Medulloblastoma: molecular genetics and animal models

Abstract

Medulloblastoma is a primary brain tumor found in the cerebellum of children. The tumor occurs in association with two inherited cancer syndromes: Turcot syndrome and Gorlin syndrome. Insights into the molecular biology of the tumor have come from looking at alterations in the genes altered in these syndromes, PTC and APC, respectively. Murine models of medulloblastoma have been constructed based on these alterations. Additional murine models that, while mimicking the appearance of the human tumor, seem unrelated to the human tumor's molecular alterations have been made. In this review, the clinical picture, origin, molecular biology, and murine models of medulloblastoma are discussed. Although a great deal has been discovered about this tumor, the genetic alterations responsible for tumor development in a majority of patients have yet to be described.

Figure 1

MRI of medulloblastoma. This T1-weighted, gadolinium diethylenetriamine pentaacetic acid (DTPA)-enhanced MR scan of a patient with a medulloblastoma demonstrates a mass (large area of white) in the cerebellum, which fills the fourth ventricle and displaces it anteriorly.

Figure 2

(A) Photomicrograph of a human desmoplastic medulloblastoma, demonstrated as small, tightly packed cells with little cytoplasm. A pale island is seen in the center of the image as an area of less tightly packed cells. Hematoxylin and eosin staining, x400. (B) Photomicrograph of murine tumor of the cerebellum from a Ptc^+/- mouse. Note the similarity to the human tumor. Hematoxylin and eosin staining, x400. (Image courtesy of Dr. Cynthia Wetmore, Rochester, MN.)

Figure 3

The SHH/PTC pathway. By binding to the membrane-bound PTC receptor, SHH removes the inhibition of v-smo mediated by PTC. This ultimately results in increased gli-mediated transcription. Su-fu and PKA are downstream inhibitors of this process.

Figure 4

The role of SHH in cerebellar development. Granule neuronal precursors (A–D) migrate tangentially from the rhombic lip and may use the SHH pathway in transient autocrine manner. Purkinje neurons and later-born Bergmann glia (B) derive from the ventricular zone and migrate toward the EGL. SHH from the Purkinje neurons induces Bergmann glia maturation (C). In the later EGL, granule neuronal precursors proliferate in the outer zone, utilizing SHH secreted from Purkinje neurons. At the same time, mature glia send their extensions toward the inner EGL (D) and these or other cortical cells may provide factors that promote the differentiation if granule neurons, antagonizing the effects of SHH. Granule cells then migrate on glial fibers across the molecular and Purkinje layers to form the IGL. Maintained autocrine SHH signaling in the EGL (E) may result in the development of cerebellar tumors. (Reprinted with permission from Ref. [3].)

Figure 5

The wnt signaling pathway. Binding of wnt to its receptor, frizzled, leads ultimately to translation of β-catenin and Tcf into the nucleus, resulting in transcription of genes controlled by this transactivator. The large complex involved in regulating free cytoplasmic concentrations of β-catenin contains axin1 and axin2, APC, and GSK-3β. Phosphorylation of β-catenin by GSK-3β in the complex leads to degradation of β-catenin by the ubiquitin system.