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Life and death in the genesis of the tumour cell
1Department of Pathology, University Medical School, Edinburgh, Scotland, UK. david.harrison@ed.ac.uk
Abstract:
Most tumours arise because of an aberrant response of cells following exposure to chemicals deliberately ingested, for example cigarette smoke, or present as an environmental pollutant, for example dietary aflatoxin. Recent evidence has highlighted the importance of tumour suppressor genes and oncogenes in determining the response of a cell to potentially mutagenic or growth disrupting events. Many toxicants in vivo can cause apoptosis in a dose dependent manner. At low dose apoptosis is engaged, but with high exposure cells may undergo necrosis as cellular metabolism is catastrophically overwhelmed preventing the ordered set of events that constitute apoptosis from occurring. Mutations in genes that control deletion of potentially damaged cells result in overriding of death signals and may result in survival of a cell that otherwise should have been deleted. This gave rise to the concept of the 'undead' cell--the aberrant cell that has escaped normal growth controls taking the first step towards cancer. However, not all cell lineages respond to injury in the same ways, and even the same gene may have quite varied effects depending on the cellular and tissue environment.
Insights
Chemicals can cause cancer by disrupting cell death pathways. Mutations in genes controlling cell deletion can lead to
Area of Science:
- Toxicology
- Molecular Biology
- Cancer Research
Background:
- Environmental toxicants and ingested chemicals are major causes of cancer.
- Tumor suppressor genes and oncogenes play critical roles in cellular response to damage.
- Cellular response to toxicants varies based on dose, leading to apoptosis or necrosis.
Purpose of the Study:
- To explore the mechanisms by which chemical exposure leads to cancer.
- To understand the role of cell death pathways in cancer development.
- To investigate the concept of the 'undead' cell in oncogenesis.
Main Methods:
- Review of recent evidence on gene function in cellular response.
- Analysis of dose-dependent effects of toxicants on cell death (apoptosis vs. necrosis).
- Examination of genetic mutations that override cell death signals.
Main Results:
- High doses of toxicants can overwhelm cells, causing necrosis instead of apoptosis.
- Mutations in cell death regulatory genes allow damaged cells to survive.
- This survival of aberrant cells is a key step towards cancer initiation, termed the 'undead' cell.
Conclusions:
- Aberrant cellular responses to chemical exposure, particularly the survival of damaged cells due to overridden death signals, are crucial in cancer development.
- The 'undead' cell concept highlights a critical transition in oncogenesis.
- Cellular and tissue context significantly influences gene function and response to injury.