Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers

Abstract

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. 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). Genomically, human medulloblastomas were closest to mouse P1-P10 cerebella, and normal human cerebella were closest to mouse P30-P60 cerebella. 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. Genewise, down-and up-regulated MB genes segregate to late and early stages of development, respectively. Comparable results for human lung cancer vis-a-vis the developing mouse lung suggest the generalizability of this multiscalar developmental perspective on tumor biology. 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.[Keywords: cerebellar development; medulloblastoma; comparative genomics; multiscale models; metastasis; principle component analysis] Supplemental material is available at http://www.genesdev.org. Received December 30, 2003; revised version accepted February 25, 2004. 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). 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). 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.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). The cerebellum is the brain structure largely responsible for coordinating motor activities. Granule neurons, the most abundant cell type in the cerebellum during development, are derived from precursors of the embryonic hindbrain (Hallonet et al. 1990). In mice, the major phase of granule cell proliferation commences at birth and peaks by P8-P10 (Altman and Bayer 1987). Differentiation is complete by P60 in mice, and at ∼18 mo of age in humans. Granule neuron progenitors are thought to be the predominant dysregulated cell type from which the majority of MB cases arise (Kadin et al. 1970;Reddy and Packer 1999). MBs are the most common pediatric CNS malignancy and comprise two primary histological...

Medulloblastoma stem cells: where development and cancer cross pathways

“…Therefore, classic MBs were thought to originate from the VZ, whereas GNPs in the EGL were believed to give rise to desmoplastic MBs. Gene expression profiling of these two histological subtypes corroborated the findings for desmoplastic MBs as they expressed genes associated with proliferating GNPs in the EGL, but classic MBs were found to express genes not specific to a particular cerebellar cell type (6,29). Additional microarray analyses have failed to find clear correlations between lineage markers and histological subtypes (30), and with the identification of high levels of putative stem cells, including the VZ-associated CD133 + MB BTICs in both subtypes (19), it has become apparent that both histological subtypes of MB contain cells that resemble multipotent NSCs.…”

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

“…Striking overlaps exist between genes involved in development and cancer (Kho et al 2004;Liu et al 2006;Ben-Porath et al 2008;Kopantzev et al 2008). All three transcription factors in this study are well-established developmental regulators.…”

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

“…The lung cancer transcriptome is thought to contain a 'developmental signature', a set of genes that are collectively activated during development (Kho et al, 2004). Genes that are normally only expressed in early developmental stages are re-expressed in lung cancer, while genes that are expressed in fully differentiated lung are repressed (Borczuk et al, 2003;Liu et al, 2006;Naxerova et al, 2008).…”