Currently we test and support the following browsers:
Please note that this is not intended to be an exhaustive list of browsers that support web standards, nor a test of browser compliance, nor a side-by-side comparison of various manufacturers’ browsers.
Brain tumors are the second most common malignancy in children and the most common and deadly form of childhood solid tumors. Two studies published last year highlighted the remarkable diversity of genetic alterations that occur in childhood brain tumors and identified important differences between them and their adult counterparts. One study reported efforts to solve the mystery of which retinal cell type undergoes malignant transformation during fetal development to form retinoblastoma.
Diffuse intrinsic pontine glioma (DIPG) is a devastating disease of the brainstem that has few treatment options and a dismal outcome. The probability of long-term survival for children with DIPGs is less than 10%; thus, new treatment approaches to DIPG are urgently needed. Suzanne J. Baker, PhD (Developmental Neurobiology), and colleagues recently performed genome-wide analysis of DNA copy number alterations (CNAs) in tumor samples obtained from 43 pediatric patients with DIPGs and compared their results with data from pediatric non-brainstem gliomas and adult gliomas to identify deletions and amplifications of genes that are unique to DIPG and to examine the differences in gene-expression profiles across the three groups.
In the Journal of Clinical Oncology1, the investigators reported that 41 (95%) of the DIPG samples contained CNAs. They identified gene amplifications driving signaling through the Ras and PI3K pathways in almost 50% of the DIPGs, most commonly in the tyrosine kinases PDGFRA and MET. Mutations in the RB protein pathway, which regulates the cell cycle, were detected in 30% of the DIPGs. Both pathways were affected in 21% of the tumor samples. The upregulation of specific HOX genes has been associated with treatment resistance in adult gliomas and lower probability of survival in pediatric high-grade gliomas. The HOX genes that were upregulated in DIPGs were not the same as those in the other two groups. Thus, DIPGs represent a distinct subgroup of gliomas. Dr. Baker’s team is now investigating the potential use of a combination of broad tyrosine kinase inhibitors and selective inhibitors of PDGFRA as a therapeutic option for pediatric patients with DIPG.
The development of mouse models of cancer that faithfully recapitulate the human disease is essential to understanding the molecular basis of cancer development and to identifying candidate pathways and genes to target with novel therapeutic approaches. Glioblastoma multiforme (GBM) is an aggressive brain tumor that is associated with very poor outcome. Recently, several groups, including that of Dr. Baker, have performed detailed genomic profiling studies of GBM.
In an article in Cancer Cell2, the investigators identified multiple common targets of mutation that distinguish childhood GBM from adult GBM, particularly mutations activating receptor tyrosine kinase signaling, such as inactivation of PTEN and amplification of the epidermal growth factor receptor gene EGFR, TP53 (p53) signaling, and RB1-mediated control of cell cycle progression. To gain insight into the interaction between these mutations and the development of GBM, Dr. Baker’s team modeled alterations of Pten, Tp53, and Rb1 by using mice in which the expression of these genes was selectively inactivated in astrocytes, the normal cellular counterpart of GBM cells. They found that Pten inactivation alone was insufficient to induce brain tumors, whereas the loss of Pten and Tp53 induced high-grade brain tumors, and concomitant loss of Rb1 further enhanced tumorigenesis.
Genomic profiling of the mouse tumors revealed additional alterations activating tyrosine kinase signaling. The expression of Met and Egfr was amplified in the tumors in which Pten and Tp53 were knocked out, and that of Pdgfra was amplified in the double-knockout tumors and in triple-knockout tumors in which Pten, Tp53, and Rb1 were inactivated in astrocytes. The tumors commonly showed biochemical evidence of signaling pathway activation, harbored additional gene mutations also observed in the human tumors, and exhibited transcriptional signatures highly similar to those of primary human GBM.
This study demonstrates the power and importance of carefully designed mouse models of human cancer to confirm the role of genetic alterations in the development of human tumors and provide a platform for the testing of novel therapeutic approaches.
All tumors arise from the transformation of a normal cell that, at a particular stage of development, acquires genetic or epigenetic alterations that confer the hallmarks of cancer, including abnormal growth, self-renewal, lack of responsiveness to growth signals, and the ability to invade locally and disseminate throughout the body. Identifying the stem cell or progenitor cell that is susceptible to transformation is essential to understanding the basis of cancer and guiding the development of novel therapy.
Retinoblastoma is a rare childhood cancer of the eye that arises during fetal development and is diagnosed within the first few years of life. The disease is characterized by the inactivation of both alleles of the RB1 tumor-suppressor gene. The cell of origin of retinoblastoma has long been debated, and the disease has been thought to arise from retinal photoreceptors. Using highly detailed analyses and gene-expression profiling of single cells isolated from human retinoblastomas, mouse retinoblastomas, and normal retinae, Michael A. Dyer, PhD (Developmental Neurobiology), and colleagues pursued the disease’s evasive cell of origin.
Reporting in Cancer Cell3, the investigators showed that both human and murine retinoblastoma cells coexpress multiple developmental programs for photoreceptors, interneurons, and progenitor cells; these programs are never coexpressed at any stage during normal retinal development. Upon examination of the cell-type signatures (e.g., neuroanatomical, neurochemical, and morphometric features), Dr. Dyer’s team concluded that the most common features were those of amacrine cell differentiation. However, they stopped short of declaring amacrine cells as the retinoblastoma cell of origin. Because signaling pathways are deregulated during tumorigenesis, the amacrine cell differentiation program may simply be activated independently of amacrine cell fate as retinoblastoma arises.
Treatment with small molecules targeting monoamine oxidase neurotransmitter signaling perturbed the growth of retinoblastoma cell lines, further supporting the importance of neuronal signaling pathways in retinoblastoma development. These data provide insight into potential therapeutic targets for retinoblastoma.
1Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, Olson JM, Geyer JR, Chi SN, da Silva NS, Onar-Thomas A, Baker JN, Gajjar A, Ellison DW, Baker SJ. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol Oct 20;29(30):3999-4006, 2011. doi: 10.1200/JCO.2011.35.5677. Epub 2011 Sep 19. PubMed PMID: 21931021; PubMed Central PMCID: PMC3209696. Abstract | Full Text
2Chow LM, Endersby R, Zhu X, Rankin S, Qu C, Zhang J, Broniscer A, Ellison DW, Baker SJ. Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain. Cancer Cell Mar 8;19(3):305-16, 2011. PubMed PMID: 21397855; PubMed Central PMCID: PMC3060664. Abstract | Full Text
3McEvoy J, Flores-Otero J, Zhang J, Nemeth K, Brennan R, Bradley C, Krafcik F, Rodriguez-Galindo C, Wilson M, Xiong S, Lozano G, Sage J, Fu L, Louhibi L, Trimarchi J, Pani A, Smeyne R, Johnson D, Dyer MA. Coexpression of normally incompatible developmental pathways in retinoblastoma genesis. Cancer Cell Aug 16;20(2):260-75, 2011. PubMed PMID: 21840489. Abstract | Full Text