouse medulloblastoma models. The incidence and pathology of medulloblastomas driven by the SmoA1 transgene was unchanged by the bi-allelic absence of Notch1, Notch2, or Hes5 genes. These data show that notch signaling is not essential for the initiation, engraftment, or maintenance of sonic hedgehog pathway-driven medulloblastomas.
Hatton
B A
BA
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Villavicencio
E H
EH
Pritchard
J
J
LeBlanc
M
M
Hansen
S
S
Ulrich
M
M
Ditzler
S
S
Pullar
B
B
Stroud
M R
MR
Olson
J M
JM
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D053823:Hedgehog Proteins; D051880:Receptors, Notch; C509239:SHH protein, human