30, 31, 32 Flashcards
Chemical carcinogens
PAHs, nitrosamines
Infectious carcinogens
HPV, H.Pylori
Radiation carcinogens
UV light, radon
Mineral carcinogens
Asbestos, heavy metals
Phsyiological carcinogens
Oestrogen, androgens
Chronic inflammation carcinogens
Free radicals and growth factors
What does aflatoxin cause
Liver cancer (hepatocellular carcinoma) Low in the UK, High in East asia
What produces alfatoxin
Aspergillus flavus
Also due to Hep A and Hep B
What does alcohol cause
Pharynx, laryns, oesophagus, liver
What does asbestos cause
Lung Pleura (mesothelioma)
What do X-rays cause
Bone marrow cancer (leukaemia)
What does UK light cause
skin cancer
What does oestrogen cause
breast cancer
What does Hep B cause
liver cancer
What does HPV cause
cervical cancer
What does tobacco smoke cause
Mouth, lung, oesophagus, pancreas, kidney and bladder cancer
What is a carcinogen
Any agent that significantly increases the risk of developing cancer
What is an initiator
Carcinogens that are genotoxic
Can chemically modify, damage/alter DNA
What is a promoter
Carcinogens that are non-genotoxic
Induce proliferation and DNA replication
What is complete carcinogen
A carcinogen that is an initiator and a promoter
E.g. UV Light
Who is bladder cancer high in
Higher incidence in men
Due to the dye and rubber industry
Due to beta napthyl-amine
How do initiatiors (mutation induction work)
Chemical modification of DNA
Replicating of DNA
Mis-incorporation by DNA polymerases
What happens with methylate guanine
Can only form 2H bonds
Read as an A not a G
2 rounds of cell division to fix the mutation
What is required for a promotor carcinogen
Stimulates 2 rounds of DNA replication - required for mutation fixation
Stimulates clonal expansino of mutated cells - enables accumulation of further mutation
How many rounds of DNA replication are needed for mutation fixation
2
Describe Initiation - Promotion - Progression
Genotoxic initiating agent damages DNA
Promoting agent fixes damage as mutation and converts normal cell to mutant cell
Promotor stimulates clonal expansion - papilloma
Further mutation and clonal expression causes papilloma to become a carcinoma
How are tumour suppressor genes inactivated
Aberrant methylation of CpG islands in the promotor regions of gene
Causes closed chromatin - stops it being expressed
Occurs normally but if hijacked then TSG switched off (most common way to cause cancer)
Mutation in oncogenes
Cause gain of function
Substitutions, ,amplification, translocations (to an area expressed more, inversion)
Mutation in tumour suppressor genes
Loss of functions
Frameshifts, deletions, substituions, chromosomal arrangements (all BUT AMPLIFICATION)
What are direct acting carcinogens
Directly act on the DNA
E.g. UV Light, ionising radiation, Oxygen free radicals
What are indirect carcinogens
Require metabolic activation before they react with the DNA
e.g aromatic amines, polycyclic aromatic hydrocarbons (PAHs)
How do we get rid of indirect carcinogens
Need to make them soluble
Unfortunately this can make them more toxic and cause more damage
What is benzopyrene
Indirect carcinogen found in tobacco smoke
Causes lung tumours in smokers
Benzopyrene activation path
Benzopyrene (P450 mixed function oxidases)
Benzypyrene 7-8 epoxide (Epoxide hydrolase)
Benzopyrene 7,8 dihydrodiol (P450 mixed function oxidases)
Benzopyrene 7,8, diol 9,10 epoxide
Describe path of damaging agents to disaese
Damaging agent - DNA lesions - Repair Process (same as in E. Coli) –> Disease syndrome
Name a compound involved in detoxification/exretion
Glutathione S. transferase
Defence against carcinogens
Exxposed to myriad carcinogenic agents
many levels of defence
Dietary antioxidants
Detoxification mechanism
DNA repair enzymes
Apoptotic responseto unrepaired DNA damage
Immune response to infection and abnormal cells
Carcinogens in tobaccos smokes
PAH - e.g. benzopyrene
Acrolein - acrid smell, direct acting
Nitrosamines - formed due to during of leaves
Radioactive lead and polonium - sit in alveoli for years
Heavy metals - cadmium and chromium
With alcohol, smoking increases the risk of head and neck cancer by 100x
How does alcohol cause cancer
Concerted to acetaldehyde - damages DNA
Increased levels of oestrogen and testosterone
Increased uptake of carcinogens in the upper GI
Reduces folate - needed for accurate DNA replication
Can kill surface epithelium causing unscheduled proliferation
How are we exposed to oestrogen
HRT Oral contraceptive Early menarche Late menopause Post menopausal obesity Age of 1 st pregnancy >30 Alcohol consumption
How does higher oestrogen cause breast cancer (and endometrium and uterine)
Increased exposure to oestrogen
Oestrogen binds to transcription factors
Induces DNA damage
How does chronic inflammation cause cancer
DNA damage and the release of free radicals by immune cells (INITIATOR)
Growth factor induced cell division to repair tissue damage (Promotion)
What cancers are associated with chronic inflammation
Colitis Hepatitis Barret's metaplasia Gastritis Gallstones
50% of cancers are due to environmental or behaviour factors
Diet (most common)
Tobacco
Infection
Reproductive behaviour (4th most common)
What can epstein barr virus cause
Bursts lymphoma (B cell) Nasopharyngeal carcinoma
What can RNA retroviruses cause
T cell leukaemia/lymphoma
What is more dangerous than UV light
UV-B
Melanin is protective
What can androgenic and anabolic steroids cause
Hepatocellular tumours
What can schistosomiasis haematoburium cause
Bladder cancer
What can liver flukes cause
Dwell in bile ducts
Cause malignant cholangiocarcinoma
What do we need for carcinogenesis
Activation of protooncogenes
Inactivation of tumour suppressor genes
Carcinogens can do both of this
What is the process of carcinogensis
Darwinian Evolution and clonal expansion
Mutation - clonal expands providing big cell pop
Mutation in one of descendent cells
Cells accumulate mutations etc.
What are caretaker genes
Maintain genetic stability by repairing damaged DNA and replication errors!
Mutant forms cause genetic instability
Why is genetic instability/mutation in caretaker genes essential for carcinogenesis
As otherwise the rate of mutation isn’t high enough
Genetic instability is a common feature to most cancer
What do gate kaper genes do
Regulte normal growth
-ve regulation of cell cycle and proliferation
+ve regulation of apoptosis and cell differentiation
What does the 2 Hit hypothesis apply to
Only tumour suppressor genes
What do caretaker genes
Maintain genetic stability
DNA Repeaire genes, control access to mitosis
INDIRECT ROLE - just allows conditions for mutation to occur
Retinoblastoma due to what mutated gene
RB1 (gatekeeper gene)
Li-Fraumeni due to mutation in what gene
p53 (gatekeeper/caretaker)
What cancers does li-fraumeni cause
Sarcomas, breast
Familial adneomatous polyposis due to mutation in what gene
APC (Gatekeeper gene)
Causes colorectal cancer
What type of gene is RB1
gatekeeper
What type of gene is P53
Gate/care
what type of gene is APC
gate keeper
Familial breast cancer due to mutation in what gene
BRCA1/2 (caretaker)
What type of gene are BRCA
caretaker
what type of gene are hMLH
caretaker
Gene mutation in HNPCC
hMLH
Cancer in familial breast cancer mutation
Breast/ovary
Cancers in HNPCC
Colorectal/endometrial
What are protooncogenes
Promote cell proliferation, survival, angiogenesis, negative reduction of apoptosis
These are normal
What are oncogenes
Mutation - causes increased expression of protooncogene - causes gain of function
How many mutated oncogenes do we need to cause cancer
Only 1 - mutant gene is dominant to normal gene
Contrast to TSG where both genes need to be mutated
How are oncogenes activated
1) translocation - to a more transcriptionally active area
2) point mutation - base pair substitution becomes more hyperactive
3) amplificiation - multiple copies
Minimum genetic alteration needed to transform a norma cell into a neoplastic cell
3
Commonly
APC - causes hyper plastic epithelium
TSG
p53
What are the 6 key hall marks of cancer (need all 6 to become malignant)
1) self sufficency in growth signals
2) Insensitivity to negative growth signals
3) Limitless replication potential
4) Evading apoptosis
5) Sustained Angiogenesis
6) Tissue invasion and metastasis
What is self-sufficiency in growth signals
Normal cells need +ve growth factors (most from outside cell) to proliferate
Tumour cells frown in the absence of these!
What is typically activated to cause self-sufficiency in growth signals
RAS - an important oncgogene
How dose RAS work
EGFR - activates RAS
RAS bound to GDP = inactive
Guanine-Exchange Factor (GEF) - swaps GDP for GTP and activated RAS
GAP needed t hydrolyse GTP and inactive RAS
Mutation in oncogene means can’t cleave GTP and RAS remains active
Ras mutation common in which cancers
Pancreatic
Papillary thyroid
Colon
Non-small cell lung caner
EGFR overexpression in which cancer
Colorectal
Pancreatic
Lung
Non-small cell lung
How does Rb protein work
Key regulator of cell cycle
Negative growth factors active Rb
Arrests cell in G1 to S phase
How are cancers insensitive to -ve growth signals
Usually due to mutation in Rb
Why do normal cells have a limited productive life
Normal bit of telomere lost in each replication
Eventually enough is lost after a certain number of replications meaning cells die
Why do cancer cells have limitless potential replication
Tumour cells have telomerase to replace lost material and cells become immortal
Abnormal telomerases seen in 86/90% of tumour cells
Where are telomerase normally seen
Stem cells and angiogenesis
What is the TP53 gene function
Main gene in apoptosis
Arrests cell cycle to allow DNA repair but if too much damage has occurred causes apptosis
How do tumour cells evade apoptosis
Mutation in TP53!
Most common mutation in human tumours (>50%)
Inherited in Li Fraumeni syndrome
When do cells need there own blood supply
When they are over 2mm
How does angiogenesis occur
Hypoxia stabilizes HIF-1 transciption factor
This induced VEGF - an angiogenic factor that recruits endothelial cells to produce new capillaries and vesels
What growth factors cause angiogenesis
VEGF and fibroblast growth factor
Why can’t normal cells invade
Normal cells unable to detach from neighbouring cells or grown into new compartments outside of their own tissue
How can tumour cells invade
Malignant tumours can invade tissue, detach and migrate
What is E-cadherin
Holds epithelial cells together
What is often inactivated in solid tumour cells
E-cadherin
How do E-cadherin mutations cause tissue invasion/metastasis
Inactivation due to mutation/hypermethylation
Results in Epithelial-Mesenchymal Transition - cells become floppy mobile and spindly
Mesenchymal cells are mobile and secrete proteases - allows them to break through the basement membrane and invade the underlying stroma!
