Wk 24 Flashcards
External control of the cell cycle is by?
What point in the cycle does this occur?
Growth Factors
Throughout G1 only (before restriction point)
Internal control of the cell cycle is?
Where are they? (3)
- What are they checking?
Restriction points
End of G1 to enter into S: Can DNA synth begin?
–> if there has been enough GF and the conditions are right for DNA replication, is DNA intact?
End of G2 to enter into Mitosis: Can cell commit to mitosis?
–> Has DNA been correctly replicated?
Metaphase in Mitosis before anaphase: Spindle checkpoint
–> Are chromosomes attached to spindle and aligned along equator?
What is Anoikis?
Cell detachment mediated apoptosis
What are the 6 hallmarks of cancer cells?
- Evading growth suppressors
- Producing own growth signals
- Angiogenesis
- Metastasis
- Replicative immortality
- Resisting cell death
What is a carcinoma and what percentage of human cancers are carcinomas?
Cancer from epithelial cell origin
90%
What is the most fundamental trait of cancer?
The ability to sustain chronic proliferation
Sustained proliferative signalling linked to gene mutations in which genes?
Proto-oncogenes
What do tumour suppressor genes do?
What do mutations do to these genes?
Encode proteins that limit cell growth and proliferation (halt cell in G1)
Can switch off or inactivate tumour suppressor genes= cancer
How do cancer cells evade programmed cell death?
Anti-apoptotic proteins up-regulated and pro-apoptotic proteins down regulated
How do cancer cells enable replicative immortality?
They turn on the enzyme telomerase so they can replicate forever
How do cancer cells induce angiogenesis?
When does this happen?
Secrete angiogenic factors (e.g. VEGF) that stimulate angiogenesis
When cells in the tumour become too far away from the blood supply and send emergency signals for angiogenesis
What is the process of epithelial-messenchymal transition?
Disruption of normal cell adhesion induces loss of cell polarity (allows cells to acquire a motile and invasive phenotype)
Secretion of what promotes cancer cell migration and invasion and how does it do it?
Secretion of proteases
degrades basement membrane/ ECM compounds
What are the emerging hallmarks of cancer cells?
- Deregulating cellular energetics
- Avoiding immune destruction
What are the enabling characteristics of cancer cells?
- Genome instability and mutation
- Tumor promoting inflammation
What is the major bioenergetic adaptation in cancer? (and what is the technical name?)
Upregulation of aerobic glycolysis (Warburg effect)
How do cancer cells avoid the immune system?
Emerging
Reduce the expression of tumour antigens on their surface
Also express surface proteins that induce immune cell inactivation
What is the ‘stem cell model’ ? (also called hierarchical model)
Only stem cells contribute to tumour growth
What is the 1st phase of carcinogenesis?
immortalization of a normal cell followed by its neoplastic transformation
Where are the 3 checkpoints in the cell cycle and what are they called? (The whole cycle incl Interphase and mitosis)
- Cell growth checkpoint (at the end of G1)
- DNA synthesis checkpoint (in S phase)
- Mitosis checkpoint (in Mitosis)
Control of genome integrity…
What are the 2 gatekeeper genes and what do they do?
What are the caretaker genes and what do they do?
What are telomeres?
2 gatekeeper genes=
- Proto-oncogenes: encode proteins that stimulate growth (when these are mutated, they turn into oncogenes which cause cancer)
- Tumor suppressor genes: encode proteins that act as a brake to stop cell growth
Caretaker genes=
- DNA repair genes: encode proteins that repair damaged DNA
Telomeres: limit the amount of times a cell can proliferate
Carcinogens or spontaneous mutation may result in what 3 things to do with genes (specifically oncogenes)?
And what is the result of this?
Point mutations (within the gene or its regulatory regions)
Gene amplifications
Chromosomal rearrangements
Result= over-expression or gain of function of the oncogene
What is neuroblastoma?
How does it most commonly occur?
Cancer that affects immature nerve cells
- usually develops in the adrenal glands on the kidneys but can also develop in the spinal cord
Most common cancer in infants
It occurs by gene amplification of N-myc gene (normally only one copy present but in neuroblastoma, over 1000 copies)
Amplification of N-myc gene results in too much N-myc protein and this leads to increased cell proliferation
What 3 roles do tumor suppressors do?
