Flashcards in Molecular hallmarks of cancer cells Deck (57)
What 2 key events are needed for the transformation from normal to neoplastic cells?
1) Oncogene activation
2) Tumour suppressor gene inactivation
What are caretaker genes?
Genes which maintain genetic stability by repairing damaged DNA and replication errors, controlling the accuracy of mitosis - mutant forms of these genes cause genomic instability
What role do caretaker genes play in carcinogenesis?
Mutations in caretaker genes results in genomic instability - genetic instability is important for enabling specific genetic alterations to accumulate in carcinogenesis
Genetic instability is a common feature of most tumour cells
Why is genetic instability important a common feature of tumour cells?
Just clonal expansion is not enough to aquire the necessary mutations for neoplasm as the normal mutation frequency is not high enough so genetic instability is a key factor
What are the 2 types of tumour suppressor genes?
What are gatekeeper genes?
Genes which play an important role in regulating normal growth
Name 3 types of gatekeeper genes?
1) Negative regulators of the cell cycle and proliferation
2) Positive regulators of apoptosis
3) Positive regulators of cell differentiation
Carcinogens induce molecular abnormalities in tumour suppressor genes which lead to what change in function?
loss of function
What is required for TSG's to become inactivated?
A first and a second hit - loss of heterozygosity
After the first hit, the single remaining normal copy of TSGs is capable of doing the job of 2 genes - the second hit is required for complete loss of function
The first hit in TSG inactivation is normally what kind of mutations?
A point mutation in the coding sequence of the gene
The second hit in TSG inactivation is normally one of what 3 types of mutation?
1) Chromosomal non-dysjunction
2) Epigenetic inactivation through promoter methylation
3) Mitotic recombination
What is different about TSGs in people with familial cancer syndromes?
Every cell in their body will carry the first hit mutation
Individuals with retinoblastoma carry a mutation in what gene, is this a caretaker or gatekeeper gene and what is the principle tumour?
RB1 - gatekeeper gene
Retinoblastoma is principle tumour
Individuals with Li-Fraumeni syndrome carry a mutation in what gene, is a caretaker or gatekeeper and what are the principle tumours?
p53 - gatekeeper/caretaker gene
Sarcomas and breast tumours are the principle tumours
Individuals with familial adenomatous polyposis carry a mutation in what gene, is it a caretaker or gatekeeper and what is the principle tumour?
APC - gatekeeper gene
Individuals with familial breast cancer carry a mutation in what gene, is it a caretaker or gatekeeper gene and what is the other principle tumour?
BRCA-1, BRCA-2 - caretaker gene
(breast) and ovarian tumours
Individuals with hereditary non-polyposis colorectal cancer carry a mutation in what gene, is it a caretaker gene or gatekeeper gene and what is the other principle tumour?
hMLH1, hMSH2 - caretaker gene
(colon) and endometrial cancer
What a proto-oncogenes?
Genes which promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
What is meant by oncogenes?
Proto-oncogenes which have aquired a mutation. Mutations of proto-oncogenes lead to activated versions or increased expression of proto-oncogenes - oncogenes
Mutations in proto-oncogenes lead to what change in function?
Gain of function
What 4 things do oncogenes cause?
1) Increased levels of cell proliferation
2) Cell survival
4) Inhibition of apoptosis
How many copies of proto-oncogenes need to be activated in order to induce a gain of function?
Only 1 copy of the gene needs to be activated to induce a gain of function, mutated gene is dominant to the other normal parental gene
What are the 3 mechanisms of oncogene activation?
1) Translocation of proto-oncogene from a low transcriptionally active site to an active sight - aberrant expression of the oncogene
2) Point mutation - altering an amino acid and causing it to become hyperactive
3) Amplification - by insertion of multiple copies of an oncogene get increased expression
What is the minimum number of mutations needed to transform a normal cell into a neoplastic cell?
What is the 5 step sequence of genetic alterations in colon carcinoma expression?
1) loss of APC
2) DNA hypomethylation
3) activation of K-ras
4) loss of 18q TSG
5) loss of p53
What are the 6 hallmark acquired functional capabilities of cancer cells?
1) Self-sufficiency in growth signals
2) Insensitivity to antigrowth signals
3) Tissue evasion and metastasis
4) Limitless potential for replication
5) Sustained angiogenesis
6) Evading apoptosis
What is meant by self-sufficiency in growth signals in cancer cells?
Tumour cells have the ability to grow in the absence of the positive growth factors required by normal cells to stimulate them to enter the cell cycle and divide
How do cancer cells aquire the ability to grow in the absence of positive growth factors?
Normal growth factors activate growth factor receptors which cause a cascade of signalling events which culminate in the nucleus with changes in gene expression. In most cancer cells oncogene-encoded proteins are able to trick the cells into believing it has encountered growth factors in its surroundings
What is meant by the fact that cancer cells have an insensitivity to anti-growth factors?
In normal cells once the required level of cell division has taken place they will respond to negative growth factors and leave the cell cycle, tumour cells are unable to respond to these factors