Week 1 Flashcards
What is cancer
Uncontrolled growth of abnormal cells in a tissue, invasive and spreading
Origins of cancer- tumours arise from normal tissues
Majority of tumours originate from epithelial tissues
Benign and malignant tumours
Squamous cell carcinomas and adenocarcinomas
Other tumours arise from non-epithelial cells
Sarcomas- from mesenchymal cells
Leukaemias and lymphoid and myeloid tumours- from haematopoietic tissue and cells of immune system
Neuroectodermal tumours- cells from central and peripheral nervous system
Brain tumours- eg gliomas, neuroblastoma
Complexity of disease
“Microevolution” process leading to accumulation of 5-10 critical mutations requires many years
Cancer is a genetic disease:
Mutations causing cancer occur: in germline and in somatic cells
Mutations in different types of genes may initiate cancer
Genes that normally control:
-growth
-passing on of signals from outside the cell
-receptors across the cytoplasm to the nucleus
-programmed cell death (apoptosis)
-the cell cycle
-stemness
-the integrity of the genome- DNA repair
How do mutations arise
Copying errors during DNA replication
Spontaneous depurination
Exposure to different agents
-background ionising radiation
-UV light
-Tobacco products
Cancer is a monoclonal growth
Cancer quickly becomes heterogenous due to genetic instability of cancer cells masking monoclonal origin of this cell population
Cancer a disorder resulting from multiple genetic steps
Gate keeping mutation
Driver mutation
Progressive development of cancer- tumour progression
Tumour suppressor gene (protein)
Normal function- negative regulator of cell growth (prevents cell growth)
Even protein from one of the two alleles is enough to
Need to lose both alleles to lose suppressor effect
Oncogene
Positive regulator of cell growth- makes cells grow
Even when only one allele is mutated
Hallmarks of cancer
Sustaining proliferative signalling
Evading growth suppressors
Avoiding immune destruction
Enabling replicative immortality
Tumor promoting inflammation
Activating invasion and metastasis
Inducing or accessing vasculature
Genome instability and mutation
Resisting cell death
Deregulating cellular metabolism
Hallmark 1- self sufficiency in growth signals, sustaining proliferative signalling
Alterations of :
-extracellular growth signals
-transmembrane transducers of growth signals
-intracellular circuits that translate those signals
Hallmark 2- insensitivity to anti growth signals, evading growth suppression
Disruption of pRb (TSG) pathway- loss of control over progression from G1 into S phase
The central governor of growth and proliferation
Tyrosine kinase receptors, GPCRs, TGF-b receptors, integrins, nutrient status
—cell cycle clock
-enter into G0 quiescent state, enter into active cycle, programming of cell cycle phases
PRB serves as a guardian of the restriction point gate
G1 period during which cells are responsive to mitogenic GFs and to TGF-b
DNA damage checkpoint: entrance into S is blocked if genome is damaged
DNA damage checkpoint: DNA replication halted if genome is damaged
Entrance into M phase blocked if DNA replication not complete
Anaphase blocked if chromatids are not properly assembled on mitotic spindle
Hallmark 3 - evasion of apoptosis, resisting cell death
Loss or mutation of p53 (TSG)- proapoptotic regulator, disruptions in DNA repair
P53 activating signals and P53s downstream effects
Lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia, blockage of transcription.
