ABSTRACT
Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.
Subject(s)
Bone Neoplasms/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP/metabolism , Gene Expression Regulation, Neoplastic , Osteosarcoma/genetics , Parathyroid Hormone-Related Protein/genetics , Tumor Suppressor Protein p53/genetics , Animals , Apoptosis , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Bone and Bones/metabolism , Bone and Bones/pathology , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Line, Tumor , Cell Proliferation , Cyclic AMP Response Element-Binding Protein/antagonists & inhibitors , Cyclic AMP Response Element-Binding Protein/metabolism , Disease Models, Animal , Gene Expression Profiling , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mutation , Osteoblasts/metabolism , Osteoblasts/pathology , Osteosarcoma/metabolism , Osteosarcoma/pathology , Parathyroid Hormone-Related Protein/metabolism , Primary Cell Culture , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Tumor Suppressor Protein p53/deficiencyABSTRACT
Osteosarcoma is the most common form of bone cancer. Pivotal insight into the genes involved in human osteosarcoma has been provided by the study of rare familial cancer predisposition syndromes. Three kindreds stand out as predisposing to the development of osteosarcoma: Li-Fraumeni syndrome, familial retinoblastoma and RecQ helicase disorders, which include Rothmund-Thomson Syndrome in particular. These disorders have highlighted the important roles of P53 and RB respectively, in the development of osteosarcoma. The association of OS with RECQL4 mutations is apparent but the relevance of this to OS is uncertain as mutations in RECQL4 are not found in sporadic OS. Application of the knowledge or mutations of P53 and RB in familial and sporadic OS has enabled the development of tractable, highly penetrant murine models of OS. These models share many of the cardinal features associated with human osteosarcoma including, importantly, a high incidence of spontaneous metastasis. The recent development of these models has been a significant advance for efforts to improve our understanding of the genetics of human OS and, more critically, to provide a high-throughput genetically modifiable platform for preclinical evaluation of new therapeutics.
