Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.

Medulloblastoma: a disease with disorganized developmental signaling cascades.

Sonic Hedgehog, Wnt and PI3K/Akt are three developmental signalling cascades that all have crucial functions during normal brain development. The activation of one or several of these cascades is also found in the majority of medulloblastoma, the most common pediatric malignant tumor of the central nervous system. The aberrant expression of key molecules in developmental signalling pathways or inhibition of the activity of proteins regulating the activity of these cascades is important for medulloblastoma proliferation and survival. These developmental signal transduction pathways transfer signals from the cell membrane to transcription factors in the nucleus, resulting in an altered gene expression. Molecular cross-talks between these developmental cascades have been described in several cancers and may have important functions in tumorigenesis. One common kinase for these three signalling cascades is GSK-3ß, which seems to be the glue that links these cascades together. Medulloblastoma cells display many characteristics that are interrelated to the progenitor cells of the embryonic brain where these developmental cascades are essential for proper development. Hence, understanding the relationship between normal brain development and medulloblastoma molecular pathogenesis is essential for more efficient, less toxic tailored therapies to be developed and implemented.

Medulloblastoma: developmental mechanisms out of control.

Medulloblastoma, which is a highly aggressive central nervous system neoplasm, represents an intriguing example of how deregulated developmental mechanisms can lead to tumour development. Recent advances in the understanding of the role of Sonic Hedgehog, Wnt and Notch signalling pathways in the development of the cerebellum have shed new light on medulloblastoma pathogenesis.

Class III beta-tubulin isotype: a key cytoskeletal protein at the crossroads of developmental neurobiology and tumor neuropathology.

The expression of the cytoskeletal protein class III beta-tubulin isotype is reviewed in the context of human central nervous system development and neoplasia. Compared to systemic organs and tissues, class III beta-tubulin is abundant in the brain, where it is prominently expressed during fetal and postnatal development. As exemplified in cerebellar neurogenesis, the distribution of class III beta-tubulin is neuron associated, exhibiting different temporospatial gradients in the neuronal progeny of the external granule layer versus the neuroepithelial germinal matrix of the velum medullare. However, transient expression of this protein is also present in the telencephalic subventricular zones comprising putative neuronal and/or glial precursor cells. This temporospatially restricted, potentially non-neuronal expression of class III beta-tubulin may have implications in the accurate identification of presumptive neurons derived from transplanted embryonic stem cells. In the adult central nervous system, the distribution of class III beta-tubulin is almost exclusively neuron specific. Altered patterns of expression are noted in brain tumors. In "embryonal"-type neuronal/neuroblastic tumors of the central nervous system, such as the medulloblastomas, class III beta-tubulin expression is associated with neuronal differentiation and decreased cell proliferation. In contrast, the expression of class III beta-tubulin in gliomas is associated with an ascending grade of histologic malignancy and with correspondingly high proliferative indices. Thus, class III beta-tubulin expression in neuronal or neuroblastic tumors is differentiation dependent, whereas in glial tumors, it is aberrant and/or represents "dedifferentiation" associated with the acquisition of glial progenitor-like phenotype(s). From a diagnostic perspective, the detection of class III beta-tubulin immunostaining in neoplastic cells should not be construed as categorical evidence of divergent neuronal differentiation in tumors, which are otherwise phenotypically glial. Because class III beta-tubulin is present in neoplastic but not in normal differentiated glial cells, the elucidation of molecular mechanisms responsible for the altered expression of this isotype may provide critical insights into the dynamics of the microtubule cytoskeleton in the growth and progression of gliomas.

Cleaved caspase-3, caspase-7 and poly (ADP-ribose) polymerase are complementarily but differentially expressed in human medulloblastomas.

Expression of cleaved caspase-3, cleaved caspase-7 and specific product of caspase-dependent Poly (ADP-Ribose) Polymerase (PARP) cleavage have been examined by immunohistochemistry in seven human medulloblastomas. Cleaved caspase-3 and cleaved PARP expression parallels apoptosis as revealed with classical morphological criteria and with the method of in situ end-labelling of nuclear DNA fragmentation. Cleaved PARP co-localizes cleaved caspase-3 in the majority of tumors and areas thus indicating that caspase-3 is a major effector caspase leading to apoptosis in these tumors. Yet cleaved caspase-7 was also expressed in a small number of cells in four of seven tumors, but was the predominant caspase associated with cleaved PARP in one medulloblastoma. These findings indicate that effector caspase-3 and -7 may act in association, although caspase-7 may be exceptionally dominant in selected tumors.

