HALLMARKS OF CANCER Flashcards
oncogenes
refers to genes that contribute to cancer in a gain-of-function manner
proto-oncogenes
the genes that normally code for proteins involved in the control of cell division and differentiation
proto-oncogenes into oncogenes
proto-oncogenes can be mutated, which disrupts the normal function and the cell can become cancerous (oncogenes)
most common proto-oncogene that mutates into oncogenes and how is it different from its normal function
RAS
an abnormal RAS protein loses its ability to regulate itself and is always switched on, always active, which leads to continuous cell division
tumour suppressor genes (anti-oncogenes)
genes which code for proteins that are involved in cell processes of checking, repair and suicide
TP53 gene
- tumour suppressor gene (anti-oncogene)
- codes for the p53 protein
what happens if the TP53 gene is damaged
the repair mechanisms become less efficient, defects are carried forward from one cell generation to another, and as the damage increases, the chances of the cell becoming cancerous increase
consequences of genetic defects (hallmarks of cancer)
- abnormal signalling pathways
- insensitivity to growth-inhibitory factors
- abnormalities in cell cycle regulation
- evasion of programmed cell death (apoptosis)
- limitless cell division (immortality)
- ability to develop new blood vessels (angiogenesis)
- tissue invasion and metastasis
growth factors
- hormones
- extracellular chemical messengers that activate protein kinase receptors in the cell membrane
- trigger a signal transduction pathway
- this instructs the transcription of the proteins and enzymes required for cell growth and division
growth signals in cancer
- cancer cells can grow and divide in the absence of external growth factors
- they do this by producing the growth factors themselves then releasing it such that it stimulates its own receptors, often by autophosphorylation
examples of growth factors that cancer cells can produce
platelet-derived growth factor (PDGF)
transforming growth factor a (TGF-alpha)
how can cancer cells grow and divide without growth factors
- receptors can be overexpressed
- this means that an oncogene is too active and encodes for excessive protein receptor
- once these receptors are in the cell membrane, the cell becomes super sensitive to low levels of circulating growth factor
growth-inhibitory signals
external hormones such as transforming growth factor B (TGF-beta) counteract the effects of stimulatory growth factors and signal the inhibition of cell growth and division
insensitivity to growth-inhibitory signals
- insensitivity to these signals raises the risk of a cell becoming cancerous
- this can arise from damage to the genes coding for the receptors for these inhibitory hormones - the tumour suppression genes
4 phases of cell growth/multiplication
G, S, G2, M
G0 (dormant/resting state)
restriction phase (R)
- during the G1 phase which frequently becomes abnormal in tumour cells
what are checkpoints in cell growth/multiplication
- assess the integrity of the process
- delays during stages if DNA damage detected
- this gives sufficient time for damaged DNA to be repaired or for the cell to commit apoptosis
- these checkpoints can be defective in tumour cells
proteins and enzymes that control the cell cycle
proteins > cyclins (~15 types)
enzymes > cyclin-dependent kinases (CDKs) (~9 types)
moving a cell from one phase to another - how is the decision made
depends on the balance of stimulatory versus inhibitory signals being received through signal transduction
p53 protein
- protein that monitors the health of the cell and the integrity of DNA
- controls the inhibitory protein p21
extrinsic route for apoptosis
- lack of growth factors or hormones
- proteins called death activator proteins which can bind to cell membrane proteins called tumour necrosis factor receptors (TNFR) triggering apoptosis
- the immune system produces T-lymphocytes which perforate the cell membrane of damaged cells and inject an enzyme called granzyme, which initiates apoptosis
intrinsic pathway of apoptosis
- can arise from factors such as DNA damage arising from exposure to chemicals, drugs or oxidative stress
- the cell has mechanisms that detect damage and lead to the increased production of the tumour suppressor gene p53
- this gene will trigger apoptosis
cytochrome c
- released from mitochondria
- results in the assembly of a large oligomeric protein complex - apoptosome
apoptosome
- made up of a scaffolding protein called Apaf-1
- the apoptosome then recruits and activates an enzyme - procaspase 9, which in turn activates caspases
caspases
- protease enzymes containing a cysteine residue in the active site which is important to the catalytic mechanism
- as proteases they destroy the cell’s proteins, which destroys the cell
proteins that promote apoptosis
Bad
Bax
proteins that suppress apoptosis
Bcl-2
Bcl-x
telomeres
- repeated DNA sequences at the ends of chromosomes
- get shorter with age and every cell division
telomerase
- enzyme that can add hexanucleotide repeats on the end of telomeric DNA and thus maintain its length
- absent from normal cells
- cancer cells up-regulate this enzyme
how do cancer cells go into a state of hypoxia
as a tumour grows in size its cells become increasingly remote from the blood supply and become starved of these resources
hypoxia-inducible factors
- such as HIF-1
- start to build up within the tumour cells, and up-regulate genes that promote survival in oxygen-starved environments
vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2)
- interact with receptors of the endothelial cells of nearby blood vessels and stimulate these cells to divide, leading to the branching and extension of existing capillaries
- angiogenesis
angiogenesis inhibitors
angiostatin
thrombospondin
what do blood vessels in tumours lack
cells display molecules called integrins on their surface which are absent from mature vessels and which protect the new cells from apoptosis
E-cadherin
cell adhesion molecule
how can cancer cells metastasise without going through apoptosis
- cell adhesion molecules are absent in metastasised cancer cells, allowing them to break away from the primary tumour
- oncogenes in cells that code for proteins send false messages back to the nucleus implying that the cell is still attached
4 phases of metastasis
- emigration from original organ
- dispersal and survival in transportation fluid
- invasion of new organ
- colonisation
neovasculature
excessive formation of blood vessels in tumours from the constant production of VEGF
epithelial-mesenchymal transition (EMT)
process which cells delaminate from epithelium and take on appearance/properties of fibroblasts
delamination
tumour cells lose adhesion and migrate
metabolic reprogramming
the ability of cancer cells to alter their metabolism in order to support the increased energy request due to continuous growth
T-cell exhaustion
progressive loss of effector function due to prolonged antigen stimulation
induced by cancer cells to evade immune response
CTLA4
inhibits T-cell activation
RAS protein operates in 2 pathways:
mitogen-activated protein kinases (MAPK)
phosphoinositide-3 kinase (PI3K)
retinoblastoma protein (Rb)
- protein that regulates antigrowth signals
- key inhibitor of entry into S-phase of the cell cycle, thereby regulating cell proliferation
- Rb pathway also regulates apoptosis via transcriptional regulation of pro-apoptotic factors - E2F1 overexpression
- Rb pathway functionally inactivated in cancers