P53
-cell cycle arrest (or senescence, return to proliferation) DNA repair, block of angiogenesis, apoptosis
Anti-apoptotic strategies used by cancer cells
Increase in activity or levels of anti-apoptotic proteins
Decrease in activity or levels of pro apoptotic proteins
Hallmark 4- limitless replicative potential, enabling replicative immortality
Circumvention of senescence and crisis
Increased expression and activity of telomerase
Replicative senescence could be causes by culture conditions
Proliferation of cultured cells is limited by the telomeres of their chromosomes, cancer cells can escape crisis by expressing telomerase
Hallmark 5- sustained angiogenesis, inducing angiogenesis
Angiogenic switch
Control of transcription of pro-angiogenic inducers
Downregulation of angiogenic inhibitors
Vasculature is important for growth and survival of normal and neoplastic cells
Hallmark 6- activating tissue invasion and metastasis
EMT- epithelial to mesenchymal transition
Changes in expression of adhesion receptors: Cadherins, integrins
Activation of extracellular proteases
The metastatic process
Primary tumour-> vascularisation-> detachment-> intravasation -> circulating tumour cell-> adhesion to blood vessel wall-> extravasation-> growth of secondary tumour
Hallmark 7- reprogramming energy metabolism
“Aerobic glycolysis” Warburg effect
Glycolytic switch
Links to activated oncogenes and mutant tumour suppressor genes
Hallmark 8- evading immune destruction
Disabling certain components of the immune system
Recruiting actively immunosuppressive inflammatory cells
Hallmarks of cancer further progress
Unlocking phenotypic plasticity:
-dedifferentiation
-blocked differentiation
-transdifferentiation
Nonmutational epigenetic reprogramming:
-microenvironmental mechanisms of epigenetic reprogramming
-epigenetic regulatory heterogeneity
-epigenetic regulation of the stromal cells in tumour microenvironment
Polymorphic microbiomes:
-modulating tumours in barrier tissues
-impact of intratumoural microbiota
Senescent cells
Environmental factors
Non genetic factors that increase incidence of certain cancers
Eg: diet, lifestyle choices, infectious disease, outdoor/indoor air pollution,water contaminants
Geographic variation in cancer incidence and death rates
Eg skin cancer very high in Australia compared to japan (155% RR)
2 factors contribute to this hereditary and environmental factors
Investigate variations in the incidence in cancers using migratory populations:
Compare incidence common cancers in Japanese populations in Osaka, migratory Japanese population in Hawaii, native Hawaiian Caucasian population
-stomach cancer very high in japan but with one generation of migration to Hawaii the Japanese population have a low incidence of stomach cancer
These examples show that hereditary factors contribute to the incidence of cancer but there are some outside factors that may increase/decrease incidence of cancer- environmental factors
Proportion of cancer deaths attributed to non genetic factors
Tobacco main contributor followed by diet
Alcohol, food additives, reproductive and sexual behaviour, occupation, pollution, medicine and medical procedures, geophysical factors, infection, unknown
Carcinogens- cancer causing agents
IARC carcinogen classifications
Carcinogens are characterised by their ability to cause cancer when they are applied to lab skin of mice
Many are mutagenic (mutagenesis may contribute to cancer and tumour progression)
IARC classification based on probability and possibility of causing cancer in humans
How do we assess harmful nature of certain carcinogens
Risk assessment to determine 3 factors
-potency: potential of a given amount of a substance to cause cancer
-type of exposure required to cause harm: it acute or prolonged exposure required and is it avoidable or unavoidable
-dose response: indicates what happens if some of the carcinogen is either removed or added
Outdoor air pollution
What makes up outdoor air pollution:
-particulate matter PM- PM10 and PM2.5
-nitrogen dioxide
-sulphur dioxide
-ozone gas
-carbon monoxide
-polycyclic aromatic hydrocarbons (PAHs)
Sources of air pollution:
-transport, industry, fossil fuel power stations, farming, fuels people use to cook and heat their homes, natural pollutants
IARC hazard classification air pollution
Outdoor air pollution classified as human carcinogen, particulate matter in outdoor air pollution classified as human carcinogen
-sufficient evidence for lung cancer
-positive associations with urinary bladder cancer
Diesel engine exhaust classified as human carcinogen
-sufficient evidence for lung cancer
-positive associations with urinary bladder cancer
Uncertainty of effect at low dose environmental exposure levels
Indoor emissions from household combustion of coal classified as human carcinogen (lung cancer)
Household use of solid fuels (biomass) classified as probable human carcinogen
Particulate matter and it’s role in cancer hallmarks
Sustaining proliferative signalling
Resisting cell death
Genome instability and mutation
Inducing angiogenesis
Tumor promoting inflammation
What is indoor air pollution
