Bmi1 and Hedgehog Signaling in Medulloblastoma Pathogenesis.

[摘要] Medulloblastoma is the most common malignant brain tumor in children, and occurs in up to 5% of patients with Gorlin syndrome, a familial cancer susceptibility disorder characterized by inappropriate activation of the Hedgehog (Hh) signaling pathway.Activation of Hh signaling is also seen in a significant fraction of sporadic medulloblastomas, many of which are believed to arise from the external granular layer (EGL) of the cerebellum, a transient, highly proliferative pool of Hh-responsive neural progenitors that disappears within the first several weeks of life, in mice.I investigated where and when medulloblastomas arise using a novel mouse model expressing SmoA1, a constitutively activated allele of the proximal Hh effector Smo, in the brain in a temporally restricted manner.SmoA1 induction in the developing cerebellum induced 100% penetrant medulloblastoma as early as two weeks old.Once the EGL had disappeared, however, mice were completely refractory to induction of de novo medulloblastomas, providing strong evidence that the EGL represents a bona fide pool of cells with the potential to become medulloblastoma, and that other SmoA1-expressing cells in adult mice are not competent to form medulloblastomas.To test whether SmoA1-induced medulloblastomas remain dependent on continued Hh signaling, I repressed transgene expression in established tumors.I observed that even relatively brief 3-week inhibition of SmoA1 resulted in complete and durable elimination of tumors.Tumors did not recur following resumption of transgene expression, suggesting that no dormant tumor cells remain.This is a timely finding, as a Hh antagonist is currently in Phase II clinical trials for antitumor therapy.Lastly, I examined the dependence of tumor formation on the stem cell maintenance gene Bmi1, which is required for physiologic cerebellar development and is expressed in Hh-active human medulloblastomas.Breeding SmoA1 mice onto a Bmi1-null background revealed that in the absence of Bmi1, tumor initiation occurs, but lesions do not progress to frank medulloblastomas.This implicates Bmi1 as a key downstream target of Hh in a pathologic setting.The work presented herein provides several important insights into the pathogenesis of Hh-driven medulloblastoma, and may suggest a more general role for Bmi1 in Hh-mediated cancer.

[发布机构] University of Michigan

[效力级别] Hedgehog Signaling

[关键词] Bmi1;Hedgehog Signaling;Medulloblastoma Pathogenesis;Mouse Models of Cancer;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology