cancer pathophysiology Flashcards
name the different environmental determinants of cancer…
radiation
chemicals
hormones
nutrition and lifestyle
how can radiation lead to cancer?
ionising radiation has high energy and can damage cellular structures and DNA - Xrays and nuclear. radiation can also indirectly cause mutation by the production of free radicals
non ionising (UV) damages DNA but does not penetrate further than skin - UVB is most dangerous. causes thymine dimerization in DNA. nucleotide excision repair (NER) pathway can fix such changes however sometimes changes can persist.
why are people with xeroderma pigmentosum more at risk of cancer?
defect in nucleotide excision repair (NER) pathways and thus UV light can induce skin malignancies
how do chemical carcinogens contribute to cancer?
initiate, promote and progress cancer
e.g. tobacco
which cancers is smoking linked to?
all cancers. but particularly lung, pharyngeal and bladder.
which infections are linked to cancer?
HIV - immunosuppresses host so that cancer cells can escape. also less protection against other viral carcinogens e.g. HHV8 and kaposki sarcoma
HPV and cervical cancer - direct oncogenic effect of viral proteins (E6 inhibits p53, E7 inhibits Rb)
EBV - hodgekins/ burkitts lymphoma
hepatitis virus and HCC - mainly from chronic inflammation and repair.
overall different mechanisms - inflammation, directly via viral oncogenes and by immunosuppression
which hormones can promote cancer?
HRT - oestrogens can increase risk of breast and endometrial cancer.
which cancers is alcohol linked to?
HCC
CRC
gastric cancer
breast and ovarian
name the 6 hallmarks of cancer (now 10)
- genetic instability and mutation - most important
- resisting cell death - p53 mutation (cell does not respond to apoptosis signals when genome is damaged)
- sustained proliferation e.g. overproduction of growth factor ligands, altered receptors , MAPK
- evading growth supressors e.g. mutation in Rb (restricts G1 to S)
- immortality - telomerase to expand telomeres
- inducing angiogenesis e.g. VEGF
- invasion and metastasis - cadherins are involved in adhesion, by loss of cadherins cancer cells can dissociate and metastasie
- reprogramming energy metabolism - upregulation of glucose transporters so that cancer cells have more energy
- . tumour promoting inflammation - allows the tumour to increase local blood flow to deliver more nutrients
- evading immune destruction
what gene(s) and cancers are implicated in:
a) breast/ ovarian syndrome
b) bloom syndrome
c) cowden syndrome
d) FAP
e) Fanconi anaemia
a) BRCA1/2…. breast, ovarian, colon, prostate and pancreatic cancer
b) BLM gene …. leukaemia, tongue, oesophagus, colon and wilms tumour
c) PTEN gene …. breast, thyroid, GIT, pancrease
d) APC… colon and upper GI
e) FACA, FACC and FACD… leukaemia, oesophagus, skin and hepatoma
what gene(s) and cancers are implicated in:
a) Gorlin syndrome
b) Li Fraumeni syndrome
c) HNPCC
d) MEN1
e) MEN2
a) PTCH gene…. BCC, skin, brain
b) TP53….. sarcoma, breast, lung, colon, leukaemia
c) MSH genes …. colon, endometrium , ovary, gastric, pancrease
d) MEN1 gene - pancreatic, pituitary
e) RET - protooncogene - thyroid, pheochromo etc
what gene(s) and cancers are implicated in:
a) neurofibromatosis
b) Peutz Jeghers syndrome
c) retinoblastoma
d) Von hippel lindau syndrome
e) xeroderma pigmentosum?
a) type 1 = NF1 and type 2 = NF2
b) STK1 … colon, ileum, breast, ovary
c) Rb gene…. retinoblastoma, osteosarcoma, small cell lung cancer
d) VHL gene - pheochromocytoma, CNS and retinal tumours
e) XPA, XPC etc … skin, leukaemia
what is the definition of benign and malignant? what are the other differences?
benign = abnormal growth of a tissue that persists after initial stimulus is removed but remains confined to its original site. Well defined margins, closely resembles parent tissue.
malignant - as above… and has the ability to invade surrounding tissues with the potential to spread to distant sites. show areas of necrosis and ulceration. range from well to poorly differentiated
what is the definition of a tumour?