Indoor air pollution can have many sources. For example the burning of solid fuels to heat homes and to cook with could be a source, but this is less common in the UK
The main source of indoor air pollution in the UK is second hand smoke from cigarettes. Second hand smoking also known as passive smoking, can cause lung cancer and other health problems like heart disease. Most exposure to second hand smoke happens in the home and is particularly dangerous for children
Linking nicotine addiction and lung cancer through tobacco smoke carcinogens
Nicotine addiction leads to continuous exposure to carcinogens found in tobacco
When they enter cells in the body they undergo metabolic activation and produce DNA adducts (covalently bound compounds that damage DNA)
If they persist it leads to miscoding and so during cell division DNA adducts contribute to mutagenesis
If these mutations happen in specific tumour suppressor genes it will lead to lung cancer
The cell has many regulator mechanisms to prevent harm via metabolic detoxification or through DNA repair mechanisms but persistent smoking will lead to lung cancer
Diet and cancer
Direct effect of particular components added to the diet that are responsible for increased or decreased risk of
Indirect effect involving the balance of the diet
AICR reports are based on the expert analyses and assessment of published papers on the links between particular dietary components and cancer risk, these links were designated as ‘convincing’ or ‘probable’
IARC (international agency for research on cancer) evaluates carcinogenicity of agents (including dietary components) according to its own classification
Mediterranean diet was most likely decrease risk of pancreatic, colorectal, breast and gastric cancer
Consumption of red and processed meat
Deviation from the recommended intake levels is responsible for 2.7% of cancers in 2010 in UK
Red meats have been given group 2A classification IARC carcinogenic
Processed meats have been given group 1 IARC carcinogenic classification
Tobacco vs meat risk
Cancers caused by tobacco 86% lung cancers, 19% all cancers
Cancers caused by processed and red meat 21% bowel cancer, 3% of all cancers
Foods that fight cancer
Fibre- NSP (non starch polypeptide)
Fruit and vegetables- fibre, folate, vitamin C, vitamin E, flavonoids etc
Obesity and physical activity
The relative risks of 7 most common cancers is increased in obese and overweight people
There are increases in up to 17000 cases of cancer in Uk due to being obese/overweight the main contribution to colon and breast cancer
Main pathways linking obesity and adiposopathy to cancer
Hyperinsulinemia and abnormalities of the IGF-1 system and signalling
Sex hormones biosynthesis and pathway
Subclincial chronic low grade inflammation and oxidative stress
Alterations in adipocytokine pathophysiology
Factors deriving from ectopic fat depositions
Microenvironment and cellular perturbations
Altered intestinal mircobiome
Obesity related mechanisms breast cancer
Obesity promotes primary breast cancers and metastasis
Obesity also promotes inflammation of adipose tissue
This inflammation primes the tissue microenvironment and premalignant epithelial cells
This changes the contents of the microenvironment of adipose tissue:
-inflammation attracts myeloid cells that can provide certain growth factors eg IL1-beta which stimulates growth of tumour cells and adipocytes
-you may also get production of pro-angiogenic factors that may induce tumour angiogenesis in the progressing tumours
Also inflammation increases presence of myofibroblasts in the tissue
-myofibroblasts are known to produce lots of extracellular matrix proteins that are signalling molecules
-these that contribute to signalling in tumour cells and also stiffen the environment that supports migration of tumour cells
What other non genetic risk factors play role in cancer development
Physical activity
Alcohol consumption
Exposure to asbestos
Radiation exposure
Physical activity
Contributes to decrease in risk of cancer
Shown in breast cancer that it decreases risk of reoccurrence
Decreases hormone levels (insulin and oestrogen)
Decreases level of inflammation
Alcohol and cancer
Increases risk of many different cancers
Mechanism of how chronic ethanol consumption promotes carcinogenesis:
-production of acetaldehyde
-induction of oxidative stress and conversion of procarcinogenes to cardiongenes
-induction of DNA hypomethylation by depletion of SAMe
-induction of Gi proteins and Erk-MAPK signalling
-accumulation of iron and associated oxidative stress
-inactivation of BRCA1 and increased oestrogen responsiveness (in breast)
-impairment of retinoic acid metabolism
Cancer risk from environmental exposure to asbestos
Asbestos- naturally occurring fibrous silicates, commonly used in acoustical and thermal insulation
Prolonged inhalation of asbestos fibres can cause serious and fatal illnesses. Pleural mesothelioma is caused almost exclusively by exposure to asbestos
No treatment
Develops over very prolonged time periods (up to 20-30 years)
Cancer risk from exposure to radiation
