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Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth.

ABSTRACT: Medulloblastomas are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Treatment-related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral neurologic injury. In genetically engineered mice, activation of Sonic Hedgehog (Shh) signaling in neural stem cells in the developing cerebellum induces medulloblastomas. Hepatocyte growth factor (HGF) and its cell surface receptor c-Met are highly expressed in human medulloblastomas, and elevated levels of c-Met and HGF mRNA predict an unfavorable prognosis for patients. HGF is neuroprotective for cerebellar granule cells and promotes growth of human medulloblastoma cells in culture and in murine xenografts. We modeled the ability of HGF to induce medulloblastomas in mice using a version of the RCAS/tv-a system that allows gene transfer to cerebellar neural progenitors during their postnatal expansion phase when these cells are highly susceptible to transformation. Here, we report a high frequency of medulloblastoma formation in mice after postnatal expression of HGF in cooperation with Shh. Some tumors showed neurocytic differentiation similar to that in human nodular medulloblastomas with activated Shh signaling. Systemic administration of a monoclonal antibody against HGF prolonged survival of mice bearing Shh + HGF-induced medulloblastomas by stimulating apoptosis. These findings indicate a role for HGF in medulloblastoma initiation and growth and show efficacy of HGF-targeted therapy in a mouse model of endogenously arising tumors.

SUBMITTER: Binning MJ

PROVIDER: S-EPMC2638505 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth.

Binning Mandy J MJ Niazi Toba T Pedone Carolyn A CA Lal Bachchu B Eberhart Charles G CG Kim K Jin KJ Laterra John J Fults Daniel W DW

Cancer research 20081001 19

Medulloblastomas are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Treatment-related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral neurologic injury. In genetically engineered mice, activation of Sonic Hedgehog (Shh) signaling in neural stem cells in the developing cerebellum induces medulloblastomas. Hepatoc ...[more]

PMID: 18829539

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Project description:Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH? subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

Dataset Information

Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth.

Publications

Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth.

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