Flashcards in Carcinogenesis - Molecular Hallmarks of Cancer Cells Deck (61)
What is carcinogenesis?
The formation of cancer.
What 2 steps are necessary for neoplasia to develop?
-Tumour suppressor gene inactivation
What are the main causes of mutations leading to cancer? (2)
-Spontaneous replication error
-Induced by carcinogens
What happens to mutated cells?
-cells with a selective growth advantage (Darwin)
What is a common feature of most tumour cells?
-enables mutations to accumulate
What are the main tumour suppressor genes? (2)
What is the function of gatekeeper genes?
Regulate normal growth.
-negative regulators of cell cycle and proliferation
-positive regulators of apoptosis and cell differentiation
What are gatekeeper genes negative regulators of? (2)
What are gatekeeper genes positive regulators of? (2)
What is the function of caretaker genes?
Maintain genetic stability.
-repair damaged DNA
-Control mitotic accuracy
How can carcinogens affect tumour suppressor genes?
Induce molecular abnormalities >> decreased protein expression / inactivation.
-LOSS OF FUNCTION
What effect do mutations in caretaker genes have?
Don't directly contribute to tumour phenotype.
-create conditions where gatekeeper mutations can arise
What does inactivation of TSGs require?
Mutations of both copies.
What normally causes the '1st hit' in TSG inactivation?
Point mutation in coding sequence.
-1 in 10 million divisions
-present in every cell in an individual with a familial cancer syndrome
What happens after a '1st hit' in a TSG?
Remaining normal copy is capable of maintaining function.
-mutant version is recessive
What are the main processes that cause the '2nd hit' in TSG inactivation? (3)
Are the '2nd hit' processes more or less common than point mutation?
1000x more common.
What does chromosomal non-disjunction lead to?
-abnormal number of chromosomes
What is chromosomal recombination?
-in meiosis >> genetic variation
-in mitosis as 2nd hit >> inactive TSB
Summarise the general process of TSG inactivation.
Requires mutation of both copies.
-1st hit : normally point mutation
-2nd hit : chromosomal non-disjunction / gene conversion / mitotic recombination
What are epigenetics?
A change in phenotype without a change in genotype.
-e.g. chemical modification
What epigentic process can cause TSG inactivation?
What do familial cancer syndromes involve?
Inheritance of a mutant copy of a caretaker / gatekeeper gene (TSG).
-70-90% risk of developing cancer
FAMILIAL CANCER; what gene is involved in retinoblastoma?
FAMILIAL CANCER; what gene is involved in Li-Fraumeni?
FAMILIAL CANCER; what gene is involved in familial adenomatous polyposis?
FAMILIAL CANCER; what gene is involved in familial breast cancer?
FAMILIAL CANCER; what genes are involved in HNPCC?
What are the main functions of proto-oncogenes?
-Promote cell proliferation, survival and angiogenesis
-Negative regulation of apoptosis
What can proto-oncogenes become if they are over-expressed or mutated?
-gain of function
-potential to cause cancer
What do oncogenes cause?
-Increased levels of cell proliferation, survival and angiogenesis
-Inhibition of apoptosis
How many copies of the gene need to be activated to cause a gain in function of proto-oncogens?
Only one copy.
-mutated gene is dominant
What are the main mechanisms of oncogene activation? (3)
What is the minimum number of genetic alterations required to transform a normal cell into a tumour cell?
3 genetic alterations.
What does tumorigenesis involve?
-Activation of oncogenes
-Inactivation of TSGs
Describe the general process of colon carcinoma progression.
>> hyperplastic epithelium
>> invasion / metastasis
NB. p53 mutation
What are the main hallmarks (characteristics) of cancer cells? (6)
-Self-sufficiency in growth signals
-Insensitivity to antigrowth signals
-Tissue invasion and metastasis
-Limitless replication potential
What do normal cells require before entering the cell cycle and dividing?
Stimulus of positive growth factors.
What is signal transduction?
Transmission of a signal from outside the cell to inside.
-growth factors bind to GF receptors
-deregulated in cancer cells
Why don't cancer cells require a signal from growth factors?
Oncogene-encoded proteins make cell think they have encountered a growth factor.
What are common causes of cancer cells not requiring signals from growth factors? (4)
What is Ras?
-inactive when normal cell is not proliferating
-stimulation >> drops GDP and acquire GTP >> active
How do Ras oncogene mutations affect their function in cancer cells?
Unable to revert to inactive state after acquiring GTP.
>> continual positive growth signal
What happens in normal cells once the required level of cell division has occurred?
They respond to negative growth signals and leave cell cycle.
-tumour cells cannot respond
What is the function of the retinoblastoma(RB) protein in normal cells?
Binds to transcription factors, preventing progression from G1 to S phase.
- negative growth factors activate it
How can cancer cells escape inhibition by negative growth factors?
Mutational inactivation of retinoblastoma protein.
What are epithelial cells held tightly together by?
How do cancer cells invade and metastasise?
-Loss of E-cadherin >> break through epithelium
-Secrete proteases to break through basement membrane
What happens to normal cells after 50-60 cell divisions?
They deteriorate and die due to loss of DNA from telomeres.
-hexanucleotide sequence loss
How do tumour cells have a limitless potential for replication?
Tumour cells express telomerase.
-replaces lost DNA from telomere
What is the main gene involved in apoptosis, and what is the general process?
-codes for transcription factor
-P53 induces cell cycle arrest when cell damage, and apoptosis (if too much damage)
How do cancer cells evade apoptosis?
-Li-Fraumeni cancer sydrome
What size tumours need to stimulate angiogenesis in order to survive?
What growth factor is often produced by cancer cells in order to stimulate angiogenesis?
Vascular endothelial growth factor (VEGF).
-especially invasive tumours
What are tumour markers?
Biomarkers found in blood / urine / tissues that can be elevated by the presence of cancers.
How are tumour markers used clinically?
What is a tumour marker used for prostate cancer diagnosis?
Prostate specific antigen (PSA).
-however, 1/3 with raised PSA don't have prostate cancer
What cancer is CA-125 serum antigen present in?
-good for monitoring, but not for detecting early disease
What is a problem with current serum protein markers?
They lack sensitivity and specificity.
What are predictive markers used for?
Prognosis and deciding therapy.
-e.g. acute myeloid leukaemia