Studies of occupational exposure and of atomic bomb survivors has clearly shown a dose-response relationship between exposure to radiation and the risk of cancer
Radiation causes cancer due to the DNA damage
If radiation exposure is continuous then DNA repair mechanism may fail which then promotes different types of cancer
Lifestyle modifications in cancer prevention
Quit smoking
Avoid sunlight
Clean water supply
Chemoprevention
Anti cancer vaccines
Healthy diet
Exercise
Metastasis
A metastasis is a tumour spread from its tissue of origin
Metastasis is a Multifactorial process
Metastases are the major cause of death from malignant disease because widespread metastatic disease is difficult to treat
What happens during metastatic progression
Firstly cells will detach from the primary tumour
They then migrate towards the vasculature (requires vascularisation of the tumour)
They then go specific locations throughout the body (site of metastases)
They then leave the vasculature via extravasation and they start forming secondary micro metastatic lesions
This later stage is where most of the cancer cells will die as they move from their favourable micro environment and end up in a foreign micro environment where they do not have sufficient supply of growth factors- rate limiting process
Therefore metastatic spread is described as inefficient
Key properties of a metastatic cell
Detachment from primary mass
Invasion of extracellular matrix eg basement membrane allows cells to reach vasculature
Adhesion to endothelium and extravasation
Colonisation of and survival in secondary organ
Oxygen level in tumour tissues is lower than in the respective normal tissues
Growing solid tumours develop hypoxic regions
Hypoxia leads to necrosis in tumours
Hypoxia activates transcriptional programme
In normoxia the interaction between HIF and pVHL causes degradation of HIF through ubiquitination
In hypoxia pVHL is S-nitrosylated and is not recognised by HIF-a, hypoxia induced gene expression (eg VEGF) stimulation of angiogenesis by VEGF
The role of hypoxia in the cancer specific biological pathways
Tissue invasion metastasis
Glycolysis
Immune evasion
Evasion of apoptosis
Limitless replicative potential
Regulation of cell proliferation
Regulation of angiogenesis
Self sufficiency in growth signals
Genomic instability
Angiogenesis promotes tumour cell survival and spread
Instead of smooth cobblestone appearance ion normal capillaries
Abnormal ECs that partition lumen, multiple intercellular openings
Tortuous capillaries
Helps tumour get inside vasculature
The ‘glycolytic switch’ altered glucose metabolism in cancer
Another way which the cancer responds to hypoxia is that it switches from an aerobic to an anaerobic form of energy generation i.e it switches to use glycolysis as its major source of energy
-in glycolysis glucose is taken up by cells and then converted to pyruvate producing ATP
-pyruvate is converted to acetyl co-A which enters Krebs cycle
-in the case of hypoxia you will have HIF stabilised
-this allows for an increased production of transporters GLUT1 which allow cells to take up more glucose for energy. It also increases production of an enzyme called PDK1
-as a result of this in hypoxic conditions you get pyruvate converted to lactate
-this inhibits production of acetyl-CoA and so you get blockage of pyruvate entering Krebs cycle
Glycolysis is an inefficient way of energy generation as when you block the Krebs cycle the number of ATP produced is lower
But glycolysis allows cells to survive in hypoxic conditions and then when you have new vasculature formed you will have better supply of glucose and oxygen so switch back to aerobic cycle
Upregulation of glycolysis in tumour cells
Enables tumour cells to outcompete normal cells for scarce glucose supply
Tumour cells also upregulate glucose uptake and metabolism:
-upregulating glucose transporters which enables them to scavenge very effectively for glucose in extracellular environment
-they also upregulate the enzymes such as hexokinases which are responsible for process of glycolysis
Oxygen independent regulation of HIF-1a in cancer
Direct HIF-1 activation by pathogens: siderophores (Ybt, Sal, DFO), adhesins (BadA, F1845), LPS (E.coli), toxins (C.difficile)
Genetic and epigenetic activation of HIF-1 expression:
-oncogenic pathways (PI3-K), mutations
HIF-1 activation by inflammation: cytokines (TNFa, IFN), chemokines (MIF), growth factors (PDGF)
Warburg effect
Defined as an increased in the rate of glucose uptake and preferential production of lactate even in presence of oxygen
This is what happens in cancer cells
Whilst this can be stimulated by hypoxia often cancer cells will switch to glycolysis even under normoxia conditions
Benefits of Warburg effect
Rapid ATP synthesis: proposal- increases access to a limited energy source
Tumor microenvironment: proposal- enhances disruption of tissue architecture and immune cell evasion
Cell signaling: allows for signal transduction through ROS and/or chromatin modulation
Biosynthesis: promotes flux into biosynthetic pathways
Lactate and tumour microenvironment
