Abstract
Medulloblastoma, the most common of the malignant pediatric brain tumors, is a group of four molecularly and clinically distinct cancers with different cells of origin. One of these medulloblastoma groups displays activation of Sonic hedgehog (SHH) signaling and originates from granule cell precursors of the developing cerebellum. Ongoing basic and clinical research efforts are tailored to discover targeted and safer therapies, which rely on the identification of the basic mechanisms regulating tumor initiation, progression, and metastasis. In SHH medulloblastoma, the mechanisms regulating neural progenitor transformation and progression to advanced tumors have been studied in some detail. The present review discusses recent advances on medulloblastoma progression derived from studies using mouse models of SHH medulloblastoma. We focus on mechanisms that regulate progression from precancerous lesions to medulloblastoma, describing novel roles played by tumor suppressor mechanisms and the tumor microenvironment.
Highlights
The multi-stage nature of cancer Cancer is a multi-step process where the development of highgrade tumors normally requires the occurrence of multiple and sequential genetic events[1], a process called multi-stage tumorigenesis[2]
TP53 mutations appear at high frequency during colon tumorigenesis, they more rarely lead to colon carcinoma when present in the germ-line; in this context, TP53 can be considered as a caretaker gene
MB-bearing mice display low numbers of peripheral T cells and smaller spleens, indicating that MB affects immune function systemically[65]. Consistent with these findings, high numbers of T helper lymphocytes (TH1) as well as high levels of IFNγ and TNFα correlate with good prognosis in human MB patients undergoing chemotherapy and hematopoietic stem cell transplantation[66]. While these findings suggest that MB cells modulate and perhaps inhibit T cell-dependent responses, further work is required to determine the specific functions of T cell subpopulations and NK cells in MB pathogenesis and whether they could be exploited for therapies
Summary
The multi-stage nature of cancer Cancer is a multi-step process where the development of highgrade tumors normally requires the occurrence of multiple and sequential genetic events[1], a process called multi-stage tumorigenesis[2]. A subset of Atoh1+ and CD133– GCPs express high levels of the glycoprotein CD15 and have been shown to be tumor-propagating cells in Ptch1+/– MB93,94 Together, these results indicate that ventricular zone NSCs and GCPs from the EGL are the main cells with the potential to give origin to SHH-MB. A subpopulation of Nestin+ GCPs located in the inner layer of the EGL has been shown to display increased tumorigenic potential compared to Atoh1+ GCPs95; these cells are Shh responsive, and it was later proposed that Nestin has the ability to bind Gli[3] and prevent its conversion to a repressive form, leading to higher Hh pathway activity[96]. Whether Bmi[1] is expressed or plays a role in Sox[2] MB cells is unknown, but it is interesting to speculate that Hh signaling-dependent regulation of Bmi[1] and other potential stem cell regulators could be the source of MB Sox2+ cells
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