ABSTRACT
Paternal aging is associated with increased risk of genetic disease transmission to the offspring. The changes associated with aging arise predominantly through formation of single nucleotide variation through DNA replication errors, as well as possibly chronic exposure to environmental toxins and reactive oxygen species exposure. Several age-related reproductive factors are also contributory, including the systemic hormonal milieu, accumulation of environmental toxin exposure, aging germ cells, and accumulation of de novo genetic and genomic abnormalities in germ cells. In this article we review the age-related genetic and genomic changes that occur in the male germ line.
Subject(s)
Aging/genetics , Genomics , Paternal Age , Spermatozoa/pathology , Age Factors , Aging/metabolism , Aging/pathology , Chromosome Aberrations , Chromosomes, Human , DNA Damage , Epigenesis, Genetic , Genetic Predisposition to Disease , Heredity , Humans , Male , Mutation , Pedigree , Reactive Oxygen Species/metabolism , Risk Assessment , Risk Factors , Spermatozoa/metabolismABSTRACT
Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction-mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.
Subject(s)
Cerebellar Neoplasms/pathology , Cerebellum/metabolism , Medulloblastoma/pathology , Neuropilin-1/metabolism , Pregnancy Proteins/metabolism , Signal Transduction , Animals , Cells, Cultured , Cerebellar Neoplasms/metabolism , Humans , Medulloblastoma/metabolism , Mice , Mice, Knockout , Neoplasm Transplantation , Paracrine Communication , Placenta Growth Factor , Transplantation, Heterologous , Vascular Endothelial Growth Factor Receptor-1/metabolismABSTRACT
Tumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.