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48 Cards in this Set
- Front
- Back
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What are the factors that can alter/augment the rate at which DNA changes take place?
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Mutations induced by chemical/physical carcinogens, irradiation, or viruses
->leads to a cell that grows a bit faster than the surrounding cells ->over time, get a benign growth, that is growing at a rate slightly different rate than then the surrounding cells (neoplastic cells) |
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What happens in the early stages?
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Can get errors in DNA synthesis/replication
Still have normal number of CHR and look like normal cells Can't really deal with the growth cuz there's not enough cells to trigger an immune response |
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What are the innate esponses to neoplastic cells?
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1) Programmed cell death: when DNA is damaged or mutated
2) NK cells: detect minor differences in cell mb composition 3) Macrophages will come in and engulf apoptotic bodies 4) Natural Ab: recognize abnormalities in cell glycosylation and other things ->often in neoplastic transformation, cell carbohydrates get modified a little bit and these recognize it 5) Complement will also kill cells if the Ab bind ->generally, innate defences are quite limited. Not certain whether they do ultimately make a difference in combating the cancer |
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What is the progression neoplastic cells to metastasis?
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-Accumulation of errors: if cell doesn't die immediately through innate responses, can't accumulate various error leading to its death or the acquisition of an even more neoplastic phenotype
-Loss of regulation: also characteristic of neoplastic cell -Cell becomes immortal: can't induce apoptosis, renders it resistant to many host cytotoxic defences ->get abnormal karyotyp down the line ->eventually leads to invasive, metastatic phenotype, which can invade blood streams and lymphatic vessels and establish secondary distant tumous usually in the liver, brain and lungs, since they are "filter" organs |
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When do immune defences kick in?
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When there is sufficient immunogenic material to induce a host response
->Occurs btw benign and malignant stage (hopefully) |
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What cells are made vs cancer Ag?
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Cytotoxic T cells
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Which cytokines are used?
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IL2: from T helper cells to activate NK cells into lymphokine activated killer cells
IFN-y: activate macophages, generate specific immune Ab |
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How many cancers are avoidable?
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33% of tehm
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How are some cancers avoidable?
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Cancer risks: smoking, obesity, sex and drugs
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How many staes of cancer are there?
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4
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What is stage 1?
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Cancer in situ:
-Primary focus, confined to original site, displaces normal tissue during slow growth, no invasion -worst it can do at this stage is displace normal tissues -blood vessel occlusion can be a problem -not very problematic in the brain unless its causing vasculara problems and headaches |
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What is stage 2?
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Local growth: within original organ
-invasion through basement mbs in organ -can occur for long periods of time -1-2 cm in diameter is where malgnant tumours usually get detected ->if detected at this stae, relatively easy to cure |
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What is stage 3?
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Invasion of other adjacent organs
-invasion through organ capsule/basement mbs to adjacent tissues (in kidneys, wouold go through renal tubules, glomeruli etc) -Invasion to places like abdominal or intestinall tissues would produce symptoms at this stage |
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What is stage 4?
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Metastasis to secondary sites
-Vascular/lymphatic spread to lung, liver, brain |
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How does cancer develop?
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Clonal succession
-> Accumulation of many incremental and cumulative events -neoplastic cell is monoclonal, grows as a clone, but faster than its surrounding cells |
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What happens to most cells that are cancerous?
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99% of them will get rid of the original cancerous cell
Most die through apoptosis |
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What happens to the cancer cell that is diagnosed?
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This cancer is winning the contest for nutrition
->cancer not organized tissue .: it hoardes the nutrients |
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How many cancers are treatable by surgery/chemotherapy/radiotherapy?
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33%
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What does chemotherapy cause?
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Systemic problems
-knocks ou immune system, prevents cells in the gut from being regenerated, resulting in digestive problems, leads to hair loss, etc |
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What is the overall risk of mortality if you keep away from carcinogens and you monitor your health?
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8-10%
(33% of cancers are undetectable) |
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What are avoidable cancer risks?
