MOD - carcinogenesis + behaviours of tumours Flashcards
what two types of meat can cause colorectal cancer?
- red meat
- processed meat
what carcinogens are workers exposed to in aluminium production, coal gasification, coke production, iron and steel industries?
heavy metals
eg cadmium and nickel
mining of hematite and uranium exposes miners to what carcinogen?
radon
what sort of cancers have been reported among woodworkers\?
cancers of the sinonasal cavities and paranasal sinuses
what industry exposes workers to the carcinogens B-napthylamine and 4-aminobiphenyl?
rubber industry
what type of cancer is seen in workers in boot/shoe manufacture and repair?
nasal adenocarcinoma
what is EPIC?
The European Prospective Investigation into Cancer and Nutrition (EPIC) study is one of the largest cohort studies in the world, with more than half a million (521 000) participants recruited across 10 European countries and followed for almost 15 years. EPIC was designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors, and the incidence of cancer and other chronic diseases.
what are the 6 categories of human carcinogens?
Chemicals e.g. PAHs, nitrosamines
Infectious agents e.g. human papilloma virus, Helicobacter pylori
Radiation e.g. UV light, radon
Minerals e.g. asbestos, heavy metals
Like cadmium and nickel
Physiological e.g. oestrogen, androgens
Chronic inflammation – free radicals and growth factors
what are PAHs
Polycyclic aromatic hydrocarbons (PAHs) are a group of more than 100 different chemicals that are released from burning coal, oil, gasoline, trash, tobacco, wood, or other organic substances such as charcoal-broiled meat
they are carcinogens
what type of cancer does exposure to aflatoxin cause? and what is it?
liver cancer
a mold found on food products such as corn and peanuts, peanut butter
what 4 types of cancer does alcohol cause?
pharynx, larynx, oesophageal, liver
what type of cancer does asbestos cause?
mesothelioma
ie of the lung pleura
what type of cancer do x-rays cause?
leukaemia (bone marrow)
what kind of cancer does oestrogen cause?
breast cancer
what 6 types of cancer does smoking cause?
lung, mouth, oesophagus, pancreas, kidney, bladder
and others!!
what kind of cancer does HPV (human papilloma virus) cause?
cervix
what is a carcinogen?
any agent that significantly increases the risk of developing cancer
what are the 3 types of carcinogen?
initiators
- modify or damage dna (genotoxic)
promotors
- induce proliferation and DNA replication (non-genotoxic)
complete carcinogens
- initiate and promote
- eg UV light
what 2 steps does initiation of cancer (mutation induction) require?
- chemical modification of DNA
- replication of modified DNA and mis-incorporation by DNA polymerase
what are the two ways in which promoters contribute to carcinogenesis?
- by stimulating the 2 rounds of DNA replication required for mutation fixation
- by stimulating clonal expansion of mutated cells, which enables the accumulation of further mutations
what are the 3 stages of carcinogenesis?
- initiation
- promotion
- progression
why are you a lot more likely to get a basal cell carcinoma than a melanoma?
because cancer is directly related to levels of cell division
Basal cells and maelanocytes (produce melanin) are exposed to the same amount of uv light but, because basal cells replicate more in normal physiology, you are 10 fold more likely to get a basal cells carcinoma than a melanoma
This would support a hypothesis that cell division, and by inference DNA replication, is a significant risk factor for the development of cancer
what genetic change is associated with chronic myeloid leukaemia?
translocation on chromosome 22 (Philadelphia translocation)
what is aneuploidy?
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46.
mutations which result in an over-activation in which genes can cause cancer?
activation of proto-oncogenes
mutations which result in an inactivation in which genes can cause cancer?
inactivation of tumour suppressor genes (TSGs)
what is a colloquial name for a common type of promoter sequence?
CpG islands
what does methylation of promotor sequences result in?
loss of gene expression of said gene
what are the two ‘umbrella’ ways that carcinogens can induce cancer?
