- Created by: MazzaW
- Created on: 05-12-19 16:17
Sustained proliferative signalling
Proliferative signalling occurs by growth factors binging to cell-surface receptors. This is deregulated in cancer.
Ca cells produce growth factor ligands to stimulate normal cells in the tumour-associated stroma, have increased levels of cell-surface receptors, and mutations activate downstream signalling pathways.
Mutation: EGFR (NSCLC), B-Raf mutation (melanoma)
EGF and TGFa bind to EGFR to cause cell proliferation. Many Ca cells express EGFR on the cell surface- can inhibit EGFR with tyrosine kinase inhibitors.
Other methods of inhibiting EGFR: monoclonal antibodies, toxin conjugates, antisense ligands
Evading growth suppression
Normal methods of growth suppression: tumour suppressor genes, contact inhibition, TGF-beta pathway.
Cancer cells have loss of contact inhibition
Mutations in tumour suppresor genes (RB1, TP53) can lead to cancer.
RB1 mutations: lead to retinoblastoma in children. Rb mutations can be germline or somatic (55% = acquired mutation in early foetal development). Germline Rb mutations are on chromosome 13 and generally have earlier onset of disease, bilateral disease, may be associated with pinealblastoma. Rb mutations affect management- ofen resistant to platinum therapy.
Resisting cell death
Cell death occurs by 3 methods: apoptosis, autophagy, necrosis.
Necrosis: premature cell death, release of LDH and stimulatory factors to promote proliferation of neighbouring cells. Causes inflammatory response which can promote tumour growth, angiogenesis, cellular proliferation and tissue invasion.
Autophagy: can be induced due to environmental stresses (especially lack of nutrition). Cytoprotective for Ca cells as they can shrink down into a reversible dormant state in response to chemo/radiotherapy.
Apoptosis: programmed cell death with regulated disassembly of cell. May be intrinsic (loss of survival signals), extrinsic (death signals) or due to inappropriate activation of proliferative signals. Extrinsic death signals include Fas/Fas ligand and TNFa/TNFR1 pathways. p53 is the central control of apoptosis/cell cycle and can initiate apoptosis (mostly due to cellular injury) so most Ca cells disable p53 (or downstream molecules e.g. p21).
Germline p53 mutation (chromosome 17p) = Li Fraumeni syndrome: childhood sarcoma, early onset breast Ca (e.g. in 20s), brain tumours, leukaemia, lymphoma, adrenocortical carcinoma
Enabling replicative immortality
Normal cells have 2 barriers to immortality: senescence and crisis. Senescence usually occurs due to short telomeres, causing breakage-fusion-bridge cycles, chromosome instability and apoptosis
Ca cells use telomerase to restore telomere length (like stem cells). Telomerase is expressed in >90% immortalised cells.
Long telomeres allow persistent growth but also cause chromosome instability, breakage and deletions (allows more mutation).
Telomestatin (telomerase inhibitor) currently in clinical trials
Stimulated by VEGF- physiologically only used for wound healing and female reproductive cycling.
VEGF switched on in response to hypoxia- tumours are nearly always hypoxic so VEGF always switched on in cancer. Tumours cannot survive beyond 1mm^3 without vasculature.
VEGF causes vascular sprouting (usually from venous end) and then recruits smooth muscle cells and pericytes.
VEGF inhibitors: bevacizumab, thalidomide. Sorafenib inhibits downstream pathway.
Invasion and metastasis
E-cadherin assembles epithelial cell sheets- it is downregulated/occasionally inactivated in cancer.
Ca cells migrate along extracellular matrix (using actin) and invade through using invadopodia (using cofilin and N-WASP). Invadopodia degrade the basement membrane- the cells then migrate along ECM fibres to blood vessels where they again invade through the basement membrane
Genome instability and mutation
Ca occurs by a succession of clonal expansions (multistep tumour progression) where cells gradually acquire new enabling mutations. This is accelerated by compromising the systems that repair DNA, check for mutations and arrest the cell cycle (e.g. TP53)
DNA repair occurs by several genes including BRCA1/2, PARP, MLH1, MSH2.
PARP is responsible for ssDNA repair, BRCA genes are responsible for dsDNA repair. Mutations in BRCA1/2 mean that cells can't repair dsDNA breaks leading to more mutation. However if there is too much DNA damage the cell will die so cells with these mutations use PARP to repair some of the damage -> can therefore use PARP inhibitors (e.g. olaparib, rucaparib, niraparib) to kill off Ca cells if have BRCA mutations
Inflammation promotes tumour formation:
- immune cells release mutagens (reactive oxygen species)
- immune cells supply growth factors, survival factors, and angiogenic factors
- increases blood flow
- increases permeability of blood vessels
- allows migration of cells out of blood vessels
- complement cascades, coagulation cascades and fibrinolytic cascades initiate and propagate inflammatory responses
Deregulating cellular energetics
Tumours are hypoxic- generally when hypoxic, cells use anaerobic glycolysis for ATP production
Ca cells upregulate glucose transporters (especially GLUT1) to change glucose metabloism to aerobic glycolysis. This is less efficient for ATP production but allows diversion of resources to be used for production of amino acids and nucleosides
Evading immune destruction
Deficiencies of T-cells and NK cells lead to increased incidence of tumours- these cells are anti-cancer
Cancer can disable parts of the immune system and recruit immunosuppressive cells (T-regulatory cells, myelod-derived suppressor cells/MDSCs) to downregulate T-cells and NK cells