the biology of cancer Flashcards
cancer
a term used for diseases in which abnormal cells divide without control and are able to invade other tissues.
hyperplasia
over proliferation of cells that appear otherwise normal
metaplasia
normal in appearance but in wrong place (usually from adjacent tissue layer)
dysplasia
cells that appear abnormal; often increased nuclear to cytoplasmic ratio and loss of features of differentiation
adenomas/polyps/warts
larger growths of dysplastic cells
cancer/malignant tumour
invading other tissue, usually by breaking through BM of epithelium.
what is a cancer cell?
- divides continuously and inappropriately
- no longer maintains its original function
- some cancer cells must have the ability to spread to other sites
hanahan and weinberg
1) insensitivity to anti-growth signals
2) self-sufficiency in growth signals
3) evading apoptosis
4) sustained angiogenesis
5) limitless replicative potential
6) tissue invasion and metastasis
cancer is clonal- what does this mean
all cells share some mutations with common ancestors but they also develop subclones (subpopulations)
carcinogens resulting in mutations
- carcinogens lead to a high rate of mutation.
- most mutations not in genes or don’t affect gene function
- most that affect gene do not affect features of cell that would lead to cancer
- need to identify those mutations that do affect function of genes that regulate proliferation, apoptosis, immortality etc- these are ‘driver’ mutations
- all other mutations that are not relevant to the promotion of cancer are ‘passenger’ mutations.
(proto)-oncogenes
- promote cell proliferation (most regulate proliferation
- gain of function mutations in cancer
tumour suppressor (TS) genes
- inhibit events leading to cancer (most regulate proliferation, immortality and apoptosis)
- loss of function mutations in cancer
proliferation: the cell cycle
Cell division (proliferation) progresses through the following two main phases
M phase
S phase
interspersed by two “gap” phases (G1 & G2)
• Cells can also enter G0 (long-term inactivation of cell cycle)
• Mitogens (e.g. EGF) promote proliferation of cells in G0 & G1
EGF: epidermal growth factor
single gene regulates restriction point (termed ‘start’ in yeast)
Proliferation: cell cycle control
- the restriction (R) point in G1 phase (beyond which a cell is committed to cell division without growth factors)
- DNA damage checkpoints in late G1 and G2
- metaphase checkpoint (spindle attachment checkpoint) in M.
oncogenes promote proliferation (via restriction point).
tumour suppressors inhibit proliferation
restriction point control
in the G1 phase, after which the cell is ‘committed’ to the cell cycle, after which the extracellular signals are no longer required to stimulate proliferation.
The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events.
processes in limiting the number of times a cell can divide
- senescence- cells into G0; don’t proliferate
- apoptosis- programmed cell death; response to DNA damage, cell stress etc.
Both processes severely restrict tumour growth. Both processes much be overcome to develop cancer.
senescence
- cells in senescence are metabolically active, but have irreversible lost ability to re-enter cell cycle
- normal cells have a finite proliferative capacity (Hayflick limit)
- at this point they stop dividing and go into replicative senescence
telomere shortening
normally shortening results in senescence.
cells only bypass senescence and reach ‘crisis’ if key tumour suppressors (such as P53) are inactivated.
telomere loss leading to chromosome instability
Telomere loss can lead to incorrect DNA repair and chromosome fusion. especially fusion between ends of sister chromatids which are then torn apart at anaphase. this results in translocations.
excess telomere shortening leading to crisis
- damage to chromosomes will eventually make the cell unlivable
- cells undergo apoptosis if they can.
- ‘genetic catastrophe’ is so severe it triggers apoptosis even in the absence of p53
TERT
telomerase reverse transcriptase.
TERT regenerates telomeres, to avoid genetic catastrophe. Almost every cancer has telemorase reactivated; usually after significant chromosome rearrangement has occurred
apoptosis
triggered by damage to cell/DNA, stress, oncogene activation. uses energy to kill cell without releasing contents and so avoid inflammation- uses caspases. caspases digest proteins. P53 is a regulator of apoptosis, as are many tumour suppressors
key genes in control
2 key genes in control, proliferation, senescence and apoptosis:
p53 and Rb (key regulator of restriction point)
sustained angiogenesis
- O2 and other nutrients supplied by vasculature are essential for cell function and survival.
- newly arisen tumours must promote angiogenesis to survive
- hypoxia induced factor 1alpha (1α)
VEGF
vascular endothelial growth factor.
• induces angiogenesis (new vessel growth)
• Promotes endothelial precursor cell formation in bone marrow (travel to tumour)
imperfect vasculature
vascularisation is disorganised.
- probably due to imbalance of signals for growth vs. differentiation
- leaky due to imperfect cell-cell junctions
tissue invasion and metastasis
- Loss of adhesion – delamination* (e.g. E-cadherin loss)
- Activation of endogenous metalloproteinases
- Invasion of leaky blood vessels (or lymph system)
- Blood flow: millions travel, few survive (immune surveillance)
secondary tumours
2 theories:
- ‘seed and soil’ therory; cells move to a part of a body where the environment is suitable e.g. stomach -> liver, breast -> lung, lung -> anywhere
- capillary beds: tumour cells are larger and tend to get stuck in the capillary bed of the next target organ on in the circulatory system
