Molecular Basis of Carcinogenesis (Exam 3) Flashcards
Name some of the properties of a malignant, or transformed, cell (11 total)
- Loss of contact inhibition/high saturation density
- Immortalization (avoid apoptosis)
- Ability to grow w/o attachment to solid substrate
- Reduced requirement for mitogenic growth factors (constitutive activation of pathways) and inability to halt cell cycle in the absence of growth factors
- Altered morphology (little/no cytoplasm; rounded)
- Invasive, that is capable of outgrowth into neighboring normal tissues to extend the boundaries of the tumor.
- Metastatic, that is capable of shedding cells that can drift through the circulatory system and proliferate at other sites in the body.
- Increased transport of glucose (lower O2 requirement–ferment sugar in place of oxidative phosphorylation)
- De-differentiated, that is, lack many of the specialized structures and functions of the tissue in which they grow.
- Sustained angiogenesis
- Clonal in origin (derived from a single cell)
What differentiates a benign tumor from a malignant one?
Benign tumors have lost cell controls (are immortal), but are not invasive or metastatic.
What are two critical types of genes in which mutations are likely to cause cancer?
- Oncogenes, which normally stimulate cellular proliferation (analogous to the “gas pedal” of your car), are activated.
- Anti-oncogenes or tumor suppressors, which normally inhibit cellular proliferation (analogous to the “brake pedal” of your car), are inactivated.
What is the Knudson theory, and how does this apply to Loss of Heterozygosity? What is LOH?
The Knudson “two hit” theory is that two mutations must occur to knock out both copies of a gene. Refers to a tumor suppressor like Rb. This is why sporadic retinoblastoma is so much less less common than hereditary; two mutations in the same spot is much more rare, and takes longer. People born with a mutation are at a much higher risk because only one recombination event is required to turn off the brakes. LOH occurs as an “inappropriate” crossing over during mitosis between non-homologous chromosomes. Odds are 50% that heterozygosity is maintained, 50% that one cell gets both mutations and one gets none, in which case heterozygosity is lost.
Examples of cancers that are inherited as autosomal dominant disorders are (4):
- Familial Adenomatous Polyposis (FAP-APC gene)
- Familial Retinoblastoma (RB gene)
- Familial Breast and Ovarian Cancer (BRCA1 and BRCA2 genes)
- Wilms tumor syndromes
Examples of cancers that are inherited as autosomal recessive disorders are (4):
- Xeroderma pigmentosa (XP genes)
- Ataxia-telangiectasia (AT gene)
- Bloom’s syndrome
- Fanconi’s congenital aplastic anemia (FA genes)
This is the hallmark of a antioncogene or tumor suppressor gene.
In cases of “inherited” retinoblastoma (i.e. when there was a parent and other family members who also had the disease), the DNA from normal tissue of the patient or from other unaffected family members often shows a defect in the retinoblastoma gene, but has one normal copy of the gene per cell.
+++++++ In these patients it appears that normal, nonmalignant retinal cells, are heterozygous for the retinoblastoma gene, but the tumor cells have descended as a clone from a single cell that has acquired homozygosity for the retinoblastoma susceptibility gene. ++++
The Rb protein is ______ in rapidly proliferating cells at ____ of the cell cycle, but is ____ in non-proliferating cells in ____ of the cell cycle. ______ are responsible for phosphorylating Rb, allowing it to proceed from G1 to S phase.
hyperphosphorylated; S or G2; hypophosphorylated; G0 or G1; CDK (Cyclin Dependent Kinases);
HPV encodes two proteins, ____ which targets Rb, and ___ which targets p53.
E7, E6
____ encodes a T antigen (Large T) that targets ____ and ____.
SV40; Rb and p53
HeLa cells were isolated from a cervical carcinoma and have been growing in culture for over 60 years. These cells express HPV _____
E7 and E6 protein (E6 inhibits p53, another important tumor suppressor). If E7 and E6 expression is blocked, the cells return to normal phenotype. This bodes well for therapy as affecting just two proteins can have a drastic effect.
Kaposi Sarcoma encodes a ____, which binds ___ to push cells into S phase. Often seen in patients who have ____.
cyclin; CDK; AIDS
Rb appears to have a dominant inheritance pattern. We know, however, that a cell must be homozygous for the mutation to become tumorigenic. Explain.
What is inherited in a dominant fashion is the susceptibility to retinoblastoma. People who are heterozygotes for retinoblastoma have only one normal RB gene in each cell of their body including the cells of the retina. These cells will regulate their proliferation normally and will be non-malignant. However, loss of the single, normal RB gene by any number of events will produce a tumor. Thus if one cell among the millions of retinal cells has no RB protein, it will lose the ability to regulate its proliferation, grow out of control, thereby generating a clone of cells, which will become a malignant tumor. Thus people who are heterozygotes for the RB gene are likely to develop the disease and will pass on the defective gene to 1/2 of their children, so it appears to be autosomal dominant in its inheritance.
Persons who survive inherited retinoblastoma have an increased risk for developing a second neoplasm, which is typically mesenchymal in origin, for example,______. Cells of these tumors are also defective in RB function.
osteosarcoma
Lets go over CML one more time. Called the ______ chromosome, this involves a translocation between chromosomes ___ and ____. This creates a novel gene product called the _____, which is a ______. This protein is constitutively activated, and inhibits p27, an inhibitor of the cell cycle. The drug for this is _____ aka _____.
Philadelphia; 9/22; Bcr-Abl; protein kinase; Imantinib; Gleevec. (We conclude that Bcr-Abl promotes cell cycle progression and activation of cyclin-dependent kinases by interfering with the regulation of the cell cycle inhibitory protein p27.)
