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Cancer Hallmarks Flashcards

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1
Q

what are the 10 hallmarks of cancer

A

Self-sufficiency in growth signals

Insensitivity to anti-growth signals

Evading programmed cell death

Limitless replicative potential

Sustained angiogenesis

Tissue invasion and metastasis

Deregulated metabolism

Evading the immune system

Genome instability

Inflammation

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2
Q

what is used to treat sustained proliferative signalling

A

EGFR inhibitors

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3
Q

what is used to treat evasion of growth suppressors

A

cyclin dependent kinase inhibitors

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4
Q

what is used to treat avoidance of immune destruction

A

immune activating anti CTLA4 mAb

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5
Q

what is used to treat replicative immortality

A

telomerase inhibitors

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6
Q

what is used to treat tumour promoting inflammation

A

selective anti inflammatory drugs

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7
Q

what is used to treat activating invasion and metastasis

A

inhibitors of HGF/c-Met

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8
Q

what is used to treat induction of angiogenesis

A

inhibitors of VEGF signalling

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9
Q

what is used to treat genome instability and mutation

A

PARP inhibitors

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10
Q

what is used to treat resistance to cell death

A

pro apoptotic BH3 mimetics

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11
Q

what is used to treat deregulated cellular energetics

A

aerobic glycolysis inhibitors

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12
Q

what is cancer

A

the accumulation of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the body by invasion and or distant mets via blood/lymph

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13
Q

do benign things metastasise

A

no

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14
Q

what is clonal evolution

A

a series of mutations accumulating in successive generations

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15
Q

what are monoclonal tumours

A

contain cells ALL originating from same ancestral cell- minority of solid tumours, most polyclonal

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16
Q

what are the emerging characteristics

A

deregulating cellular energetics

avoiding immune destruction

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17
Q

what are the enabling characteristics

A

genome instability and mutation

tumour promoting inflammation

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18
Q

how does tumour micro envirnoment affect tumour

A

tumour recruits normal cells that form tumour associated stroma and are active participants in tumourgenesis by maintaining beneficial microenvirnoment

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19
Q

what do growth signals do

A

instruct entry into and progression through the cell growth and division cycle

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20
Q

what domains are commonly in cell surface receptors that bind growth signals

A

intracellular tyrosine kinase domains

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21
Q

what else can cell growth signals influence

A

cell survival and energy metabolism

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22
Q

how are growth factor signals controlling cell number and position in tissues transmitted

A

paracrine signalling

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23
Q

what does uncontrolled cell proliferation require

A

multi step gene damage:
-gain of function of oncogenes (cyclin , RAS, MYC)
AND
-loss of function of tumour suppressors (p53, retinoblastoma)

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24
Q

what is an oncogene

A

key regulator of cell growth- when proto- oncogenes mutated permanently switch on cell growth

