Causes of cancer Flashcards
lecture 39
effect of tobacco smoking on cancer
estimated to cause 30% of cancer in the UK, even higher if you include passive smoking
3 groups of envrionmental factors
- chemicals
- radiation
- infectious agents
occupational risks in cancer
- historically - scrotal cancer in chimney sweeps, bladder cancer in dye industry workers.
- sex workers - cervix and anal cancer
- construction workers - mesothelioma after asbestos exposure
x rays during pregnancy?
increase risk of leukaemia
most chemical carcinogens…
are pro-carcinogens and need o be activated via metabolic alteration to derive the ultimate carcinogen.
- show tissue specificity and species specificity
what’s the ultiate carcinogen
a highly reactive electrophilic molecule that directly damages DNA.
examples of synthetic chemical carcinogens
- require in vivo activation
1 - polycyclic hydrocarbons - benzpyrene, benzanthracene, methylcholanthrene
2 - aromatic amines and azo dyes - beta napthylamine
reason for bladder cancer in dye industry
many substances used as dyes were aromatic amines derived from aniline and aminobenzene.
2-napthylamine is activated by addition of a hydroxyl in the liver, then rapidly converted to a harmless derivative by addition of a glucuronyl group and excreted in the urine. in man though, the glucuronyl is removed in the bladder and the reactive compound is released. hence bladder cancer.
2 examples of naturally occuring chemical carcinogens
1 - nitrosamines eg dimethylnitrosamine
2 - aflatoxin - derived from the aspergillus flavens
how are nitrosamines formed
interaction of a secondary amine with nitrous acid under acidic conditions. the stomach is such an environment for the interaction of nitrites (food preservatives and in water) and amines (meat, drugs)
issue with aflatoxin
probably the most potent carciogen known to man. natrual contaminant of peanuts infected with A flavens. activated to a highly reactive epoxide by oxidases in the liver. the epoxide binds directly to DNA bases.
how is radiation exposure measured
in greys = the amount of energy absorbed per unit of tissue. 1 grey = 100 rads
action of radiation
produces free radicals and ions as it passes through tissue, these alter structure of bases or cause strand breaks.
why are alpha particles such an issue
they leave dense tracks of ions and radicals so if they pass close to DNA are likely to cause DSBs.
action of UV
photoactivates pyrimidine residues in DNA so they form dimers where 2 thymidines occur sequentially. usually repaired by NER, defective in XP
cancers in smokers, pipe smokers and tobacco chewers
smokers - squamous cell carcinoma of the bronchus
pipe smokers - carcinoma of the tounge
- tobacco chewers - head and neck cancer
ways of identifying carcinogens
- epidemiology
- animal experiments
- in vivo testing
problems with animal experiments using carcinogens
ethical issues, species specificity, organ specificity, stage specificity
primary screen for carcinogens
bacterial and animal cells, to detect mutagens. cheaper and more reproducable. but limited ability to identify those that require metabolic activation.
difficulty with estimating the risk of exposure to an agent
difficult as we need to know how much is needed to cause cancer, at a high dose may things act as carcinogens.
3 types of infectious agent that can cause cancer
1 - parasites
2 - bacteria
3 - viruses
a parasite that can cause cancer
schistosoma haematobium - carcinoma bladder, probably by inducing chronic irritation.
a bacteria that can cause cancer
helicobacter pylori - a cause of some gastric ulcers and a major risk factor for development of gastric carcinoma and gastric lymphoma
viral association with cervical carcinoma
HPV 16 and 18
viral association with hepatocellular carcinoma
HBV and HCV
cancers associated with EBV
1- nasopharyngeal carcinoma
2 - burkitt’s lymphoma
3 - post-transplant lymphoma
viral association with adult T cells leukaemia
Human T cell lymphotrophic virus type 1 (HTLV1)
viral association with kaposi’s sarcoma
HHV8 (human herpesvirus type 8)
why is it difficult to associate a viral infection with a cancer
As cancer is a chronic disease, a multi-stage phenomenon and there is usually a long time between the initiating event, the virus infection and the emergence of a clinical disease.
