Lecture 23_Cancer II

Question 1

What is the initial step in the genesis of cancer?

Answer 1

The covalent binding of the ultimate carcinogen to DNA, which alters the coding of the DNA at that site. The actual initial step itself is the error being passed on to daughter cells as a mutation.

Question 2

Not all chemically induced mutations result in the development of cancer. Name a few ways.

Answer 2

• Some mutations are at relatively unimportant sites.
• Others may actually result in cell death.
• Many are corrected by DNA repair enzymes

Question 3

Oncogenes

Answer 3

The primary molecular targets of carcinogens (which is why they are referred to as cancer-causing genes).

Question 4

What role do oncogenes play in cancer?

Answer 4

The conversion of proto-oncogenes to oncogenes is a key event in the development of cancer.

Question 5

What are proto-oncogenes?

Answer 5

Genes that code for proteins that normally have important or essential cellular functions (primarily as growth factors or growth factor receptors or transcription factors).

Question 6

What are important examples of proto-oncogenes?

Answer 6

myc, fos, jun, erbB

Question 7

When a proto-oncogene is damaged by a carcinogen to become an oncogene…

Answer 7

…it drives abnormal cell division and cell differentiation that are typically found in neoplastic growths.

Question 8

Tumor suppressor gene p53

Answer 8

• p53 is a transcription factor that can arrest the cell cycle and it also can induce programmed cell death (apoptosis). It can also activate DNA repair systems.
• Normally cell p53 levels are kept low. A variety of stressors including DNA damage can activate p53, increasing its half life and also altering its conformation so it can act as a transcriptional regulator.

Question 9

What is the most common genetic target in human cancer?

Answer 9

p53. It - May be mutated in about half of all human cancers and appears to be the most common genetic target in human cancer.

Question 10

Why is p53 so easy to be targeted? Can this be fixed?

Answer 10

Lacking even one functional allele predisposes individuals to some cancers. It may be possible to boost p53 activity in those who are deficient by using a viral vector to transfect cells with a wildtype p53 gene.

Question 11

The two main stages in the development of cancer are…

Answer 11

…initiation and promotion.

Question 12

Cancer promotion

Answer 12

Promotion refers to the circumstances or variables allowing the initiated cancer cells to enter a proliferative stage and thus to produce tumor masses. - NOTE: Some chemicals that are not initiators (i.e. they are not complete carcinogens) may yet act as promotors to promote the development of tumors initiated by other compounds.

Question 13

Initiators

Answer 13

Compounds (or their metabolites) that physically interact with DNA to produce mutations.

Question 14

Promoters

Answer 14

Not mutagenic but instead exert their effects through non-genotoxic pathways involved with selective stimulation of proliferation of the initiated cell.

Question 15

Two stage model with cancer in animals?

Answer 15

When producing tumors in experimental animals, promoters must be given after an initiator and then administered repeatedly thereafter. This is referred to as the two stage model.
- NOTE: Alternatively use genetically engineered mice (p53 knockout)

Question 16

Human cancer cells contain high frequencies of chromosomal abnormalities, as well as mutations, suggesting that one hallmark of cancer is a…

Answer 16

…general instability of the genome.

Question 17

Damage to genes responsible for maintaining genomic stability is likely an…

Answer 17

…early event in the process of carcinogenesis. If stability genes (i.e., genes responsible for DNA replication and repair and chromosomal localization) are damaged by mutation, that sets the stage for a cascade of further mutations that may affect oncogenes and tumor suppressor genes. This would lead to unregulated growth, invasiveness of the tumor into healthy tissue, and eventually metastasis.

Question 18

Knudson two-hit hypothesis

Answer 18

• Cancer occurs due to the effects of accumulating mutations.
• Knudson compared retinoblastoma rates in families predisposed to it with those in the general population. In predisposed individuals they already have a defective Rb allele so only one ‘hit’ to the other allele will lead to cancer. Not so for those in the general population.
• This explains why cancer rates rise as we age.

Question 19

(T/F) Carcinogens and effect have a dose response curve.

Answer 19

TRUE. For the most part, risk of cancer increases linearly as the dose of carcinogen increases logarithmically.

Question 20

Very low vs. very high exposure levels of carcinogens

Answer 20

• VH: Animals may die of a toxic effect of the compound unrelated to its carcinogenic ability.
• VL: Important in humans since this is how we are typically exposed to low but chronic doses of carcinogens. A threshold dose of a carcinogen may exist (below which there is no cancer risk). There may be a background level of tumor production, such that tumors are still seen even at very low doses (even approaching the complete absence of carcinogen).

Question 21

Why do some people with no apparent carcinogen exposure develop cancer while others with chronic exposure don’t?

Answer 21

• 1. DNA repair and immune system functioning: Individuals with DNA repair enzyme deficiencies are more susceptible to certain cancers. Patients receiving immunosuppressive therapy (eg. after kidney transplant) or those with HIV are more likely to develop cancers.
• 2. Imbalance in enzymes that activate or detoxify carcinogens: Risk of developing cancer is highly correlated with the activities of enzymes important for biotransforming the carcinogen to which the patient is exposed. Eg., a polymorphism allowing high CYP1A1 gene expression in African-American women markedly increases breast cancer susceptibility; in Japanese men it elevates lung cancer risk. However, the same polymorphism does not affect lung cancer susceptibility in Nordic men.