+ examples?
direct acting
- interact directly with DNA
(eg oxygen radicals, UV light, ionising radiation, nitrogen mustard)
procarcinogens
- require enzymatic (metabolic) activation before they react with DNA
(eg polycyclic aromatic hydrocarbons - PAH, found in burnt organic products)
what is benzopyrene? what is it an example of? and what happens to it in the body?
a type of PAH
can be generated through combustion of most organic material (eg meat, tobacco, fuel)
example of a procarcinogen
- requires activation to convert it to BPDE (= ultimate carcinogen)
however genetic variation in enzymes between individuals determines how much bpde you produce from a set amount of benzopyrene
so same level of exposure but different likelihood of developing cancer
what condition can inherited defects in the NER (nucleotide excision repair) pathway lead to?
Xeroderma pigmentosum (XP) - a rare autosomal recessive condition
extreme sensitivity to UV light (as damage cannot be repaired)
- with UV, get abnormal skin pigmentation and very high frequency of skin cancers, have to completely avoid sun!
what condition arises from inherited defects in the ATM gene?
ataxia telangiectasia (AT) - autosomal recessive
much increased risk of cancer
- haematological cancers in childhood and solid tumours as adults
what is lynch syndrome?
aka HNPCC (hereditary nonpolyposis colorectal cancer)
autosomal dominant condition
inherit faulty DNA mis-match repair genes
increadibly high risk of colorectal cancer 80%
(as well as endometrial 60%, ovarian 12% and others)
what 5 levels of defence does the body have against carcinogens?
- dietary antioxidants (fruit/veg inactivates free radicals which –> DNA damage)
- detoxification mechanisms
- DNA repair enzymes
- apoptotic response to unrepaired genetic damage
- immune response to infection and abnormal cells
how are heavy metals carcinogenic?
not, in themselves, carcinogenic but they react with other molecules to form free radicals which then –> dna damage
name 5 carcinogens present in tobacco smoke
- polycyclic aromatic hydrocarbons (PAHs)
- acrolein (arid smell, potentially direct acting)
- nitrosamines
- radioactive lead + polonium (v. small level but accumulate over time)
- heavy metals (cadmium, chromium)
HOW is alcohol carcinogenic?
5 reasons
- converted into acetaldehyde, can –> DNA damage
- increases levels of oestrogen + testosterone (both carcinogens)
- increases uptake of other carcinogens into upper GI cells (eg cig smoke absorbs into bloodstream using alcohol as a solvent)
- reduces levels of folate (needed for accurate DNA replication)
- can kill surface epithelium –> unscheduled proliferation to replace dead cells (a potent promoting stimulus)
what increases a woman’s likelihood of breast cancer? (7)
- early menarche
- age of 1st pregnancy >30years
- late menopause
- post-menopausal obesity
- oral contraception (combined, not progesterone only)
- hormone replacement therapy (HRT)
- high alcohol consumption
basically all of these are risk factors as they increase body’s exposure to OESTROGEN (= a complete carcinogen, initiates and promotes)
why does chronic inflammation often lead to cancer? (2)
- DNA damage from release of free radicals by immune cells = INITIATION
- growth factor induced cell division to repair tissue damage = PROMOTION
therefore inflammation is a complete carcinogen
what % of cancers are due to preventable causes?
over 50%
what is the difference between proto-oncogenes and oncogenes?
proto oncogenes - promote cell proliferation, survival and angiogenesis in a normal cell
oncogenes- mutated versions of proto-oncogenes
= uncontrolled proliferation, angiogenesis, inhibition of apoptosis etc,
nb oncogenes are DOMINANT GAIN-OF-FUNCTION: ie one mutant copy of the gene acts dominant to the remaining normal parental gene
what are the 4 mechanisms of oncogene activation?
TRANSLOCATION of an oncogene from a low to an active transcriptional site
POINT MUTATION - substitution of a single base within the amino acid sequence, produces a hyperactive oncoprotein
AMPLIFICATION by insertion of multiple copies of an oncogene - increased expression
INSERTION of a promoter or enhancing gene (by retroviruses) near an oncogene -> increased expression
what is an oncoprotein?
what are 3 different types of oncoprotein? and give an example for each
a growth factor that activates cell growth
a GROWTH FACTOR RECEPTOR that activates cell growth
(eg HER2 amplification in some breast cancers, a drug targets this)
BINDS DNA to STIMULATE TRANSCRIPTION and expression of other genes
(eg translocation/overexpression of c-myc - which stimulates transcription - is seen in a lot of cancers + is potential drug target)
cytoplasmic SECOND MESSENGER that ACTIVATES SIGNALLING for cell cycle progression and cell growth (eg KRAS and PI3K mutations - in lots of cancers)
what are the two different types of tumour suppressor genes (TSGs)?
GATEKEEPERS (antioncogenese)
- negative regulators of the cell cycle and proliferation and positive regulators of apoptosis
CARETAKERS
- can fix problems on genes which are caused by carcinogens
what 4 types of mutations can cause the inactivation of TSGs?
inactivating point mutations
deletions
translocations
epigenetic silencing
what is epigenetic silencing?
shutdown of gene expression via methylation of CpG sequences in promoter regions
are mutations within TSGs recessive or dominant? why is this clinically relevant?
TSG mutations are recessive (protooncogene mutations are dominant)
both copies of a TSG have to be mutated (or epigenetically inactivated) for complete loss of function and cancer to develop
important for familial cancers, they inherit one mutated copy of the gene from parents so only need one more mutation to cause cancer (instead of 2 in normal people)
what is an example of a familial cancer syndrome which is due to one inherited copy of a mutated TSG?
and how does it prevent differently to the sporadic equivalent of this cancer?
inherited retinoblastoma
- germline mutation: absence of one copy RB1 gene
predisposes individuals to developing retinoblastoma (as only have one more gene to mutate) - in sporadic cases there has to be 2 mutations, in the SAME CELL!
inherited retinoblastoma tends to be bilateral (in both retinas) whereas sporadic retinoblastoma tends to be unilateral
what is Li-Fraumeni syndrome?
a cancer syndrome that is the inheritance of ONLY ONE copy of the TSG p53 (a gatekeeper)
thus predisposes patients to sarcomas and breast tumours
what are BRCA1 + BRCA2?
caretaker TSGs
if one mutated copy of gene inherited then high likelihood of breast and ovarian cancer = familial breast cancer
what specific genes are knocked out in HNPCC (aka lynch syndrome)?
hMLH1, hMSH2
these are caretaker TSGs
how many mutations are generally needed in a cell for it to become cancer? (carcinogenesis)
minimum of 3 genetic changes are needed to transform a normal cell –> neoplastic cell
importance of mutation accumulation, rather than the sequential order of specific mutations (as this varies between patients)
what is K-RAS
a proto-oncogene
what are the 7 hallmarks of cancer cells?
self-sufficiency in growth signals
insensitivity to antigrowth signals
tissue invasion and metastasis
limitless potential for replication
sustained angiogenesis
evading apoptosis
genomic instability
what does self-sufficiency in growth signals mean?
and what are some examples which lead to this quality?
normal cells require the stimulus of positive growth factors before they enter the cell cycle and divide.
tumour cells acquire the ability to GROW IN THE ABSENCE OF THESE FACTORS
- EGFR overexpression
- EGFR mutation
- Ras mutation
- B-Raf mutation
(all above examples are in MAPK/ERK pathway)
what is an example of a mutation which leads to cells not responding to negative growth factors and leaving the cells cycle? (ie insensitivity to antigrowth signals)
Rb protein prevents progression of G1 –> S phase (in cell cycle) in normal cells
inactivation of Rb gene (common in cancer cells) –> resistance to -ve growth regulation
(lost the gatekeeper between G1 and S phase) –> uncontrolled proliferation
what is meant by limitless potential for replication? (in cancer cells)
cells have a finite lifespan. During each cell division, they loose some DNA from the telomere. After the telomeres become very short the cell –> apoptosis
rapidly proliferating tumour cells can OVEREXPRESS the TELOMERASE enzyme to maintain normal telomere length
what is an example of a mutation which leads to resistance to apoptosis in a tumour cell?
p53 inactivation
(present in >50% of tumours)
leads to loss of apoptotic response
(in normal cells transcription factor p53:
- controls expression of >100 genes
- pauses cell cycle to allow for DNA repair
- induces apoptosis if too much damage)
what cancer syndrome is due to an inherited loss of one copy of p53 gene?
