BLOCK10 - Oncology

fewer proto-oncogenes

e.g., polyps of the colon
papillomas of the cervix

enlarged nucleus
loss of differentiation
disordered arrangement
increased proliferation

lost uniformity, architecture and orientation

10%

tumour cells are originally monoclonal
accumulate additional mutation = phenotypic change
this renders them more anaplastic - less differentiated
causing increased aggression

growth rate
invasiveness
metasttic potential
susceptibility or resistance to anticancer drugs
hormone responsiveness
paraneoplastic effects

because neoplastic cells are susceptible to DNA damage in genetic gatekeepers

exerts gate keeper function regulating DNA binding and repair protein Rad-51

regulated by BRCA-1 it initiates repair of double stranded DNA

mutated in HNPCC
encodes a proof reading and DNA mismatch repair protein

detects DNA damage and arrests the cell cycle until the DNA is repaired OR initiates apoptosis

lead to positive selection by expressing fewer surface antigens --> less susceptible to immune surveillance

inhibits cell growoth via binding surface receptors regulating DNA repair protein rad-51

unknown mechanism - but is present in MOST familial breast cancer

10%

codes for surface proteins involved in cell-cell and cell-matrix communication

decrease capacity to differentiate --> proliferation

regulates E-cad which forms intercellular junctions
mutation of 1 allele --> benign adenomas of which some may become malignant

both can be mutated
decreasing adhesion allowing invasion

cause invasive gastric carcinoma

regulates signal transduction
GAP proteins --> increase GTPase signal transduction which increases the rate of ras --> inactivating ras faster
this slows the proliferative signal transducion

associated with benign neurofibromas - which may be come malignant

2 mutations required - 1 inherited and 1 result of a somatic mutation
regulates G1-S transition of cell cycle

on chromosome 17
50% of all human cancers
binding of p53 to DNA = growth inhibitory gene suppresion
inactivated p53 = proliferation to neoplasm

chromosome 11
nephroblastoma
codes transcription factors that act as transcription repressors e.g. PDGF-a or ILGF-2

is an example of an oncovirus which binds via E6 and E7 proteins to Rb and p53 respectively to initiate oncogenic processes

Familial Adenomatous poliposis
1/10000
accounts for colorectal cancer
usually develop cancer by 40years
germline mutation on ch5

true

FALSE
75% of occupational cancers are in the lungs and pleura

13-27%

5000

TRUE

squamous cell carcinoma
34%
cells effecting the main bronchi
low rate of metastises

26%
occurs in the bronchial glands
may develop in non-smokers too

22%
strong association with smoking
spreads early
poor prognosis

16%
develops in the airways

free cells
time cancer is in the body
loss of differentiation of cells --> ability to grow elsewhere in the body

seeding within the body cavity
spread through the lymphatics
spread through the blood system - venous or arteriole

ovarian cancer through the peritoneal cavity
lung cancer through the peural cavity

cancer of the upper outer quadrant of the breast likely to spread via the axillae lymph nodes

tumour adheres to the BM
proteolytic enzymes released to break down the BM
amoiboid movement through the matrix and BM
cell intravasates due to reduced adhesions
cell attaches to lymphocyte to form a tumour cell emboli
cell extravasates through a dstal BM
the tissue at this site determines the success of seeding a growth of tumour

can spread via the portal vein to the liver meaning that there is downstream and upstream capability to spread

Ca in the blood is 50% ionized, 40% bound to protein and 10% complexed with citrate or phosphate
hypercalcaemia refers to ionized Ca

due to excessive uncoupled bone reabsorption which overwhelms the kidney's ability to excrete it.

tumour cells releasing cytokines including IL-1, IL-6 and TNF-a which may stimulate reabsorption
humoural effects like parathyroid-hormone related polypeptide (PTHrP) made excessively by tumour cells may increase Ca

there is impaired concentrating ability in the kidney
increased urinary water loss
dehydration

anorexia
vomitting
nausea
dehydration
nerve and muscle cells hyperpolarise --> constipation and arrhythmias

loop diuretics may be useful to reduce Ca however careful not to dehydrate further

e.g., methotrexate

inhibits dihydrofolate reductase (30x) --> causing an accumulation up to 2.5uM which inhibits de novo biosythesis of purine nucleotides
used in ALL and breast cancer