what are Koch’s postulates for an infectious disease to have caused a pathology
1 - the agent must be isolated from each case of the disease
2 - the isolate must be grown in culture as a clonal isolate
3 - the disease must be induced in naive animals by inoculation of a cultured isolate
impossible to fulfil for putative human tumour viruses
ways of implicating a virus in a particular cancer
- epidemiology
- does prophylactic vaccination reduce the incidence of the cancer
- can you detect viral genomes and are the viral genes expressed in the tumour cells
2 types of epidemiological study
1 - case control studies (retrospective) - show that the patients with the cancer have been infected with the virus vs the controls either have not been infected or only a few have. eg HTLV1
prospective studies - infected and non-infected populations monitored over time for the development of disease eg HBV and hepatocellular carcinoma
difficulty with obtaining good epidemiological evidence with ubiquitous viruses
eg EBV infection is associated with several cancers but it is difficult to provide good evidence since nearly everyone is infected at an early age in the relevant populations.
3 sets of convincing epidemiological evidence for virus and cancer
1 - HBV - chronic infection raises risk of hepatocarcinoma irrespective of race, socioeconomic status or geographical location.
2 - HTLV-1 infection ‘causes’ adult T cell elukaemia
3 - FeLV (feline leukaemic virus) infection increases leukaemic risk. epidemiology suggests cats must be infected when young, must persist and only a few individuals will develop the disease
where prophylactic vaccination demonstrates evidence that a virus causes a cancer
HBV vaccination reduces incidence of hepatocarcinoma
lab alternative to Koch’s postuates
1- detect viral genome in each cancer biopsy in the cancer cells
2 - clone the viral genome from a cancer biopsy
3 - transfect cloned viral genomes into normal cells and show a biological effect - usually immortalisation
viruses that can immortalise a cell
1 - EBV in B cells
2 - HPV 16 and 18 in cervical and foreskin keratinocytes
3- adenovirus and the mouse virus polyoma but neither have an association with human cancer.
does this virus appear in the genomes of tumour cells, immortalise cells in vitro, have an epidemiological association. - Mareks
genome - yes
immortalise cells - no
epidemiological ass - good
does this virus appear in the genomes of tumour cells, immortalise cells in vitro, have an epidemiological association. - FeLV
genome - yes (sometimes)
immortalise cells - no
epidemiological ass - good
does this virus appear in the genomes of tumour cells, immortalise cells in vitro, have an epidemiological association. - HBV
genome - yes
immortalise cells - no
epidemiological ass - good
does this virus appear in the genomes of tumour cells, immortalise cells in vitro, have an epidemiological association. - HPV 16, 18
genome - yes
immortalise cells - yes
epidemiological ass - good
does this virus appear in the genomes of tumour cells, immortalise cells in vitro, have an epidemiological association. - EBV
genome - yes
immortalise cells - yes
epidemiological ass - difficult
does this virus appear in the genomes of tumour cells, immortalise cells in vitro, have an epidemiological association. - HHV -8
genome - yes
immortalise cells - yes
epidemiological ass - good
does this virus appear in the genomes of tumour cells, immortalise cells in vitro, have an epidemiological association. - HTLV-1
genome - yes
immortalise cells - yes
epidemiological ass - good
3 mechs of viral contribution fo tumour formation
1 - chronic damage and repair
2 - oncogene activation
3 - inactivation of tumour suppressors
how does chronic damage and repair cause tumours
several proliferative events will increase risk of ‘fixing’ (making permanent) mutations.
eg HBV, liver damage, hepatocyte prolif.
in developing countries many with chronic HBV also are exposed to aflatoxin as peanuts are important foodsource.
virus mech of causing Burkitts lymphoma?
- rare cancer of children, mainly tropical africe, strong EBV association.
