The Biology of Cancer
These notes are from the final third of the Spring 1995 Biology of Cancer class
given at Berkeley.
The Multistep Genesis of Carcinoma
Stages in Human Carcinogenesis
- Evidence for the Multistep Genesis of Carcinoma
- The Monoclonal Origin of Tumors
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Overview:Normal cells become tumor cells in a multistep process. Tumors are monoclonal in origin, but a population of tumor cells is heterogeneous due to neccesary differentiation or a highly unstable genome.
Initiation
Heritable changes are made in the genome of a normal cell, resulting from exposure to a carcinogen. These cells are known as initiated cells.
Promotion
Initiated cells, upon repeated exposure to a noncarcinogenic promoter, become expanded to a visible population. Examples are the benign tumors such as papillomas and polyps. This phenomena of clonal expansion of inititated cells is known as carcinoma in situ.
Progression
One or more of the clonally expanded initiated cells, as a result of a secondary insult, evolves into a cancer cell. This cell again undergoes clonal expansion, and through further changes becomes progessively malignant.
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Evidence for the Multistep Genesis of Carcinoma
- Epidemologic studies show that there is a long period between exposure to a carcinogen and the appearance of cancer
- Tumors are monoclonal in origin
- Morphological studies all show an intermediate stage, such as papilloma (skin), polyp (gastric), and hyperplastic nodules (breast); here, cells are no longer normal but not yet cancer
- Molecular Transfection Studies
- The SV40 Large T protein is suffcient to transform a cell, but it is a large multifunctional complex which provides immortality and anchorage independance.
- Transfection of the H-ras oncogene into normal cells does not transform them, but it does transform the immortal cell line NIH3T3
It appears that, at least in vitro, two genes must be transfected in order to transform a cell culture. One must be a nuclear protein, such as PLT (Polyoma Large T), E1A, E7, or myc. The other must be cytoplasmic, such as ras, pmt, E6, or 11B.
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Evidence for the Monoclonal Origin of Tumors
A female's cells contains one inactive X chromosome. This inactivation is heritable, and heterozygous alleles create a mosaic pattern, as is seen in a calico cat. Tumor cells all have the same X chromosome inactivated, indicating that they originated from the same cell.
How Do Tumors Come to Have a Heterogeneous Cell Population?
There are two theories as to how a monoclonal population of tumor cells can become the heterogeneous population seen in large tumors:
- A "stem" tumor cell may differentiate to provide the functions necessary for a living organ
- The more malignant a tumor is, the more unstable its phenotype becomes
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Last revised: 1995 May 5 by
sev@byz.org