- Induce DNA repair
- Induce differentiation
- Induce apoptosis
What is the most common tumour suppressor gene involved in cancer?
p53 (often called the master regulator)
What is the ‘two-hit’ hypothesis?
It says you start with normal alleles and then if you have a rare event and a tumor suppressor gene of 1 allele gets a mutation, that person has a predisposition to cancer and if they have another rare event and the other allele’s tumor suppressor gene gets mutated then that person gets cancer.
Someone who inherits a mutation in their tumor suppressor gene on one allele has already had their first hit so they only need one rare event to get cancer (higher probability that both alleles will get affected)
What is Li-Fraumeni syndrome?
Inherited mutations in p53 gene so people with Li-Fraumeni syndrome have increased susceptibility to different cancers
Do mutations in DNA repair genes cause cancer or just increase the chances of cancer?
Increase the chances of cancer because they allow cells with damaged DNA to replicate and therefore there is an accumulation of mutations
What is xeroderma pigmentosum?
Caused by mutations in genes involved in nucleotide excision repair so they are unable to repair damage caused by UV light
What are telomeres and how do they work?
They are protective sequences at the end of each chromosome and become shorter with each cell division
- They eventually become too short so cells die instead of replicating again
What is telemerase and what does a mutation in telemerase do?
Telomerase adds telomere sequences to end of chromosomes so a mutation in telomerase allows cells to replicate indefinitely (so they are immortal)
How many mutations is usually required to cause cancer?
2-8 in key genes
What is penetrance?
What impacts penetrance?
Occurrence of cancer
Genetic and environmental factors (risk and protective factors)
Where are the 2 places in the body where benign tumors can be fatal?
In meninges and pituitary gland region
When cells are undifferentiated, they are referred to as _______ cells
anaplastic (the more malignant a tumor is, the more anaplastic it is)
What is the order of events from cell with mutation to invasive cancer? (3 steps in between)
Cell with mutation
Hyperplasia
Dysplasia
In situ cancer
Invasive cancer
Metastasis….
What are the surface proteins that undergo a change, making the cancer less connected to the neighbouring cells?
The cancer uses _____ to penetrate through interstitial connective tissue layers and anchor to the walls of blood and lymphatic vessels
Fibronectin and cadherin
Pseudopodia
What is hyperplasia?
Physiological or pathological?
An increase in the number of cells in an organ
- Can be physiological or pathological (when pathological, usually due to excessive hormonal or growth factor stimulation)
What is metaplasia?
Physiological or pathological?
Reversible or irreversible?
Example of disease?
An adaptive process where one differentiated cell type is replaced with another differentiated cell type
Can be physiological (normal maturation process) or pathological (abnormal stimulus)
Barret’s oesophagus from reflux disease
What is dysplasia?
The presence of cells of an abnormal type within a tissue (pre-cancerous cells- has not invaded underlying tissue)
What is neoplasia?
New growth (moles and warts) that serves no physiological purpose
What is carcinoma in situ?
It is a neoplasm that hasn’t broken any barriers
What are the 5 common manifestations of cancer?
Pain Fatigue Cachexia Anaemia Infection
What do most colon cancers arise from?
Adenomatous polyps
Differentiation of tumours…
If evidence of normal function still present (production of keratin, bile, hormones) what does that mean?
If no evidence of this, it is_____?
Likely to be low grade tumour
Anaplastic
What are the 2 primary issues associated with classification of tumours?
- The tissue and cell source –> type of tumour
- Grading of the tumour (TNM system)
T= primary tumour
N= Regional lymph node involvement
M= Presence or absence of metastases
Classification of tumours…
What does the grade of a tumour describe?
What does the stage of a tumour describe?
What is more important?
Grade= degree of differentiation (higher grade= more poorly differentiated)
Stage= how far it has spread
Stage is more important that grade when determining prognosis
What is the staging system for prostate cancer called?
Gleason grading system
Stages of cancer spread…
Stage 1=
Stage 2=
Stage 3=
Stage 4=
1= Confined to organ of origin
2= Locally invasive
3= Spread to lymph nodes
4= Spread to distant sites
