ABSTRACT
BACKGROUND: The homeobox containing transcription factor MSX2 is a key regulator of embryonic development and has been implicated to have a role in breast and pancreatic cancer. METHODS: Using a selection of two- and three-dimensional in vitro assays and tissue microarrays (TMAs), the clinical and functional relevance of MSX2 in malignant melanoma was explored. A doxycyline-inducible over-expression system was applied to study the relevance of MSX2 in vitro. For TMA construction, tumour material from 218 melanoma patients was used. RESULTS: Ectopic expression of MSX2 resulted in the induction of apoptosis and reduced the invasive capacity of melanoma cells in three-dimensional culture. MSX2 over-expression was shown to affect several signalling pathways associated with cell invasion and survival. Downregulation of N-Cadherin, induction of p21 and inhibition of both BCL2 and Survivin were observed. Cytoplasmic MSX2 expression was found to correlate significantly with increased recurrence-free survival (P=0.008). Nuclear expression of MSX2 did not result in significant survival correlations, suggesting that the beneficial effect of MSX2 may be independent of its DNA binding activity. CONCLUSIONS: MSX2 may be an important regulator of melanoma cell invasion and survival. Cytoplasmic expression of the protein was identified as biomarker for good prognosis in malignant melanoma patients.
Subject(s)
Homeodomain Proteins/metabolism , Melanoma/metabolism , Melanoma/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Antigens, CD/metabolism , Apoptosis , Blotting, Western , Cadherins/metabolism , Cell Cycle , Cell Line, Tumor , Cell Survival , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Disease-Free Survival , Down-Regulation , Electrophoresis, Polyacrylamide Gel , Fluorescent Antibody Technique , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Melanoma/genetics , Multivariate Analysis , Neoplasm Invasiveness , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Protein Array Analysis , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Signal Transduction , Skin Neoplasms/genetics , Spheroids, Cellular , Survival Analysis , Survivin , Up-RegulationABSTRACT
Cellular senescence is an irreversible arrest of proliferation. It is activated when a cell encounters stress such as DNA damage, telomere shortening or oncogene activation. Like apoptosis, it impedes tumour progression and acts as a barrier that pre-neoplastic cells must overcome during their evolution toward the full tumourigenic state. This review focuses on the role of transcriptional regulators in the control of cellular senescence, explores how their function is perturbed in cancer and discusses the potential to harness this knowledge for future cancer therapies.
Subject(s)
Cellular Senescence/genetics , Gene Expression Regulation/physiology , ADP-Ribosylation Factors/genetics , ADP-Ribosylation Factors/metabolism , ADP-Ribosylation Factors/physiology , Animals , Apoptosis/genetics , Apoptosis/physiology , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p16/physiology , Genetic Loci/genetics , Genetic Loci/physiology , Humans , Models, Biological , Signal Transduction/genetics , Signal Transduction/physiology , Transcription, Genetic/physiologyABSTRACT
During its lifetime, the mammary gland undergoes many phases of development and differentiation. Much of this occurs during puberty, when the ductal epithelium expands by branching morphogenesis, invading the surrounding fat pad to form an organised mammary tree. Throughout its existence, the epithelium will go through several cycles of proliferation and cell death during pregnancy, lactation and involution. Many of the signalling mechanisms which control the initial invasion of the fat pad by the epithelium, and regulate its continuing plasticity, can be harnessed or corrupted by tumour cells in order to support their aberrant growth and progression towards invasion. This is true not just for the epithelial cells themselves but also for cells in the surrounding microenvironment, including fibroblasts, macrophages and adipocytes. This review examines the complex web of signalling and adhesion interactions controlling branching morphogenesis, and how their alteration can promote malignancy. Current in vivo and in vitro mammary gland models are also discussed. (Part of a Multi-author Review).