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25
what commonly inactivates p53 or Rb
mutation of loss of heterozygosity
26
what is loss of heterozygosity
the absence of a functional tumour suppressor gene in the lose gene, with one functioning gene left on the other chromosome of the chromosome pair
27
what does RAS do
is an oncoprotein the oncogenic mutation affects RAS GTPase activity which usually operates a negative feedback system which shortens periods of active proliferative signalling
28
why can DISRUPTION of self attenuating proliferative signalling contribute towards drug resistance
as it develops mechanisms resist anti mitogenic signalling drugs - finds a way to grow without the signals
29
can increase proliferative signals from RAS, MYC and RAF causes senescence
yes and/or apoptosis this is due to cell anti proliferative defences cancers need to balance these signals or disable to senescence/ apoptosis inducing circuitry
30
how can cancer cells reduce their dependence on growth signal
producing their own extracellular GFs (autocrine) (or send GF to neighbouring normal cells which supply the cancer with other GFs) overexpression of GF receptors or structural alterations in receptors (cell becomes hyper-responsive) alterations to intracellular signalling pathways (RAS, RAF)
31
what does a truncated receptor do
emits (growth) signal even in the absence of ligand binding (how to stimulate proliferation in cancer cells independent of GF conc)
32
what are the steps of growth factor signals
ligands bind to cell surface receptors adaptors and enzymes activated signalling cascades activated transcription factors activated
33
how do cancer cell become insensitive to antigrowth signals
disruption of tumour suppression genes (e.g. pRb pathway, TP53 proteins) these work to limit cell growth and proliferation, and are inactivated in cancer also avoid contact inhibition via loss of tumour suppressor gene NF2 corruption of TGF-b pathway stops it working as an antiproliferative agent and instead activates the EMT
34
what does pRB do
prevents the inappropriate transition from the G1 phase of the cell cycle to the S (synthase) stage phosphorylation of Rb releases and activates E2F family transcription factors which enables cell cycle progression
35
what is the purpose of EMT (epithelial to mesenchymal transition)
confers traits to cancer cells that are associated with high grade malignancy
36
name 2 tumour suppressor genes
retinoblastoma (Rb) and p53
37
what cancer is associated with the loss or inactivation of Rb tumour suppressor gene
retinblastoma (cancer in immature cells in the retina, most common malignant eye tumour in children
38
what does Tp53 do
receives inputs from stress and abnormality sensors that function within the cell’s intracellular operating systems: if the degree of damage to the genome is excessive, or if the levels of nucleotide pools, growth-promoting signals, glucose, or oxygenation are suboptimal, TP53 can call a halt to further cell-cycle progression or cause apoptosis
39
what can p53 trigger
cell cycle arrest (-> senescence or return to proliferation) DNA repair blovk of angiogenesis apoptosis
40
what condition is associated with germline p53 mutations
Li fraumeni syndrome- rare AD cancer pre-disposition, early onset multiple cancer with high frequencies of rare cancers
41
what mediates angiogenesis
vascular endothelial growth factor (VGEF) also growth factors: fibroblast GF (FGF), platelet derived growth factor (PDGF) (angiogenesis needed to supply oxygen and nutrients to the tumour and remove waste and CO2 allowing it to grow)
42
name an antiangiogenic factor
thrombospondin (TSP-1)
43
name an anti-angiogenic drug
bevacizuman (avastin)
44
what is avastin used to treat
ovarian cancer
45
how do cancer metastasise
pioneer cells invade adjacent tissues intravasation makes cells interact with platelets, lymphocytes and other blood components which transports them through circulation/ lymph system arrest in micro vessels of various organs extravasation form micrometastasis colonisation- formation of macrometastasis
46
where do tumours want to met to
areas where oxygen and nutrients are not limiting
47
what changes occur at the epithelial mesenchymal transition
cell polarity -> no cell polarity cell adhesion (to each other and to extra cellular matrix) -> loss of adhesion (involves E-cadherin) stationary -> ability to migrate and invade high level of E cadherin -> low level of E cadherin Low level of N cadherin -> high level of N cadherin loss of: -cytokeratin (intermediate filament) expression -epithelial gene expression program gain of: - fibroblast shape - motility + invasivenesss - increased apoptosis resistance - mesechymal gene expression - protease secretion - vimentin exoression (int. filament) - fibronectin secretion - PDGF receptor expression - stem cell like traits changes morphology of cell so that it can fit into vessels when cells become mesenchymal they get stem cell like phenotypes