clinically detectable lump / swelling
what is the definition of dysplasia?
pre-neoplastic alteration in which cells show disorganised tissue organisation. the change is still reversible therefore not neoplastic\
what is meant by anaplastic
cells with no resemblance to any other tissue.
what features mark loss of differentiation of cancer cells?
increase nuclear to cytoplasmic ratio
increased nuclear staining (Hyperchromasia)
increased mitotic figures
pleomorphism - variation in size and shape of cells
how is differentiation classed?
grade low to high.
high being poorly differentiated
what is the difference between an initiator and promoter in the development of cancer?
initiators = mutagenic agent = can be infection, chemical, radiation
promoters = causes cell proliferation
together they result in a monoclonal population of mutant cells and can progress into neoplasm by accumulating mutations.
which two gene types are implicated in cancer?
tumour suppressor genes
oncogenes
how does a tumour gain invasive and metastatic potential?
invade:
- changes in adhesion - reduced cadherins
- proteolysis - increase MMPs (metalloproteinases)
metastasis:
- motility - changes to cytoskeleton
- use of a transport system (blood, lymph)
- adaptation at new site
what are micrometastasis?
one or two tumour cells which have reached distant sites but fail to grow and can remain dormant there. after individual is treated for their primary they can appear disease free but later these micrometastasis can grow
what determines the site of metastasis for a tumour?
the regional drainage of blood and lymph.
- lymph to local lymph nodes.
- within body fluid cavities to nearby organs
- blood until vascular organ is reached e.g. often lung and liver.
seed and soil phenomena - some tumour cells will only suit and grow in certain places.
what factors contribute to likelihood of metastasis?
size of primary
type of primary e.g. small cell lung cancer is aggressive whereas BCC is very unlikely to metastasise
what are the local affects of tumours?
direct invasion and destruction of normal tissue
ulceration and bleeding
compression of adjacent structures (SVC)
blocking tubes e.g. bowel obstruction
what are the systemic effects of tumours?
paraneoplastic syndromes
cachexia - cytokines reduce appetite and lead to weight loss.
immunosuppression
thrombosis - increases coagulopathy
produce hormones - thyroid adenoma may produce T3/4 etc
pruritic, clubbing, myositis
what factors cause cancer?
intrinsic - genes, age, gender
extrinsic - chemicals, radiation, infection , level of exercise, BMI , diet
name some chemical carcinogens?
tobacco, asbestos, coal tar, aflatoxin, napthylamine (dye causing bladder cancer), vinyl chloride
which bacteria can cause cancer?
H.pylori and gastric cancer from chronic gastric inflammation
what parasites can cause cancer?
parasitic flukes - inflammation of gall bladder and bladder mucosa. therefore cholangiocarcinoma and bladder carcinoma
what is the two hit hypothesis?
TSGs require both alleles to be mutated in order for the gene to be completely non-functional.
a lot of inherited cancers are via mutations in one of the TSG and thus these individuals are already half way to receiving 2 mutations in a cell which will reduce protection against malignancy.
the majority of inherited cancers show what pattern of inheritance?
autosomal dominant (due to 2 hit hypothesis - with all cells already half way there the probability of one extra mutation in one cell is likely)
except xeroderma pigmentosum = auto recessive
name and explain some proto-oncogenes
RAS - G protein which is involved in cell cycle signalling. mutant ras is always active and thus promotes cell cycling.
growth factors - PDGF GF receptors - HER2 intracellular kinase - BRAF transcription factors - MYC cyclin D - cell cycle regulators Apoptosis regulator - Bcl2
name and explain some TSGs.
Rb - restriction of cell through restriction point of cell cycle
Tp53 - recognises DNA damage and signals the cell to apoptose. if this is mutated = genetic instability
in general how is outcome of cancer predicted?
WHO performance tumour type tumour grade tumour stage age availability of treatment
when is the bloom Richardson system used?
for breast carcinoma
- involves tubular formation, nuclear variation and number of mitosis
what does the growth fraction of cancer represent?
percentage of cells actively progressing through the cell cycle.
what is meant by de novo disease?
metastatic at presentation
what is the biggest predictor of cancer prognosis?
WHO performance scale
