Carcinogenesis Flashcards
What is a benign cancer?
A cancer that grows slowly, is non invasive, and does not metastasise.
What is a malignant cancer?
A cancer that grows rapidly, is invasive, and has the potential for metastasis.
What is carcinogenesis?
The process of transformation of a normal cell to a cancer cell
What is initiation?
Initial mutation due to carcinogenic initiator
What is promotion
The induction of cell division that confers a selective advantage over other cells within the tissue
What is progression?
Clonal expansion of tumour cells via conversion, propagation, and dedifferentiation
What is transformation?
Potential for regression
What is evolution?
Formation of a drug resistant clinical tumour
What is metastasis?
Spread of transformed cells
In colorectal carcinogenesis, what is often the first “hit”?
APC gene mutation leading to inactivation
What does APC gene inactivation lead to?
Change in frequency of division leading to an increase in stem cells.
What does the APC gene normally do?
Code for the tumour suppressor APC protein which helps control how often the cell divides and checks how many chromosomes it has after cell division.
What does a higher rate of proliferation mean?
Higher mutational risk for a “second hit”
Give examples of what the subsequent “hits” may be
- Ras mutation -> activation
- p53 inactivation
What is mutagenesis?
When the genetic information of an organism is changed in a stable way, resulting in mutation
What are the 2 stimuli for mutagenesis?
- Environmental stimuli
- Intracellular stimuli
Give 3 examples of how environmental stimuli can cause mutagenesis
- Ultimate carcinogens (bind to DNA and alter sequence)
- Ionising radiation/UV (strand breaks, cross links)
- DNA translocation to transcriptionally active regions
Give 3 examples of how intracellular stimuli can cause mutagenesis
- Misinterpretation of code
- Polymerase slippage/base malalignment
- Ineffective repair
Give 6 examples of initiating stimuli
Chemical carcinogens Oncogenic viruses Radiation UV light Oxygen-free radicals Replication errors
Give 2 examples of direct acting carcinogens
- Alkylating/Acylating agents
- Weak carcinogens (cytotoxic drugs)
Name 3 alkylating/acylating agents
- Dimethylsulphate
- Chlorambucil
- Dichloromethane
What is a procarcinogen?
A precursor to a carcinogen - it does not cause cancer itself but can be converted to a carcinogen by enzymatic action
Give 2 examples of common procarcinogen groups
- Polycyclic aromatic amines
- Combustion of organic compounds (coal, petrol, cooked foods, tobacco smoke)
Name 3 polycyclic aromatic amines
- benz(a)anthracene
- dimethylbenzanthracene
- benzopyrene
What is aflatoxin?
A procarcinogen produced by a certain type of fungi that grows on maize, tree nuts, cottonseeds and peanuts, especially in warm and humid regions.
How is aflatoxin carcinogenic once it has been metabolised?
Forms a DNA adduct
What is aflatoxin exposure linked with?
High liver cancer incidence
Why don’t we all get cancer all the time?
- Repair mechanisms in place
- mismatch and excision repair
- p53
Which is harder for a cell to deal with - single or double stranded DNA breaks?
Double stranded
How many base changes result in permanent mutation?
Fewer than 1 in 1000
What is a transition single point mutation?
Purine->purine or pyramidine->pyramidine
What is a transversion single point mutation?
Purine->pyramidine or pyramidine->purine
Where on DNA nucleotides are there nucleophilic binding sites with potential for mutagenesis?
On N, NH2, and O group, especially in Adenine and Guanine
What are the 4 outcomes of DNA changes?
- Excision repair
- Error prone repair
- Mismatch repair
- Defects in DNA replication
How does excision repair work?
For base or nucleotide repair. Modified bases/nucleotides removed error-free by base excision by DNA glycosylases. Nucleotide excision removes bases with bulky adducts.
How does error-prone repair work?
Low fidelity DNA polymerases respond to severe DNA damage - recognise specific lesions and restore original sequence.
How does mismatch repair work?
Exonuclease part of DNA polymerase proof-reads and corrects mismatched bases in the new strand of DNA during replication.
What defects in DNA replication can occur?
- Genome rearrangements
- Chromosome loss
Give 4 example of promoting agents
- Chemical promoters
- Hormones
- Inflammation
- Microbial infection
Give 4 example of chemical promoters
-Phorbol esters
-Phenols (tobacco tar)
-Xenoestrogens (phenobarbital, insecticides)
Saccharin
What can cause chronic irritation as a promoter?
Pipe smoking
What endoparasite can be an infectious promoter?
Schistosoma haematobium (bladder cancer)
What bacterial infection can be an infectious promoter?
Helicobacter pylori (gastric cancer)
Give an example of treatment for cancer targeting sustained proliferative signalling
(Hallmarks of Cancer)
EGFR inhibitors
Give an example of treatment for cancer targeting the evasion of growth suppressors
(Hallmarks of Cancer)
Cyclin-dependant kinase inhibitors
Give an example of treatment for cancer targeting the avoidance of immune destruction
(Hallmarks of Cancer)
Immune activating anti-CTLA4 mAb (CTLA-4 inhibits T cells, so overall this treatment enhances immune responses)
Give an example of treatment for cancer targeting replicative immortality
(Hallmarks of Cancer)
Telomerase inhibitos
Give an example of treatment for cancer targeting tumour-promoting inflammation
(Hallmarks of Cancer)
Selective anti-inflammatory drugs
Give an example of treatment for cancer targeting activation of invasion and metastasis
(Hallmarks of Cancer)
Inhibitors of HGF/c-Met
Give an example of treatment for cancer targeting angiogenesis induction
(Hallmarks of Cancer)
Inhibitors of VEGF signalling
Give an example of treatment for cancer targeting genome instability and mutation
(Hallmarks of Cancer)
PARP inhibitos
Give an example of treatment for cancer targeting resistance to cell death
(Hallmarks of Cancer)
Proapoptotic BH3 mimetics
Give an example of treatment for cancer targeting deregulation of cellular energetics
(Hallmarks of Cancer)
Anaerobic glycolysis inhibitors