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-Poor fetal nutrition, maternal low ptn diet: childrenshould be breast fed for 6 months
-Foods high in sugar/fat. Energy dense foods and salts -Red meats and processed meats: processed foods can contains oxyradicals, nitrites, eat mostly foods of plant origins -Obesity, particularly lower abdominal obesity: be as lean as possible, BMI btw 21-23 -Carcinogen exposuse: minimize exposure to moulds in cereals and legumes, which contain mutagenic toxins -Sedentary lifestyles: be physically active everyday -Alcoholic drinks in excess of 30gm Ethanol/day -Tobacco products in all forms |
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Is immune surveillance important?
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Incidence of cancer 100fold in ppl with not T cells (DiGeorge's syndrome)
Without CMI, the growth rate of cancers is extermely fast Lack of NK cellsmacrophages bad Grafted ppl taking anti-rejection drugs also have increased risk of cancer |
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Describe malignant cells.
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-No factor dependent growth regulation
-Loss of contact inhibition of growth: will keep growing -Surface independen growth in suspension: will grow anywhere, don't need basement mb/anchor of tissue, etc -High mitotic index (S Phase fraction) -Production of angioogenic factors: ptns, signalling mole that tell blood vessels to come and grow there so that the blood can provide the required nutrients and oxygen for the tumour's growth -Immortal: apoptosis is inhibited -Loss of "tumour suppressor genes": genes that correct mutations get KO or mutated -Abnormal DNA cotent: soze, #, shape of CHR change -Invasive phenotype, produce invasive factors -Spread by metastasus, seed to other sites |
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What happesn if you immunize a mouse with irradiated tumour cells than injecting the mouse with the same viable tumour?
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Rejection of the tumour
.: there's something different about cancer cells that the immune system can recognize |
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Do mutated self proteins produce a large response?
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Most likely produce an ANERGIC and not immunogenic response
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What are some characteristics of some tumour cells?
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-Reactivation of germ cells: tumour cells revert to a more primitive phenotype. (brain cancer celll won't have the neuron phenotype)
-Re-expression of embryonic Ag (such as fetal hemoglobin) -Overexpression of ormal cell Ag |
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How can a virus cause cancer?
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A given virus can causae multiple cancers dependigng on which gene it alters or where it may insert itself
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What kind of TSA's do virus-derived tumours express?
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Virus specific
->can immunize someone with SV40 and they're protected from either SV40-1/2 -> immunie mouse with inactivaed SV40 and inject polyoma-virus: not protected from tumours by polyoma |
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Where is the TSA derived from with chemical carcinogens?
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TSA is derived from whatever tumour has been produced following the initial tumour induction
-> Experiment with methylcholanthrene: if you inject MCA-1 into mice which have previously had an MCA-2 tumour, the mice will not reject the tumour, since the TSA i specific to MCA-2, not just methylcholanthrine-induced tumours in general .: TSAs for carcinogen-derived cancers are unique for each cancer |
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What are tumor specific transplantation Ag (TSTA)?
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Cell Ag that are specific targets of tumour rejection mechanisms
MHC I dependent peptide presentatin on target cells |
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What are tumour ass't antigens (TAA)?
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Normal tissue ptns and glycoptns that are produced in abnormal quantities by tumour cells
Not usually involved in tumour rejection but may be useful in detection and diagnosis |
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What are some examples of TAAs?
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Ig's produced by myeloma cells (B-cell)
Alpha-fetoptn produced by liver cell tumours (hepatocellular carcinoma): babies stressed in utero have an elevated lvl of a-fetoptn in their circulation Chorionic gonadotropin produced by trophoblast cell tumours Carcinoembryonic Ag produced by colon cancer cells: marker ass't with colon cancer |
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Why is cancer such a big problem if all cancer cells are immunogenic?
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Tumour TSAs are usually weakly immunogenic (form of peripheral tolerance, are more anergic)
-Tc cell mediated cytotoxic response to TSAs may be weak -immune response to TSAs in anergic patients with established tumours can't be augmented -> .: the immune system may NOT reject a cancer (even if the targt tumour cell may still be a relatively normal cell and self contained, basically none of the effectors are doing anything against it) |
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How can cancers evade the host response?
