Cell cycle and important (proto-) oncogenes
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Vrije Universiteit Amsterdam (VU)
Gezondheid en Leven
Oncologie
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Molecular Biology of Cancer (Pecorino)
Chapter 1: Introduction
Worldwide incidence (number of new cases) is estimated to be about 12.7 million cases in 2008.
Process of carcinogenesis: normal cell is transformed into a cancer cell intricacies of cell function and the
molecular pathways that underlie it.
Cancer: group of diseases characterized by unregulated cell growth and the invasion and spread of cells from the site
of origin, or primary site, to other sites in the body.
- Carcinomas: cancer in epithelial cells
- Sarcomas: cancer derived from mesoderm cells
- Adenocarcinomas: cancer of glandular tissue
The major factor that causes cancer in each target tissue is different and also differences in the molecular
mechanisms involved in carcinogenesis within each cell type and the pattern of spread of cells from the primary site.
Hallmarks of cancer:
1. Growth signal autonomy:
o No need of external signals for growth
o Acquired mutations short-circuit growth factor pathways leading to unregulated growth
2. Evasion of growth inhibitory signals
o Acquired mutations or gene silencing interfere with the inhibitory pathways
3. Unlimited replicative potential
o Cancer cells maintain the length of their telomeres (telomerase)
4. Invasion and metastasis
o Migration to other body parts is major cause of cancer deaths
o Alterations of the genome may affect the activity and/or levels of enzymes involved in invasion or
molecules involved in cell-cell or cellular-extracellular adhesion.
5. Angiogenesis
o Cancer cells induce angiogenesis, needed for tumor survival and expansion
o Altering the balance between angiogenic inducers and inhibitors can activate the angiogenic switch
6. Evasion of cell death
o Evade apoptotic signals
Emerging hallmarks:
7. Avoiding immune destruction
o Successful cancer cells may be those that do not stimulate an immune response or can interfere with
the immune response so as to avoid immune destruction
8. Reprogramming energy metabolism
o Uncontrolled cell division demands increases in fuel and biosynthetic precursors adjusting energy
metabolism
o Cancer cells can carry out glycolysis even with the presence of oxygen
Enabling characteristics:
9. Genome instability and mutation
o All tumors contain inflammatory immune cells facilitation of the ability of cancer; provide growth
factors and enzymes that promote angiogenesis and evasion
o Release of oxygen species that are mutagenic
10. Tumor promoting inflammation
o Faulty DNA repair pathways can contribute to genomic instability
, Benign tumor: not evidence of cancer. Do not spread throughout the body (no metastasis), can be life threatening
depending on the location
Malignant tumor: do not remain encapsulated, show features of invasion and metastasize.
- Physical obstructions and as they invade other organs they compromise function. They also compete fiercely
with healthy tissue for nutrients and oxygen.
Cancer cells distinguished from normal cells in cell culture conditions:
Normal cells grow as a single layer contact inhibition; contact with neighboring cells inhibits growth
Transformed cells acquire the following phenotypes:
o Fail to exhibit contact inhibition grow as piles of cells or ‘foci’
o Can grow in conditions of low serum
o Adopt a round morphology rather than a flat and extended one
o Are able to grow without attaching to a substrate exhibiting ‘anchorage independence’
Most agents that cause cancer (carcinogens) are agents that cause alterations to the DNA sequence or mutations
(mutagens). alterations in DNA
- Point mutations, deletions and chromosomal translocations
Accumulation of mutations in cells over time represents a multi-step process that underlies carcinogenesis.
increased risk of cancer with age.
- Only 5-10% of the mutations observed are thought to be directly involved in causing cancer almost all
mutations are somatic mutations (body cells) not inheritable
o Some germline mutations can cause an increased risk of developing cancer but are rarely involved in
causing cancer immediately.
Cancer = disease of the genome at the cellular level.
In cases of severe DNA damage, cell suicide is induced in order to protect the whole body from cell transformation.
- Many mechanisms exist for blocking carcinogenic events, but over-burdening the system increases the
probability that a cell carrying a deleterious mutation will escape surveillance.
Three important processes that contribute to the overall net cell number in an individual
1. Cell proliferation: cell division and cell growth
2. Elimination of cells by programmed cell death
3. During the process of differentiation cells can enter an inactive phase of cell growth
DNA mutations altered functions of genes involved in growth, apoptosis or differentiation can affect the balance
of cell numbers in the body and lead to unregulated growth.
- In some leukemias: differentiation in a cell is blocked and that cell divides increase in cell number
Normal genes that can be activated by mutation to be oncogenic are called: proto-oncogenes functional roles in
normal cells
Identification of oncogenes:
Isolated DNA of interest and introduction into a standard cell line NIH/3T3 (mouse fibroblast cells) If the
DNA contains an oncogene, folci will form and are easily identifiable against a monolayer of untransformed
NIH/3T3 cells.
Growth regulated by positive and negative molecular factors
Two major types of mutated genes that contribute to carcinogenesis:
- Oncogenes: a gene mutated such that its protein product is produced in higher quantities, or has increased
activity and therefore acts in a dominant manner to initiate tumor formation mutation on 1 allel
- Tumor suppressor genes: code for proteins that play a role in inhibiting both growth and tumor formation.
Loss of growth inhibition occurs when mutation causes a loss of function in these genes. Recessive in nature
both alleles of the gene must be mutated before the loss of function is actually phenotypically.
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