Li-Fraumeni syndrome
increased risk of breast cancer and sarcomas
what size can tumours grow to before they need their own blood supply?
2mm
any larger and the cells in the middle will die due to lack of nutrients/oxygen
what mutations lead to angiogenesis in tumours?
stabilisation of HIF-1 transcription factor
this induces VGEF (vascular endothelial growth factor) - an angiogenic growth factor
this actively recruits endothelial cells that proceed to construct new capillaries and vessels
what is the primary reason why tumours ‘want to’ induce angiogenesis and what is the side effect of this
primary reason: to get nutrients
side effect: metastasis
how are tumours able to invade local tissue?
epithelial cells are held tightly together by ADHESION MOLECULE E-cadherin
many tumours show LOSS of E-CADHERIN through mutation/hypermethylation of the gene
this –> EPITHELIAL-MESENCYMAL TRANSITION (EMT)
these mesenchymal cells are motile and secrete proteases
this allows them to break through basement membrane and invade the underlying stroma
what is PSA serum protein marker and what is it used to detect and how effective is it?
prostate-specific antigen
used to detect prostate cancer
but 1/3 of patients with high PSA do NOT have cancer!
what is the serum antigen CA-125 used to detect?
is it effective?
ovarian cancer
not good at detecting early stage disease
what predictive marker for prognosis is used for AML (acute myeloid leukaemia)?
gene expression profiling of AML subtypes
AML subtypes with different translocations are clearly distinguishable, match the translocation pattern with the known prognosis for each translocation
how is HER2+ breast cancer treated and why?
with the drug Herceptin
HER2 gene codes for a positive growth factor receptor (HER2 receptor)
overexpression of HER2 found in 30% of breast cancers
- this makes cells more responsive to +ve growth factors
Herceptin is an antibody drug targeted to HER2 and so stops the overexpression, reducing the cancers response to positive growth factors
nb individuals whose cancers are HER2- will have no response to Herceptin treatment
what is the difference between invasion and metastasis?
INVASION
- invades adjacent normal tissue
- destroys normal tissue
METASTASIS
- spreads from site of origin to distant sites and forms new tumours in these new areas
do basal cell carcinomas often metastasise?
no, almost never
what is the most lethal type of skin cancer?
malignant melanoma
- cancer of skin melanocytes (produce melanin)
often metastasises
what % of adult cancer patients have metastatic disease?
50%
what proportion of paediatric cancer patients have metastatic disease?
majority
what proportion of lung cancer patients have metastatic disease?
majority
what proportion of breast cancer patients have metastatic disease?
one third
what are cadherins?
cell-cell adhesion molecules
“Caderins begin with a C, as does Cell”
what are integrins?
cell to extracellular matrix adhesion molecules
“integrins INTERGRATE cells to the extracellular matrix”
what do mutations in cadherins lead to?
loss of cell-cell adhesion AND loss of contact inhibition
what do mutations in integrins lead to?
decreased cell-matrix adhesion
why does EMT (epithelial - mesenchymal transition) in tumours lead to invasion and metastasis?
epithelial cells are tightly connected, polarised and tethered
mesenchymal cells are loosely connected and able to migrate
therefore invade
how do tumour cells degrade extracellular matrix?
using matrix metalloproteinases
what enzyme degrades collagen types 1, 2 and 3?
interstitial collagenases
what enzyme degrades collagen type 4 and gelatin?
