Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival.
Hedgehog pathway activity has been demonstrated in malignant glioma. However, its role in tumor growth has not been determined. Here we demonstrate that pharmacological inhibition of the Hedgehog pathway in established orthotopic malignant glioma xenografts confers a survival advantage. Pathway inhibition is measured in transplanted human tumor cells and not in host mouse brain. Correspondingly, survival benefit is observed only in tumors with an operational Hedgehog pathway. These data indicate that Hedgehog signaling regulates the growth of select malignant gliomas. We also demonstrate that Hedgehog pathway component and gene target expression segregate to CD133(+) tumor initiating cells. Treated mice eventually succumb to disease, thus, targeting the Hedgehog pathway in CD133(+) cells produces significant, but incomplete tumor regression. Therefore, our studies suggest that more complete tumor regression may require the inclusion of other therapeutic targets, including CD133(-) cells.
Sarangi
A
A
Department of Neurology, Vanderbilt Medical Center, Nashville, TN 37232, USA.
Valadez
J G
JG
Rush
S
S
Abel
T W
TW
Thompson
R C
RC
Cooper
M K
MK
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D000072079:Patched Receptors; D010455:Peptides / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics; D013534:Survival; D014157:Transcription Factors / Q000235:genetics; D014183:Transplantation, Heterologous; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1
D000071916:AC133 Antigen; D015703:Antigens, CD; C400551:GLI1 protein, human; D006023:Glycoproteins; D053823:Hedgehog Proteins; C000606023:PROM1 protein, human; D000072079:Patched Receptors; D010455:Peptides; C000606024:Prom1 protein, mouse; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine