Lecture 7: Carcinogenesis

Question 1

Different Steps of Carcinogenesis

Answer 1

Initiation: Mutation in one or more cellular genes controlling key regulatory pathways of the cell (irreversible)—must be a heritable DNA alteration.

Promotion: selective growth enhancement induced in the initiated cell and its progeny by the continuous exposure to a promoting agent.

Progression: results from continuing evolution of unstable chromosomes; further mutations from genetic instability during promotion—results in further degrees of independence, invasiveness, metastasis, etc.

Question 2

Initiation

Answer 2

• Initiation is the induction of a mutation in a critical gene involved in the control of cell proliferation.
• As with mutational events, initiation requires one or more rounds of cell division for the “fixation” of the process.
• The metabolism of initiating agents to non-reactive forms and the high efficiency of DNA repair of the tissue can alter the process of initiation.
• Initiation is irreversible although the initiated cell may eventually die during the development of the neoplasm.

Question 3

Types of mutations

Answer 3

Chemical carcinogens can cause:

1) Point mutations- the replacement of a single nucleotide base with another nucleotide.
2) Frameshift mutations- addition or deletion of a nucleotide such that the protein sequence from that point onward is altered.
3) Chromosomal aberrations- any change in the normal structure or number of chromosomes
4) Aneuploidy- chromosome number is not a multiple of the normal haploid (23)
5) Polyploidy- more than twice the haploid number of chromosomes

Question 4

Mechanisms of DNA Repair

Answer 4

The persistence of chemically-induced DNA adducts is predominantly the result of failure of DNA repair, due to either:

• carcinogen-induced mutational inactivation of DNA repair enzymes.
• failure of the DNA repair mechanisms to recognize carcinogen-induced mutation.

Question 5

Targets of Initiation

Answer 5

Chemical carcinogens initiate cells via:

• Mutational activation of oncogenic (proliferative) pathways (e.g. growth factor receptors and downstream signaling proteins, proteins involved in cell cycle checkpoints.
• Mutational inactivation of apoptotic (cell death) pathways (e.g. growth inhibitory receptors, proteins involved in apoptosis, tumor suppressors).
• Mutational inactivation of DNA repair mechanisms (e.g. BER, NER, etc).
• Mutational inactivation of antioxidant response (e.g. SOD).

Question 6

Tumor suppressor p53 signaling

Answer 6

• p53 is a an important tumor suppressor (transcriptional factor) that controls cell cycle, apoptosis, DNA repair mechanisms.
• Mdm2 is a negative regulator of p53 that functions both as an E3 ubiquitin ligase and an inhibitor of p53 transcriptional activation.

Question 7

Benzopyrene Leads to Mutations in K-Ras and p53 in the Genomic Loci Found to be Mutated in Smoking-Induced Lung Cancers

Answer 7

-K-Ras and p53 are the two oncogenes most frequently mutated in smoking-related lung cancers
-If not corrected by the cell’s DNA repair mechanism, this guanine “adduct” is misread as a thymine by the DNA polymerase that copies chromosomes during replication
-Ultimately, the original G—C base pair may be replaced by a T—A base pair, a mutation called a traversion
-Cells treated with Benzopyrene show the same spectrum of G—T transversions as found in the -K-RAS and p53 of smokers.
These mutational “hot spots” map well to the guanine binding sites of BaP epoxide

Question 8

Promotion

Answer 8

• Epigenetic event—change in gene expression without change in DNA.
• Mitogenic (Not mutagenic) Stimulates proliferation. Causes both mutated and normal cells to proliferate.
• Enhances the effect of the genotoxic initiating agent by establishing clones of initiated cells.
• Long delay possible between administration of initiating agent and promoting agent.
• Promotion is reversible.

Question 9

Promoters

Answer 9

1. Reactive Oxygen Species (ROS) and redox active xenobiotics and metals
2. Phorbol esters (e.g. TPA)
3. Polycyclic aromatic compounds (e.g. Dioxin)
4. Peroxisome Proliferators (oxidized fats)
5. Endocrine Disruptors (estradiol, DES)
6. Growth factors (e.g. from inflammatory cells)

Question 10

Endocrine Receptors and Carcinogenesis

Answer 10

Endocrine disruptors are involved in breast, ovarian, colon, prostate cancers.

ERβ/ERα (estrogen receptors) ratio is decreased in cancers (ligands include estradiol); ERs are transcription factors.

2. ERβ inhibits ERα
   ERα-ERα dimerization (homodimer) leads to mitogenic activation.
   ERβ-ERα dimerization (heterodimer) leads to an inactivation.
3. Androgen Receptor (prostate) (AR) can also homodimerize with AR leading to mitogenic activation; AR can heterodimerize with ERβ to cause growth arrest (prostate also dependent on estrogenic signals).

Question 11

Mechanisms of Progression

Answer 11

Progression is an irreversible process and leads to metastasis.
Progression requires:
1) Further mutations from genetic instability (chromosomal instability) during promotion.
2) Recruitment of inflammatory immune cells to the tumor.
3) The tumor cell acquiring “wound-healing” characteristics (secretion of chemo-attractants to attract inflammatory immune cells, angiogenesis factors, proteases, etc).
-Examples of progressor agents: inflammation, asbestos fibers, benzene, benzoyl peroxide, other peroxides, oxidative stress, inflammation