Lactate transporter decreased, more lactate in microenvironment
Suppress immune response to cancer
Decrease natural killer cells, dendritic cells and CD8 cells
Stimulation monocytes to M2 macrophages
-stimulate cancer cell growth important for metastasis
Glycolysis acidifies the tumour microenvironment
Glycolysis produces lactic acid which will be responsible for the acidification of the tumor microenvironment
Normal cells are less able to survive in acidified environment compared to tumour cells
This is another contributing factor to the resulting cell death in the immediate vicinity of the cancer
Therefore the switch to glycolysis provides increases the invasive potential of cancer cell
Hypoxia induces epithelial-mesenchyme transition EMT and increases production of matrix metalloproteinases MMPs
Decreased expression of e-cadherin hand some other adhesion molecules which leads to dissociation of epithelial cells
EMT program is regulated by hypoxia via specific transcriptional programme
Hypoxia and oxygen independent activation
HIF1a
-FoxM1 pathway PAFAH1B2 gene ILK
-TGF-B SMAD pathway, Wnt/B-catenin pathway, hedgehog pathway
-EMT transcription factors TWIST, snail, slug, SIP1, ZEB1
-EMT induction
Loss of cell-cell adhesion, dynamic actin reorganisation
EMT transcription factors
Cadherin goes down
B catenin gets activated
Results in mesenchymal phenotype
TGFB and RTK—> SLUG—> epithelial to mesenchymal
Epithelial markers decease: e-cadherin, occludins, claudins,
Mesenchymal markers increase: N-cadherin, vimentin, fibronectin
Detachment- loss of adhesion
Adhesion molecules downregulated in metastatic cancer cells
Downregulation of e-cadherin is common, indicating that loss of cell attachment is important for invasion
Adherins junction
E-cadherin principal adhesion receptor in the specialised type of adhesion junctions called adherens junctions
Structure:
-a Cadherin dimer on one cell will make contact with a Cadherin dimer on opposite cell
-need some structural support- actin cytoskeleton
-the actin cytoskeleton linked to Cadherin receptors through specific linker proteins eg B-catenin
Allows adherens junctions to function properly
Free B-catenin is normally degraded
E-Cadherin function is frequency lost in cancers, leading to release of beta-catenin into cytoskeleton
In normal cells beta-catenin undergoes quick degradation as it is a dangerous protein to have in the cytoplasm
The below complex modifies b-catenin and moves to protostomes for degradation, many proteins in complex incl APC
APC frequently mutated in cancers
Excess b-catenin in cytoplasm
Can also shutdown degradation by activating Wnt signalling pathway
Why is b-catenin dangerous in cytoplasm
Stabilised b-catenin promotes oncogenic transcription
If you have excess b-catenin in the cytoplasm you will have b-catenin forming complex with transcription factors resulting in increased expression of cell cycle genes (eg MYC) which facilitate growth of tumour cells and facilitate metastatic progression of tumour cells
This is why normal cells have tight control over amount of b-catenin present in cytoplasm
Tumour cell invasion
Requires modification of adhesion of tumour cells with extraceullar matrix (basement membrane, collagen)
Requires production of degrading enzymes- matrix metalloproteinases MMPs
MMPs- normal enzymes that are involved in tissue remodelling
May be secreted by tumour cells but also by stroma (stroma important in tumour progression)
Different kinds of invasion
Collective and single cell invasion through the collagenous extracellular matrix
- collective invasion: sheets, strands, clusters
-single cell motility: amoeboid and mesenchymal
Seed and soil hypothesis colonisation and survival at distinct site
Stephen Paget explain non random pattern of metastasis
Seed-tumour cells
Soil -distinct site for metastasis
Tumour cells end up in specific locations because they find a favourable microenvironment
Cells can only survive certain conditions in certain organs
James Ewing proposed that metastasis occurs purely by anatomical and mechanical routes
Stroma is abnormal in cancer
Stromal component changes as tumour progresses
As tumour cells progress they secrete soluble factors which act on whatever is around tumour eg they will attract macrophages- important in metastatic progression
Soluble factors change function of existing cells like fibroblasts
-they will become cancer associated fibroblasts help tumour cells into metastatic phenotype
The metastatic niche
Tumour cells secrete factors which act systemically modifying local environment and recruiting host immune cells facilitating the appropriation of these sites for later colonisation
Adhesion to endothelium and extravasation
As tumour cells enter small capillaries they slow by size restriction and adhere through receptor ligand interactions
Metastatic colonisation
Ewing vs Paget
-metastatic colonisation is higher in the organs first encountered by blood flow
-organ-specific metastatic colonisation in favourable microenvironment
Arrest in organs
Trapping vs homing
-mechanical trapping in small capillaries
-specific arrest mediated by adhesion molecules