Paediatric brain tumours: an embryological perspective.

Primitive neuroectodermal tumours are amongst the most common paediatric tumours of the central nervous system. These tumours are composed of undifferentiated cells and a variable component of more differentiated cell types. Most analysis of these tumours has focused on molecules normally found in the differentiated cells or those found in all primitive neuronal precursors. In this article we describe recent advances in understanding of the molecular processes involved in normal neurogenesis. We discuss the relevance of these data to the biology of neuronal tumours and describe strategies we and others have adopted to investigate the usefulness of molecules found in undifferentiated neuronal tissues in understanding the events which underlie oncogenesis in this tumour type.

Medulloblastoma.

The histogenetic approach to the classification of embryonal tumors of the central nervous system has historically received wide acceptance as a scheme for histologic typing and nosologic definition. Medulloblastoma is a paradigm of a neuroblastic neoplasm whose origins and differentiation potential are traceable to cerebellar embryogenesis. Medulloblastomas show unequivocal neuroblastic maturational changes evidenced by neuritogenesis and expression of neuronal cytoskeletal and other neuronal differentiation-associated antigenic determinants. In addition, ganglion cells form in some lesions. Based on differential patterns of immunoreactivity for calbindin-D28k (a ventricular matrix (VM)-associated neuronal calcium binding protein, which is not expressed in the external granule layer (EGL) or its progeny) and the class III beta-tubulin isotype (beta III) (expressed metachronously in the neuronal descendants of both neuroepithelia), it is possible that distinct subsets of medulloblastomas may implicate clonally-related neuroblasts from two sources: VM for classic medulloblastomas and the EGL for desmoplastic (nodular) medulloblastomas. However, the possibility of two separate origins for the classic medulloblastomas cannot be entirely excluded. Origin from the VM is suggested for the rare subset of medulloblastomas with ganglion cells. It is, however, unclear whether these ganglion cells are neoplastic (products of terminal neuronal differentiation), or dysplastic (entrapped preexisting elements of cerebellar heterotopias). Glial differentiation (gliomatous transformation) in medulloblastomas is at issue but is documented in rare cases of classic medulloblastomas (presumed heteroclones of cotransformed VM glial precursors), or desmoplastic medulloblastomas (probable stromal glial transformation-induction). Astrocytic proliferations in desmoplastic medulloblastomas may be stroma-derived (neuronal differentiation-associated), analogous to Schwann cell contributions during maturation of peripheral neuroblastomas.

Fetal origin of the medulloblastoma: evidence from growth analysis of two cases.

Growth analysis of medulloblastomas was performed in two children. They initially manifested symptoms at the age of 3 years and 9 months and at the age of 2 months respectively. Computerized tomography (CT) scans were obtained at different points in each case. The growth curves were drawn on a semilogarithmic graph by calculating the tumor volume on CT on the assumptions that the tumor started from a single tumor cell and that the growth rate was constant. By extrapolating the curves back, tumor inception was estimated to have occurred respectively at the 14-23rd week and at the 16-17th week of gestation. Additional cell kinetic data were obtained from DNA analysis of surgical pathology specimens. Calculated cell-cycle times were 22-32 h for both cases. The S phases comprised 26.3% and 27% and the G0G1 phases 66.8% and 62% of the cell cycle, respectively, for case 1 and 2. Assuming a labelling index of 14%, the cell loss factors were estimated to be 97% and 74% (case 1 and case 2 respectively). The seventeenth week of gestation in humans corresponds to the timing of events occurring postnatally at days 3-18 in the developing cerebella of rodents, i.e., at the time of maximal activity in the migration and differentiation of the cells of the fetal external granular layer. Medulloblastomas have been experimentally induced in rodents by the injection of oncogenic viruses during the neonatal period, and statistical data on the epidemiology of human medulloblastomas have suggested a possible association with the contamination of polio vaccine by the SV 40 virus.(ABSTRACT TRUNCATED AT 250 WORDS)