5-flurouracil: colon and breast
- convereted to 5fluro dUMP which inhibits dUPM--> dTMP

cytosine arabinoside: CLL
- phosphorylated to ara CTP inhibiting DNA polymerase

Fludarabine and cladribine:
- convereted to triphosphate derivatives and induce an imblance in concentration of 4alpbNTPs via inhibition of ribonucleotides reductase and DNA polymerase --> causing cell death

from the fungus streptomycin
Doxorubicin and daunorubin
- intercalate between base pairs inhibiting transcrption of RNA and DNA
used in combination therapy

Vincristine, vinblastine, colchicine
- interfere with mitosis by binding soluble tubilin

Taxol
- stabilised tubules inhibiting depolymerisation to tubulin

inhibit the enzyme topoisomerase 1 --> produced a single stranded break to unwind DNA --> results in lots of single stranded breaks = DEATH

colour and texture: yellow and soft (except for where there is lncreased collagen)
friable with necrotic core
fingerlinke projections
irregular margins
variation in texture and colour
ulceration
local invation
errosion of local vessels

tumour of epithelium that does not break through the BM

FALSE
it is more susceptible to invasion

TAF
induces vascularisation of rapidly growing tumours

haphazard structure
increased nucleus size, decreased cytoplasm
variable in shape and size of cells
stratified with increasing growth

via indirect patheway via free radicals formed from ionizing water which produces breaks in DNA.
a single break is not fatal, but the more breaks the higher the probability of death
death occurs after 1 or more attempts by cell at mitotic devision

cells which have a higher turnover rate - more frequently in the M or G2 phase - e.g. cells of the GIT or bone.
Oxygen also sensitises cells to radiation.

sublethal damage only takes hours to repair allowing this to take place
promotes optimal cancer cell death b enhancing reoxygenation between fractions
stimulates ells to divide placing them in the sensitive M and G2 phases.

cause cervical cancer

lead to skin cancer

e6-p53
e7-Rb

Burkitts lymphoma.
however is not sufficient alone to cause the cancer
causes a translocation of cellular oncogene c-myc from ch8 to ch14 = over expression

hepatoellular carcinoma

lymphomas and leukaemias

true. these include the rapid growth genes of the embryonic and foetal stages.

1. interfere with cell cycle regulating mechanisms
2. a number of oncogene products have kinase activity suggesting phosphorylation is an important function, other related to cellular receptors for growth factors e.g. epidermal growth factor

has specificty and leads to memory
only activated once the first line of defense is breached

may induce immunosuppresion
directly: HIV and HTLV
or
indirectly: measles

X-linked -gammaglobulinaemia
di goerge syndrome

single RNA flanked by terminal repeat sequences

the RNA is surrounded by proteins enveloped in glycoproteins

codes for the viral envelope - cell binding and membrane fusion

codes for the proteins of the nucleocapsid core where unique viral enzymes live

codes for reverse transcriptase, integrase and protease

production of DNA complementary in nucleotide sequence to RNAtemplate

essential for integration of the DNA double strands

cleaves polypeptides to releasae the functional proteins in virion assembly

FALSE
HIV also invades monocytes, macrophages and dendritic cells

cell entry is receptor mediated mainly via the CD4 molecule and requires a co-receptor from co-engagment of beta chemochine receptors

occurs around the 2-3week time and corresponds to the acute illness suffered by the patients similar to glandular fever.
it is an induction of specific antibodies to HIV of the IgM, IgG and IgA type

HIV integrates into the chromosomes of the infected cell and becomes quiescent AND has the ability to mutate meaning that neither the serotologic response nor the cytotoxic CD8 and CD4 response is sufficient to eliminate the virus

~10000 nucleotide bases encoding structural and regulatory genes

binds to CD4 and co receptor --> internalisation --> uncoating --> reverse transcription of RNA and DNA and formation of 2nd DNA strand --> integration

replication of the virus RNA --> translation of virus protein/glycoprotein --. cleavage of polyprotein strands

based on the 3D structure and targents