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-Cancer cells grow faster than they can be killed (not very convincing, cuz bacteria and viruses do the same thing)
-8*Reduced MHC expression: evade CTL recognition -NK cells have limited capacity for clonal expansion -**Altered glycosylation: of outer cell mb can mask TSA recognitin (carcinoembryonic Ag has 40-60% carbohydrates) -Soluble immune complexes block cytotoxic activity -**Immunosuprressice factors reduce host response -**Angiogenic factors: augment tumour cell nutrition -**Cancer cells become immortal and evade killing -**Cancer cells lose contact inhibition and requirement for attachment and can rapidly spread by blocking other sites |
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What happens with MHC deficient tumour cells?
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Evade cytotoxic T-cells but not NK-cells
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When can cytotoxic T cells kill cancer cells?
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Only if they express MHC I antigen
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Why do normal mice die faster than nude mice (lack T cells) if you look at a tumour that's lost its MHC I expression?
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Nude mice have compensations
-> have no T cells, .: have higher NK cell number (start with 400% more NK cells) |
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How can we potentially help the host response?
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-Detect cancers early when tumour is small
-Develop tumour growth regulatory agents -Develop anti-angiogenic anti-tumour agents -Augment NK surveillance vs cancer -Augment macrophage-mediated tumour cytotoxicity -Augment Tc-cell mediated cytotoxicity -Develop anti-tumour Ab (ADCC) -Block the malignant/invasive phenotype |
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What is active therapy of tumors?
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Vaccination with cancer causing virus or tumour antigens
-Boosts specific and non-specific immune mechanisms |
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What are the non-specific mechanisms for active therapy?
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BCG: potent immunogen, activates cellular defenses
Corynebacterium parvum: bacterial derived adjuvant, potent B cell activator Levamisole: poly-IC, RNA analogue, potent IFN-a production activator, which activates NK and macrophages |
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What are the specific active therapies?
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Preventative vaccines of tuour cells, cell extracts, purified or recombinant Ag idiotypes
ex: HPV-16 vaccine |
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What is passive therapy?
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Create the immune response in another animal, transfer the produced material from donor to recipient
-Nonspecific: LAK cells, cytokines Specific: Ab alone or coupled to drugs, pro-drugs, toxins or radioisotopes, bi-specific Ab, T-cells Combined: LAK cells and bi-specific Ab |
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What happens in non-specifc active immune therapy, for biolgical response modifiers (BMRs)?
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Adjuvantsand cytokines boost the non-specific host defenses
Targeting primarily innate defenses Works well if you detect the cancer early, but not if the cancer is well established |
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What is cytokine therapy for tumours?
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IL-2 creates cascular leak syndrome
Too much IFN-y has bad consequences All cells in the body contain receptors for TNF-a Basically trying to increase MHC-1 and II expression via IFN-y, activating innate and acquired immune responses |
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What are the tumour specific Ag immunotherapies?
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Tag tumor cell with tumour specific Ab (Ab vs something other than MHC, like CEA)-> tagged tumour cell for recognition by complement or any cell with an Fc-y receptor
-Tumour-specific drug-Ab conjugate Ab conjugated to toxin conjugate isinternalized and toxin kills the cell (can't do this multiple times cuz its not a humnan Ab and your body will develop Ab vs this) -Radionuclide-conjugated Ab which allows for killing of cancer cells by radiation (doesn't work well in vivo) |
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What can you monitor to determine the state of the patient?
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CEA levels in the blood
-> surgical removal of the colon causes CEA level to go down, but goes back up as the tumour spreads to the liver |
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How can tumours be made mor immunogenic?
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Transfecting them in co-stimulatory molecules (i.e. B7), augmenting the host response and making the patient's immune defenses more effective
->anti-tumour responses to tumour rejection Ag (TRAs) decline as the T-cells become suppressed or anergic |
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What is the future for cancer?
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Better early detection immunoassays
Cancer specific drugs to regulate/slow growth Cytokine therapies to optimize innate defnses More specific Ab-based therapeutics Cytokines to augment the host CMI response Gene therapy to increase tumour immunogenicity Gene therapy to reverse tumor cell immortality Better monitoring of the effect of treatment Development of vaccines to prevent cancer |
