Characterization of cancer stem cells and primary cilia in medulloblastoma.
Medulloblastoma, a tumor of the cerebellum, is the most common pediatric central nervous system malignancy. These tumors are etiologically linked to mutations in the Sonic hedgehog (Shh) pathway, which signals through the primary, non-motile cilium. The growth of these aggressive tumors relies on self-renewal of tumor-propagating cells known as cancer stem cells (CSCs). Previous reports have implicated CD133-expressing cells as CSCs in brain tumors, while those expressing CD15 have been shown to propagate medulloblastoma. Here, we demonstrate that CD133+ and CD15+ cells are distinct medulloblastoma populations. CD15+ cells comprise approximately 0.5-1% of total human medulloblastoma cells, display CSC properties in culture and are detected in the Smoothened A1 transgenic mouse model of medulloblastoma. Additionally, we report on a medulloblastoma patient with enriched CD15+ cells in recurrent vs primary medulloblastoma. We also demonstrate that human medulloblastoma cells critically rely on establishment of primary cilia to drive Shh-mediated cell division. Primary cilia are found in external granule cells of human fetal cerebellum and in 12/14 medulloblastoma samples. Yet, CD15+ medulloblastoma cells lack primary cilia, suggesting that this CSC population signals independently of Shh. These results are important when considering the effects of current and prospective treatment modalities on medulloblastoma CSC populations.
David
D
Gate
Moise
M
Danielpour
Serguei
S
Bannykh
Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, Keck School of Medicine, 1501 San Pablo St., Room ZNI 337, Los Angeles, CA 90089, USA. ttown@usc.edu.
Terrence
T
Town
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001932:Brain Neoplasms / Q000145:classification / Q000473:pathology*; D001973:Bromodeoxyuridine; D002923:Cilia / Q000473:pathology*; D005333:Fetus; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma / Q000145:classification / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D064231:Nestin / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D000072086:Smoothened Receptor; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D036341:Intercellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D064231:Nestin; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; D055748:SOXB1 Transcription Factors; D000072086:Smoothened Receptor; D014157:Transcription Factors; C489788:MAP2 protein, human; C098995:Neurod2 protein, mouse; C491023:SMO protein, human; C527782:SOX2 protein, human; C492123:ZIC1 protein, human