Oncogenesis and Neoplasia Flashcards
What are the cell cycle stages
G0
G1 - cell grows to full size
S - DNA synthesis
G2 - rapid cell contents productions
M - cell division
Cytokinesis
What does G1 checkpoint check for
nutrients
growth factors
DNA damage
What does G2 checkpoint check for
cell size
DNA replication
What does metaphase checkpoint check for
chromosome spindle attachment
why are cyclins degraded
avoid uncontrolled chain reactions
When do CDKs become active
bound to cyclins
What is the action of cyclin/CDK
phosphorylate Rb
Rb changes in conformation
RB uncouples from E2F
E2F acts as a TF for S phase gene transcription
Types of genes which are mutated in cancer
proto-oncogenes
oncogenes
tumour suppressor genes
What are proto oncogenes
genes that possess normal gene products and stimulate normal cell development
e.g. GF (C-Myc and K-Ras)
How do oncogenes form
gain of function mutation of protooncogenes
What are oncogenes
more active than normal or active at inappropriate times and stimulate unregulated cell proliferation
What is a tumour suppressor gene
gene that’s normal function is to constrain cell proliferation and partial or complete inactivation lead to an increased likelihood of cancer development
e.g. p53 and Rb
loss of function can cause cancer
When is p53 activated
DNA damage
cell cycle abnormalities
hypoxia
What is the function of normal p53
apoptosis
cell cycle arrest
DNA repair
cell cycle restart
mutant p53
present in >50% of all cancers, inhibits self removal of the mutant cells, prolongs propagation and proliferation
Two groups associated with tumorigenesis
gain of function - inappropriate activation of oncogenes
loss of function - inactivation of tumour suppressor genes
what are common properties of cancer cells
-resisting cell death
-sustaining proliferative signalling
-evading growth suppressors
-activating invasion and metastasis
-enabling replicative immortality
-inducing angiogenesis
What are the 6 steps of cancer diagnosis/progression defined at the molecular level
- self sufficiency of growth (overproducing GFs)
- do not respond to usual growth inhibitory signals e.g. cell cycle cycle checkpoints
- evasion of apoptotic mechanisms e.g. p53 mutations
- immortalisation e.g. loss of telomere shortening
- neoangiogenesis e.g. overproduction of VEGF for new vessels
- invasion and metastasis e.g. alterations in production of cellular adhesion molecules
What are the hallmarks of cancer
emerging: deregulating cellular energetics and avoiding immune destruction
enabling characteristics: genome instability and tumour promoting inflammation
point mutations
change in an individual base pair of a DNA sequence
e.g. p53 and k-Ras mutations
What occurs in avain leukosis virus (ALV)
viral genome integrates into the host genome and uses its trong promoter and enhancer sequences to alter the expression of nearby genes (c-Myc), inducing tumours
Example of translocation
Burkitt’s lymphoma
translocation between chromosome 8 and 14
c-Myc under the control for the antibody heavy chain gene (CH)
high expression of c-myc and excessive cell division causing cancer
How long does a multi-step process take
years
Example of knudson 2 hit hypothesis
retinoblastoma - childhood cancer of the eye
hereditary (40% in both eyes) - one mutation is inherited (silent), second hit in retinal cells
sporadic (60% in one eye) - 2 hits in same eye in somatic tissue
vogelstein’s model of colorectal carcinogenesis
Chromosome 5q APC mutation
DNA hypomethylation
Chr 12p K-Ras mutation
Chr 18q DCC loss
Chr 17p TP53 loss
other alterations
Ras-Raf-MAPK pathway
- GF binding
- conformational change in shape
- adapter protein phosphorylated
- Ras activated
- MEK phosphorylation
- stimulates cell growth
- MAPK activated
cancer initiators
chemical carcinogens
viruses
radiation
BRCA mutation
unknown factors
cancer promoters
inflammation
hormones
normal growth promoters
example of occupational cancers
asbestos increases the chances of mesothelioma
alcohol related cancers
-cancer of the mouth and oesophagus
-head and neck cancer
-bowel cancer
-liver cancer
-pancreatic cancer
-breast cancer
where is cancer common due to UV exposure
australia
NZ
Virus related cancers
Hep B - Liver
Hep C - Liver
HPV - Uterine cervix
EBV - Burkitt’s lymphoma/nasopharynx, Hogdkin’s disease
microorganism related cancer
Helicobacter pylori - stomach
Schistosoma haematobrium - urinary bladder
Iatrogenic agents
ionizing radiation - breast/lung/leukemia
chemotherapy - bone marrow
immunosupressive drugs
exogenous hormones - breast
What is hyperplasia
excessive number of cells
what is metaplasia
normal cells of one differentiated type displaced by another type of differentiated cells
What is dysplasia
cytologically abnormal cells
-variability in nucleus size and shape
-increased nuclear staining
-increased ratio of nuclear vs cytoplasmic size
-increased mitotic activity
-lack of cytoplasmic features
Benign or Malignant
1) degree of differentiation/anaplasia
2) rate of growth
3) local invasion
4) metastasis
degree of differentiation/anaplasia
Benign - well differentiated, few mitosis
Malignant - well differentiated to undifferentiated (anaplasia)
more rapid growth =
less differentiated
rate of growth
Benign tumours - slow
malignant tumours - quick
local invasion
benign tumours are rarely invasive and delineated by a fibrous capsule
malignant tumours - infiltration of surrounding tissue and invasion to adjacent via breaching of basement membrane
if pre-invasive (within basement membrane) - carcinoma in situ
Metastasis
benign tumours do not metastasise - compress adjacent tissue
malignant tumours locally invade and travel to the blood/lymph to establish secondary tumours
grading of tumours
-differentiation
-pleiomorphism
mitotic index
staging of tumours
TNM
T
tumour
T0 = breast free of tumour
T1 = lesion <2cm
T2 = lesion 2-5cm
T3 = skin/chest wall involved by invasion
N
nodes
N0 = no axillary nodes involved
N1 = mobile nodes involved
N2 = fixed nodes involved
M
metastasis
M0= no metastases
M1 = demonstrable metastases
MX = suspected metastases
