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p53 and brain tumors: from gene mutations to gene therapy
G Fulci1, N Ishii, E G Van Meir
1Neurosurgery Dept., University Hospital (CHUV), Lausanne, Switzerland.
Abstract:
The p53 tumor suppressor gene (TP53) is the most frequently altered gene in human cancer and is also found mutated in several types of brain tumors. Loss of p53 function plays a central role in the development of cancer. The characterization of the biochemical pathways by which p53 alteration triggers tumorigenesis is the foundation for the design of novel therapeutic approaches. Investigations of the intracellular mechanisms at the origin of p53 tumor suppressive functions have shown that p53 is a transcription factor able to sense a variety of cellular insults and induce a dual response: cell growth arrest/senescence or apoptosis. Less well studied are p53's influences on extracellular events such as tumor angiogenesis, immunology and invasion. Here, we review these findings and specifically discuss their implications for brain tumor genesis, molecular diagnosis and prognosis. Of clinical importance are the findings that brain tumors with wild type (wt) or mutant p53 status may respond differently to radiation therapy and that novel therapeutic strategies using TP53 gene transfer or specifically targeting tumor cells with mutated p53 are being evaluated in clinical trials.
Insights
The p53 tumor suppressor gene (TP53) is crucial in cancer development. Understanding its role in brain tumors informs new therapies and diagnostics, impacting treatment responses.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The TP53 gene is frequently altered in human cancers, including brain tumors.
- Loss of p53 function is a key driver of tumorigenesis.
- p53 acts as a transcription factor, regulating cellular responses to stress.
Purpose of the Study:
- To review the role of p53 in intracellular and extracellular events relevant to brain tumor development.
- To discuss the implications of p53 status for brain tumor diagnosis, prognosis, and therapy.
- To highlight novel therapeutic strategies targeting TP53.
Main Methods:
- Literature review of p53's functions in cancer.
- Analysis of p53's influence on cellular senescence, apoptosis, angiogenesis, immunology, and invasion.
- Examination of clinical data regarding p53 status and treatment response.
Main Results:
- p53 influences cell cycle arrest, apoptosis, tumor angiogenesis, immunology, and invasion.
- Brain tumors with wild-type or mutant p53 may exhibit differential responses to radiation therapy.
- Novel TP53-based therapies are under clinical investigation.
Conclusions:
- p53 plays a multifaceted role in brain tumorigenesis, affecting both intracellular and extracellular processes.
- Molecular diagnosis and prognosis of brain tumors can be informed by p53 status.
- Targeting TP53 mutations offers promising avenues for innovative brain tumor treatments.