gelatinases
what enzyme degrades collagen type 4 and proteoglycans?
stomolysins
in normal tissues what counteracts matrix metalloproteinases to prevent excess extracellular matrix breakdown?
tissue inhibitors of metalloproteinases
what are the 4 routes of metastasis?
lymphatic
blood
transcoelomic
implantation/direct seeding
what does transcoelomic metastasis mean?
across peritoneal, pleural, pericardial cavities or in CSF
what does implantation/direct seeding mean?
spillage of tumour during biopsy/surgery
what are the 5 stages of metastasis?
detachment invasion
intravasation (goes into blood vessel)
survival against host defences (in blood stream)
adherence extravasation (goes from blood vessel to distant site)
growth
what route of metastasis do carcinomas normally follow?
lymphatic spread
what route of metastasis do sarcomas normally follow?
blood spread
what route of metastasis do ovarian tumours often follow?
transcoelomic
what are the two hypotheses of patterns of metastasis?
mechanical hypothesis
- dictated by anatomy (ie GI cancer spreads to liver as that’s where blood goes next)
seed and soil hypothesis
- bits of cancer spread everywhere but they only grow into full secondary tumours if the ‘environment’ is right!
what are 3 promoters of angiogenesis (and what are they produced by)?
VEGF (vascular endothelial growth factor) - produced by tumour cells
PDGF (platelet-derived growth factor) - produced by stromal (connective tissue) cells
TGFB (transforming growth factor beta) - produced by inflammatory cells
“anything with growth factor (GF) in is likely to promote angiogenesis”
what are 4 inhibitors of angiogenesis?
ECM (extracellular matrix) proteins
thrombospondin
canstatin
endostatin
“anything with ‘STatin’ in is likely to STop angiogenesis”
what does the STAGE of a tumour measure?
what is a common staging tool?
how ADVANCED is the tumour? (has cancer spread and how?)
TMN - tumour size - metastasis - spread to nodes values from each calculated to give an overall stage of 1-4
nb stage can be clinical, radiological, pathological
so where, along the progression from normal towards killing the patient, is the tumour currently at
what does the GRADE of a tumour measure?
how AGGRESSIVE is the tumour?
ie how different it looks from the tissue of origin
so how quickly the tumour is progressing towards killing person
what staging system is used for colorectal cancer? and what do the stages mean?
DUKES
A = invades into, but not through, bowel wall
B = invades through bowel wall but with no lymph node metastases
C = local lymph nodes involved
D = distant metastases
What four characteristics are used to GRADE tumours?
differentiation
(how much does tumour resemble tissue it originates from, poorly differentiated = looks very different from original)
nuclear pleomorphism and size
mitotic activity (incl. abnormal mitotic form)
necrosis
(also vascular proliferation)
nb grading is performed by histopathologists and is subjective
things are graded G1(near normal) –> G4 (very bad)
what does a tumour have to do to be called malignant? (as opposed to benign)
invade local tissue
(doesn’t necessarily have to metastasise!!)
eg basal cell carcinomas invade but don’t metastasise! (so technically a malignancy but, in practise, often not called malignant)
what’s more common, sarcomas or carcinomas?
carcinomas
what is the staging system for lymphomas?
Anarbor
what is the staging system for gynaecological cancers?
FIGO
what two types of women are endometrial cancers more common in?
- postmenopausal
- obese (as fat cells produce oestrogen)
what are 5 cancers which often metastasise to bone?
- lung
- prostate (because venous drainage goes next to spine)
- kidney
- breast
- thyroid
what is a pathological fracture?
a bone fracture which occurred mainly due to a medical reason (as well as minor trauma)
eg osteoporosis or bone cancer
what are 3 examples of oncogenes?
Ras
HER2
PI3K
what is the most commonly mutated TSG?
P53
most cancers have loss of this gene
what 4 things are used to assess prognosis in any cancer?
- tumour type (and subtype)
- stage
- grade
- molecular profile (happening more and more)