- tumour lymphocytes characterised by a t(8;14) chromosomal translocation, puts c-myc located on chromo 8 under control of Ig heavy chain promoters from 14.
how can retroviruses activate oncogenes
1 - transduction
2 - insertional mutagenesis
3 - transactivation
leukaemic cells from FeLV?
often insertional mutagenesis from provirus integration. also some have recombinant proviruses which have transduced cellular genes to form v-oncogenes
action of HTLV-1 in cancer
thought - transactivation of genes encoding cell cycle competence factors in T cells
- also tax protein thought to activate genes controlling the spindle assembly checkpoint.
how do HPV 16 and 18 inactivate tumour supressors
- E7 protein binds the hypophosphorylated form of the Rb protein to release E3F and override G1/S check
- ## E6 protein binds and degrades p53
HHV-8 virus and cancer
encodes homologue of cyclin D that phosphorylates Rb.
- encodes homologue of bcl-2 that inhibits apoptosis.
4 risk factors for HPV
1 - number of sex partners
2 - age at first intercourse
3 - high-risk male partner
4 - number of pregnancies
history of HPV16 18
1976 - cervical smears noticed to contain cells similar to the koilocytes characteristic of the HPV infection
1984 - HPV DNA found in human cervix cancers, but a new type of HPV. not skin wart HPV1 or genital warts HPV6 and 11
HPV16 and 18 vs cervical carcinoma
HPV DNA detected in over 95%
- HPV16 detected in 50-60%
- HPV18 detected in 10-30% (more in africa)
- same HPV DNA detected in 90% of high grade CIN
not unequivocal though - could be a passenger or not causal. need epidemiological data and experimental data demonstrating a mechanism.
epidemiology for HPV 16 and 18 and cervical carcinoma
RR for HPV 16 is 270
- prospective studies strongly suggest causal.
- 40% of high grade CIN progress to cancer.
therefore HPV16 and 18 is a major risk factor for cervical cancer.
experimental evidence for HPV16 and 18 vs cervical cancer
E6 and E7 genes immortalise primary keratinocytes.
- E7 binds unphos Rb.
- E6 binds p53 and targets for destruction
- E6 activates telomerase
issue with making HPV vaccine
antibodies are vs L1 capsid protein but it has to be in its tertiary or native form and we cant grow the virus in tissue culture.
how is the HPV vaccine made
gene for L1 put into yeast or baculovirus. grow recombinant and L1 is produced and self assembles into a virus like particle. immunologically almost identical to the HPV
2 prophylactic vaccines for HPV L1 as a VLP
Gardasil by Merck = HPV 6/1//16/18
Vervarix by GSK = HPV16/18
efficacy is over 98%
the 5 pieces of evidence that cervical cancer has a HPV16 18 basis
1 - has the epidem of a STD. prospective studies strongly suggest its a cause of CIN2/3, and we know 40% of CIN2/3 progresses to cancer.
2 - HPV DNA found in over 95% of cervix cancers. HPV 16 50-60%, HPV18 10-30%. genes E6 and E7 always present.
3 - HPV16 and 18 will immortalise human keratinocytes in culture. only E6 and E7 needed.
4 - Papillomaviruses dont kill cells but induce to proliferate and are persistent. Wart = self limiting prolif.
5 - animal papillomaviruses cause cancers in their hosts. BVP in cattle and CRPV in rabbits. Mouse models of HPV16 replicate CIN changes.
- the true test will be if prophylactic vaccination works though.
- overall though with human tumour viruses, the infection alone isnt enough, other events must occur for malignant progression. ie not the only factor
5 public health measures to combat cancer viruses
1 - education 2 - legislation 3 - intervention 4 - immunoprophylaxis 5 - screening
current screening programs in the UK
breast, cervix and bowel.
the earlier it is caught the far higher the chance of survival.
4 cancer markers followed to check for remission following surgical tumour removal
1 - hepatocellular carcinoma - alpha fetoprotein AFP
2 - gut adenocarcinoma - carcinoembryonic antigen
3 - choriocarcinoma - human chorionic gonadotrophin hCG
4 - malignant teratoma - AFP and hCG
