ABSTRACT
Osteosarcoma is the most common primary bone cancer. Mutations of the RB gene represent the most frequent molecular defect in this malignancy. A major consequence of this alteration is that the activity of the key cell cycle regulator E2F1 is unleashed from the inhibitory effects of pRb. Studies in animal models and in human cancers have shown that deregulated E2F1 overexpression possesses either "oncogenic" or "oncosuppressor" properties, depending on the cellular context. To address this issue in osteosarcomas, we examined the status of E2F1 relative to cell proliferation and apoptosis in a clinical setting of human primary osteosarcomas and in E2F1-inducible osteosarcoma cell line models that are wild-type and deficient for p53. Collectively, our data demonstrated that high E2F1 levels exerted a growth-suppressing effect that relied on the integrity of the DNA damage response network. Surprisingly, induction of p73, an established E2F1 target, was also DNA damage response-dependent. Furthermore, a global proteome analysis associated with bioinformatics revealed novel E2F1-regulated genes and potential E2F1-driven signaling networks that could provide useful targets in challenging this aggressive neoplasm by innovative therapies.
Subject(s)
Bone Neoplasms/metabolism , E2F1 Transcription Factor/metabolism , Gene Expression Regulation, Neoplastic , Osteosarcoma/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Apoptosis/physiology , Blotting, Western , Bone Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation , Child , DNA Damage , DNA Repair , DNA-Binding Proteins/metabolism , E2F1 Transcription Factor/genetics , Electrophoresis, Gel, Two-Dimensional , Female , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Male , Middle Aged , Nuclear Proteins/metabolism , Osteosarcoma/genetics , Tumor Protein p73 , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Proteins/metabolism , Young AdultABSTRACT
INTRODUCTION: In patients who have undergone a total joint replacement, any mass occurring in or adjacent to the joint needs thorough investigation and a wear debris-induced cyst should be suspected. CASE PRESENTATION: An 81-year-old man presented with a painful and enlarging mass at the popliteal fossa and calf of his right knee. He had had a total right knee replacement seven years previously. Plain radiographs showed narrowing of the medial compartment. Magnetic resonance imaging showed a cystic lesion at the postero-medial aspect of the knee joint mimicking popliteal cyst or soft tissue sarcoma. Fine needle aspiration was non-diagnostic. A core-needle biopsy showed metallosis. Intraoperative findings revealed massive metallosis related to extensive polyethylene wear, delamination and deformation. Revision knee and patella arthroplasty was carried out after a thorough debridement of the knee joint. CONCLUSION: Long-term follow-up is critical for patients with total joint replacement for early detection of occult polyethylene wear and prosthesis loosening. In these cases, revision arthroplasty may provide a satisfactory knee function.
