7/28/2023 0 Comments One acrossExisting cross-species comparative genomic studies have primarily focused on the use of DNA or protein sequence-based features to identify molecular regulatory elements, establish phylogenetic relationships, and annotate genes/proteins ( Rubin et al. To date, a comprehensive multifactorial and multiscalar comparison of gene regulation between animal models of development and human tumorigenesis has not been performed, in part because methods for cross-species expression analyses have not been established. ( 2003) have analyzed the expression profile of different mouse models of MB with a p53 -/- mutant background. The latter studies focused on metastatic human MBs and the roles of metastasis-related genes such as PDGFRα, PDGFRβ, and ERBB2 ( Chopra et al. ( 2002) found genes distinguishing human dMB from cMB, suggesting that human MBs derive from cerebellar granule cells through the activation of the sonic hedgehog (SHH) pathway. Gene expression profiling studies of human MBs have been performed ( MacDonald et al. cMBs are histologically characterized by the abundance of undifferentiated “small blue” malignant cells. dMBs are distinguished by the presence of nodules with localized neuronal differentiation within an otherwise densely cellular sea of undifferentiated malignant cells ( Kleihues and Cavenee 2000). MBs are the most common pediatric CNS malignancy and comprise two primary histological subtypes: desmoplastic medulloblastoma (dMB) and classic medulloblastoma (cMB). Granule neuron progenitors are thought to be the predominant dysregulated cell type from which the majority of MB cases arise ( Kadin et al. Differentiation is complete by P60 in mice, and at ∼18 mo of age in humans. In mice, the major phase of granule cell proliferation commences at birth and peaks by P8-P10 ( Altman and Bayer 1987). Granule neurons, the most abundant cell type in the cerebellum during development, are derived from precursors of the embryonic hindbrain ( Hallonet et al. The cerebellum is the brain structure largely responsible for coordinating motor activities. Here, we focused on the relationship between genes regulated during oncogenesis in the human cerebellar tumor, MB, and the developing wild-type mouse cerebellum during postnatal days 1-60 (P1-P60). Nevertheless, the putative relationship between underlying mechanisms in normal development and tumorigenesis remains controversial for most types of cancer, particularly the solid tumors such as medulloblastomas (MBs) and carcinomas. The brain tumor classification system of Bailey and Cushing ( 1926), from which modern taxonomies derive, emphasizes the histologic resemblance to cells of the developing central nervous system (CNS Bailey and Cushing 1926). In the 19th century, Lobstein and Cohnheim were among the first to theorize similarities between human embryogenesis and the biology of cancer cells ( Rather 1978). Our findings indicate both a recapitulation of tissue-specific developmental programs in diverse solid tumors and the utility of tumor characterization on the developmental time axis for identifying novel aspects of clinical and biological behavior. Comparable results for human lung cancer vis-a-vis the developing mouse lung suggest the generalizability of this multiscalar developmental perspective on tumor biology. Genewise, down- and up-regulated MB genes segregate to late and early stages of development, respectively. Furthermore, metastatic MBs were highly associated with mouse P5 cerebella, suggesting that a clinically distinct subset of tumors is identifiable by molecular similarity to a precise developmental stage. Genomically, human medulloblastomas were closest to mouse P1-P10 cerebella, and normal human cerebella were closest to mouse P30-P60 cerebella. We have developed a novel method to project the gene expression profiles of medulloblastomas (MBs)-human cerebellar tumors-onto a mouse cerebellar development sequence: postnatal days 1-60 (P1-P60). Identification of common mechanisms underlying organ development and primary tumor formation should yield new insights into tumor biology and facilitate the generation of relevant cancer models.
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