Week 1 Flashcards

Question

Hallmarks of cancer further progress

Answer 1

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

Answer 2

Non genetic factors that increase incidence of certain cancers Eg: diet, lifestyle choices, infectious disease, outdoor/indoor air pollution,water contaminants

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

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

Answer 7

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

Answer 8

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

Answer 9

Sustaining proliferative signalling Resisting cell death Genome instability and mutation Inducing angiogenesis Tumor promoting inflammation

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

Cancers caused by tobacco 86% lung cancers, 19% all cancers Cancers caused by processed and red meat 21% bowel cancer, 3% of all cancers

Answer 15

Fibre- NSP (non starch polypeptide) Fruit and vegetables- fibre, folate, vitamin C, vitamin E, flavonoids etc

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

Physical activity Alcohol consumption Exposure to asbestos Radiation exposure

Answer 20

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

Answer 21

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

Answer 22

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)

Answer 23

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

Answer 24

Quit smoking Avoid sunlight Clean water supply Chemoprevention Anti cancer vaccines Healthy diet Exercise

Answer 25

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

Answer 26

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

Answer 27

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

Answer 28

Growing solid tumours develop hypoxic regions Hypoxia leads to necrosis in tumours

Answer 29

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

Answer 30

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

Answer 31

Instead of smooth cobblestone appearance ion normal capillaries Abnormal ECs that partition lumen, multiple intercellular openings Tortuous capillaries Helps tumour get inside vasculature

Answer 32

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

Answer 33

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

Answer 34

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)

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

Decreased expression of e-cadherin hand some other adhesion molecules which leads to dissociation of epithelial cells

Answer 40

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

Answer 41

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

Answer 42

Adhesion molecules downregulated in metastatic cancer cells Downregulation of e-cadherin is common, indicating that loss of cell attachment is important for invasion

Answer 43

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

Answer 44

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

Answer 45

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

Answer 46

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)

Answer 47

Collective and single cell invasion through the collagenous extracellular matrix - collective invasion: sheets, strands, clusters -single cell motility: amoeboid and mesenchymal

Answer 48

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

Answer 49

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

Answer 50

Tumour cells secrete factors which act systemically modifying local environment and recruiting host immune cells facilitating the appropriation of these sites for later colonisation

Answer 51

As tumour cells enter small capillaries they slow by size restriction and adhere through receptor ligand interactions

Answer 52

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

Week 1 Flashcards

(76 cards)