48
what transcription factors mediate EMT
``` SNAL1 (snail) Slug (SNAL2) twist goosecoid FOXC2 ZEB1 ZEB2 E12/E47 ```
49
when do EMT like transitions normally
embryogenesis
50
what determines a cells replicative limits
telomeres
51
what are telomeres
multiple tandem hexanucleotide repeats that get shorter with each cell division
52
what happens to telomeres in cancer cells
are maintained
53
what is the hayflick limit
approx 40-60 cell divisions before senescence
54
name two apoptosis inducing stresses
signalling imbalances resulting from elevated levels of oncogene signalling DNA damage associated with hyperproliferation
55
what are the two components of apoptosis
extrinsic- receiving and processing extracellular death-inducing signals (Fas ligand and receptor) intrinsic- sensing and integrating a variety of signals of intracellular origin
56
what happens in apoptosis
normally latent protease (capsases 8& 9) activated initiates cascade of proteolysis involving effector caspases cell disassembled and consumed by neighbours and phagocytic cells ``` cell shrinkage, chromatin condensation membrane bibbing nuclear collapse continued bibbing apoptotic body formation lysis of apoptotic bodies ```
57
how do cancers resist cell death
lost DNA damage sensor that works via TP53 increasing expression of anti apoptotic regulator (Bcl-2, Bcl-xL), survival signals (lgf1/2) down regulating proapoptotic factors (Bax, Bim, Puma= all stress transducing BH3 proteins) short circuiting extrinsic ligand induced pathway
58
what can hyperactive signalling by oncoproteins such as Myc cause
apoptosis
59
what does autophagy release
autophagic program enables cells to break down cellular organelles allowing the resulting catabolites to be recycled and thus used for biosynthesis and energy metabolism. intracellular vesicles termed autophagosomes envelope intracellular organelles and then fuse with lysosomes wherein degradation occurs= lowmolecular-weight metabolites are generated that support survival in the stressed, nutrient-limited environments experienced by many cancer cells
60
what determines apoptotic fate
Bcl-2 family or pro and anti-apoptotic proteins
61
what signal is needed to activate cell destruction
caspase 3
62
why are there increased mutation rates and genetic instability in cancer cells
compromised cell surveillance mechanisms (e.g. p53 loss/ mutation) altered DNA damage detection and repair capability altered apoptotic capabilities
63
why does immuno suppression increase cancer risk
as immune surveillance removes early stage cancers and small mets
64
what does a PD-1/PDL-1 interaction do
binds T cells to tumour cells, hiding the cancer many cancer have high surface PD-L1 expression have a poor prognosis potential targeted immunotherapy
65
what are the normal mechanisms of cellular energetics
``` mitochondrial oxidative phosphorylation (usually dominant) cytoplasmic glycolysis (role increases when oxygen levels are depleted) ```
66
how do cancer deregulate cellular energetics
need more energy for proliferation metabolic shift to anaerobic glucose metabolism is promoted by oncogenes (c-Myc and K-ras) and inhibited by tumour suppressor genes up regulation of glucose transporters (GLUT1) (as a response to oncogene activation) to compensate for reduced ATP production
67
what does tumour hypoxia cause
increased expression of HIF-1 which orchestrates an adaptive survival response (including promotion of glycolysis by gene transcription)
68
what is the warburg effect
most malignant cells get their energy from anaerobic metabolism (at rates of up to 200 fold greater than oxidative phosphorylation of pyruvate in the mitochondria
69
how to pet scans work
radioactive glucose used as tracer dye, taken in by cells with active glycolysis
70
what happens to phenotype behaviour of cancer as it moves round body
changes due to changes in microenvironment - why treatment different for primary and secondary sites
71
what does the signaling pathway involving the PI3- | kinase, AKT, and mTOR kinases do
stimulated by survival signals to stop apoptosis and inhibt autophagy
72
why can increased autophagy be a GOOD thing for cancers
(can be increased by nutrient starvation, radio or cytotoxic drugs) can impair killing action of stress inducing situations - is cytoprotective to cancer cells severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy-
73
can cell necrosis death be genetic
yes
74
what is the different between necrosis and apoptosis/ autophagy and why is it important
necrosis releases inflammatory signals, recruiting inflammatory cells which can be tumour promoting as they can increase angiogenesis, cancer cell proliferation and invasiveness also releases bioactive regulatory factors, such as IL-1a, which can directly stimulate neighboring viable cells to proliferate, with the potential, once again, to facilitate neoplastic progression

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