What can we use tumour markers for
Screening
Diagnosis
Prognosis Therapy
Monitoring
What is CA-125
A serum antigen
Commonly seen in ovarian cancer
But not good at detecting early stage disease
Why are genetic markers good for prognosis in CML
As there are subtypes with different translocation
Each translocation correlates with a prognosis outcome can be used for diagnosis and prognosis outcome
What is HER2
A positive growth factor receptor
What is HER2 overexpressed in
30% of breast tumours
What can we treat HER2 overexertion with
Herception - dampens the effect of HER2
What is metastasis
Spread from site f origin to distant sites and forms new tumours
Kills half of all patients
What is needed for cells to invade ore
Increased motility
Decreased adhesion
Production of proteolytic enzymes
Mechanial pressure
What are cadherins needed for
Cell to cell adhesion molecules
Mutation in E. Catherine leads to loss of cell to cell adhesion and contact in inhibition (e.g. breast cancer)
What are integrins
Cell to matrix/BM adhesion molexules
Change in intern decreases cell-matrix adhesion
What is Epithelial-Mesenchymal Transition
Epithelial cells usually tightly connected, polarised and tethered
Mesenchymal cells are loosely connected and can migrate
Cancer epithelial cells gain mesenchymal properties - can invade and migrate, cause increased motility and decreased adhesion
What are the main proteolytic enzymes
Matrix metalloproteinases - these degrade the extracellular matrix
What does interstitial collegenases degrade
Collagen types I, II, III
What does getlitanases degrade
Collagen type IV, geltain
What do stromolysina degrade
Collagen type IV, proteoglycans
Why does mechanical pressure cause metastasis
Mass forms due to uncontrolled proliferation
Pressure occludes vessels
Pressure atrophy
Cancer cells spread along the lines of least resistance
What is often the first presenting sign of a tumour
Metastasis
Metastasis often occurs at different stages in differenttumours
Why is the secondary tumour burden ofthen worse than that of the primary site
Due to the metabolic burder
What are the route of tumour metastasis
Lymphatic
Blood
Transcoloemic
Implantation
What is transcoloemic spreading
Across peritoneal, pleural and pericardial cavities of the CSF
What is most commonly affected in blood metastasis
Liver, lung, bone, brain
What is implantation metastasis
Spillage of tumour during biopsy or surgery
What type of cancer can be spread particularly well by implantation
Mesothelioma
Can cause skin cancer due to biopsy
Stages of metastasis
Detachment - invasion - intravasation - survives host defences - adherence (to blood vessel wall) and extravasation - angiogenesis - growth
Pattern of metastases of carcinoma
Lymphatics
Pattern of metastases of sarcoma
Haematogenous spread (check lungs, liver)
Pattern of metastases bone
Breast, prostate, lung, kidney, thyroid
Can be lytic (lung) or sclerotic (prostate)
Pattern of metastases of transcoeloma
Ovarian
Pattern of metastases of brain and adrenal
Lung
What is the mechanical hypothesis of metastasis defined by
Anatomy
What is Paget’s seed and soil hypothesis
Seeds will go in all directions but seem to concentrate in certain areas
What organs do not usually allow metastasis
Kidney and spleen
When is angiogenesis needed
For metastases to grow larger than 1-2mm
Role of bone marroww derived endothelial stem cells uncertainty
What are angiogenesis promoters
VEGF
PDGF
TGFB
What are angiogenesis inhibitors
ECM proteins
Thrombospendin
Caristatin
Endostatin
What is the stage of the tumour
How advanced is the tumour
Has is spread and to what extent?
Stage correlates well with survival
What is the grade of the tumour
How aggressive is the tumour?
How quickly will it progress and hoe different does it look from the tissue of origin
How do we Stage tumours
TMN system T- tumour M- metastasis N- nodes TMN combined to give an overall stage of I to IV
Treatment of cancers
Surgery when not spread
Radiotherapy if locally spread
Chemo if distant spread
What do we stage colorectal cancer with
Duke’s stages
Discuss the Duke Stages
A - invades into but not through bowel wall
B - Invades into the bowel wall but no lymph node metastases
C - Local lymph nodes involved
D - distant metastasis
What does grading take into acount
Differentiation Nuclear pleomorphism and size Mitotic activity Necrosis (as can outgrowth supply) Grades G1 to G4 = G4 completely unifferentiated
What do we grade endometrial carcinomas with
FIGO grades
What are the most important indicators of prognosis
Grading and Staging
What is CEA a marker of (Carcinoembryonic antigen)
Colon cancers
What is the MLH1 an indicator of
Good indicator in colorectal cancer
Prognosis with p53 mutation
Poor prognosis
Reduced response to chemo
