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Chapter 13. Cancer—Principles and overview By Robert A. Weinberg. 13.1 Tumors are masses of cells derived from a single cell. Cancers progress from: a single mutant cell to a tumor then to metastasis Tumors are clonal. Tumors are classified by cell type.
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Chapter 13 Cancer—Principles and overview By Robert A. Weinberg
13.1 Tumors are masses of cells derived from a single cell • Cancers progress from: • a single mutant cell • to a tumor • then to metastasis • Tumors are clonal. • Tumors are classified by cell type.
13.2 Cancer cells have a number of phenotypic characteristics • Cancer cells are characterized by several distinct properties. • Unlike normal cells, cancer cells do not stop dividing when they contact a neighboring cell when such cells are propagated in a Petri dish.
13.2 Cancer cells have a number of phenotypic characteristics • Cancer cells have a greatly reduced requirement for growth factors to sustain growth and proliferation. • Unlike normal cells, cancer cells in culture do not require attachment to a physical substrate in order to grow. • The trait of anchorage independence
13.2 Cancer cells have a number of phenotypic characteristics • Unlike normal cells in culture, which halt division after a certain number of growth-and-division cycles: • cancer cells are immortal • they do not stop dividing after a predetermined number of generations • Cancer cells often have chromosomal aberrations, including changes in chromosome number and structure.
13.3 Cancer cells arise after DNA damage • Agents that cause cancer may do so by damaging DNA. • Mutations in certain genes cause a cell to grow abnormally.
13.3 Cancer cells arise after DNA damage • Ames devised a test to determine the carcinogenicity of chemical agents. • Cancers usually arise in somatic cells.
13.4 Cancer cells are created when certain genes are mutated • Oncogenes promote cell growth and division. • Tumor suppressors inhibit cell growth and division.
13.4 Cancer cells are created when certain genes are mutated • Cellular genomes harbor multiple proto-oncogenes. • Tumor viruses carry oncogenes. • Genetic alterations can convert proto-oncogenes into potent oncogenes.
13.5 Cellular genomes harbor a number of protooncogenes • Gain-of-function mutations can activate protooncogenes. • Overexpression of proto-oncogenes can cause tumors. • Translocations can create hybrid proteins that are oncogenic.
13.6 Elimination of tumor suppressor activity requires two mutations • Both copies of a tumor suppressor gene must usually be inactivated to see a phenotype.
13.6 Elimination of tumor suppressor activity requires two mutations • Mechanisms that result in loss-of-heterozygosity are often responsible for the loss of the remaining normal copy of the tumor suppressor gene. • Cancer susceptibility can be caused by the inheritance of a mutant copy of a tumor suppressor gene.
13.7 The genesis of tumors is a complex process • Cancer is a multistep process that requires four to six different mutations to reach the tumor state. • Tumorigenesis progresses by clonal expansion, where increasingly abnormal clones of cells outgrow their less mutant neighbors.
13.8 Cell growth and proliferation are activated by growth factors • Cell signaling requires extracellular factors, receptors, and other proteins that transmit the signal to the nucleus.
13.8 Cell growth and proliferation are activated by growth factors • Extracellular signals may be: • growth promoting or • growth inhibiting • Many genes encoding cell signaling molecules are proto-oncogenes and tumor suppressor genes.
13.9 Cells are subject to growth inhibition and may exit from the cell cycle • Cells that have differentiated have reached their final specialized form. • Differentiated cells are usually postmitotic. • Thus, differentiation reduces the pool of dividing cells.
13.9 Cells are subject to growth inhibition and may exit from the cell cycle • Cells can commit suicide by apoptosis. • Apoptosis eliminates healthy cells during development and at other times in an organism’s lifetime.
13.9 Cells are subject to growth inhibition and may exit from the cell cycle • Apoptosis eliminates damaged cells that can pose a threat to the organism. • Mutations that compromise a cell’s ability to carry out apoptosis can result in malignancy.
13.10 Tumor suppressors block inappropriate entry into the cell cycle • Cells decide whether or not to divide at the restriction point. • pRb is a tumor suppressor that can prevent passage through the restriction point.
13.10 Tumor suppressors block inappropriate entry into the cell cycle • pRb can be inactivated by: • mutations • sequestration by oncoproteins • hyperactivity of the Ras pathway
13.11 Mutation of DNA repair and maintenance genes can increase the overall mutation rate • DNA repair proteins keep the spontaneous mutation rate low. • Defects in DNA repair genes increase the basal rate of mutation in the cell. • Mutations in checkpoint proteins compromise chromosome integrity.
13.12 Cancer cells may achieve immortality • Cancer cells avoid senescence by inactivating tumor suppressor genes. • Cancer cells reach a crisis point at which many of them die off.
13.12 Cancer cells may achieve immortality • Cells that survive the crisis are immortalized. • Telomeres become shorter each generation unless telomerase is activated.
13.12 Cancer cells may achieve immortality • When telomeres become too short to protect the chromosomes, the chromosomes fuse. • This provokes crisis. • Most cancer cells activate telomerase transcription, thereby escaping death.
13.13 Access to vital supplies is provided by angiogenesis • Tumor growth is limited by access to nutrients and waste removal mechanisms. • Tumors can stimulate blood vessel growth (angiogenesis), which enables them to expand.
13.14 Cancer cells may invade new locations in the body • Some cells from a primary tumor can gain entrance to blood and lymphatic vessels (intravasation). • The process of intravasation often requires breaking through barriers of neighboring tissue.
13.14 Cancer cells may invade new locations in the body • Cells that survive the trip through the blood vessels may colonize other organs. • Metastasis, or colonization of other tissues, usually results in death of the individual.
