Term
|
Definition
| Overproliferation of normal cells |
|
|
Term
|
Definition
| Normal cells in wrong place |
|
|
Term
|
Definition
| cells that appear abnormal |
|
|
Term
|
Definition
Proliferation independent of signals
Immortality - ALT/hTERT
Avoides apoptosis
Angiogenesis
Metastasis |
|
|
Term
| What (non genetic factors) can increase the likelihood of cancers? |
|
Definition
Radiation
Carcinogens
Inflammation
Infection
Immune suppression |
|
|
Term
| How does cancer normally metastasize? |
|
Definition
| Breaks through to the lymph/blood vessel, enough cells spread and survive, and form new tumours |
|
|
Term
| What does wild type Rb do, and how does loss of this function lead closer to cancer|? |
|
Definition
| Controls cell proliferation by binding to E2F transcription factors. When highly phosphorylated by CDKs,it releases it. Normally, during R point, to allow replication. Pathway disrupted in most tumours to allow passing of cell cycle checkpoints. |
|
|
Term
| How does gene conversion normally occur? |
|
Definition
| Normally DNA polymerase copies some of the homologous chromosome instead, as part of a repair process. This causes loss of heterozygosity |
|
|
Term
|
Definition
| Can cause senescence and apoptosis, but also activate several cancer deefences such as CDK inhibitors and anti-angiogenesis genes by acting as a TF |
|
|
Term
| Why is p53 often highly expressed in tumour cells? |
|
Definition
| Most mutations are missense, preventing it from activating its negative feedback loop so it is not stable, and mutations in one copy allow it to form a tetraner which interferes with the WT produced from the other allele |
|
|
Term
| Useful facts for melanoma intro: |
|
Definition
5th most common cancer in uk
Women are twice as likely to get it, less likely to die
More common in young people |
|
|
Term
| What is the most important melanoma pathway? |
|
Definition
|
|
Term
| What is the familial melanoma pathway to cancer? |
|
Definition
CDKN2A - gene for p16, inhibitor of Rb, has a germ line mutation
Also some mutations in CDK4 that disrupt interactions with p16 (rare) |
|
|
Term
| Normal BRAF melanoma pathway to cancer? |
|
Definition
Activation of Ras pathway by BRAF (50%) mutations
Normally V600E (90%) mutation
Structure of BRAF changes so no longer needs upstream signalling (also reduces ERK negative feedback - makes it 'hyperactive') |
|
|
Term
| Normal NRAS melanoma pathway to cancer? |
|
Definition
Activating mutation in NRAS (30%)
Loss of PTEN (downregulates PIP3, surival and inhibition of apoptosis)
P13K activating mutations
AKT amplification - inhibition of apoptosis, cell proliferation |
|
|
Term
| What is downstream of ERK (melanoma)? |
|
Definition
Cyclin D1 - drives cell cycle
MITF - cell survival pathway
negative feedback loop of MAPK |
|
|
Term
| What drug is used for BRAFV600E mutations and how does it work? |
|
Definition
Vemurafenib
Binds preferentially to BRAFV7600E over WT - targets BRAF monomer
Blocks ERK phosphorylation |
|
|
Term
| What are the issues with the drug that inhibits BRAF? |
|
Definition
| Causes conformational change of WT BRAF so it can dimerize with CRAF and lead to cell proliferation - another form of cancer normally occurs |
|
|
Term
| What are the general methods for cancer resistance? |
|
Definition
Amplification of gene
Splice gene with other variants
Alternate pathway
Mutation lower down
Increased efflux
Decreased influx |
|
|
Term
| What is the structure of the gut (that we need to know)? |
|
Definition
Crypts with stem cells constantly producing cells - 300 a day
Constantly moving upwards
Shed from the villi |
|
|
Term
| Why is the shedding of the gut lining important? |
|
Definition
| its a possibly accidental extra defence against cancer - have to develop cancer before being shed |
|
|
Term
| What are Polyps, and what is the difference between hyperplastic polyps and adenomas? |
|
Definition
| Masses that protrude into the colon, benign, malignant |
|
|
Term
| What are the normal steps for sporadic CRC development? |
|
Definition
Loss of APC and LOH
DNA hypomethylation
Activation of K-ras (both)
Loss of TSG on 18q and LOH
loss of p53 and LOH |
|
|
Term
| What is FAP short for, what gene is mutated, and what does the disease cause? |
|
Definition
Familial adenomatous polyposis coli
APC
Autosomal dominant condition causing a mass of polyps some of which will likely be malignant, chromosomal instability |
|
|
Term
| Why do mutations in APC cause FAP? |
|
Definition
| Most occur in the mutator cluster region (MCR), and result in a truncated protein that lacks a beta catenin regulatory activity, and also cannot remove Tcf4 from beta catenin. When APC is not present, Tcf4-beta catenin complexes are formed that stimulate cell proliferation and inhibit apoptosis, and beta catenin also activates Myc which upregulates Cdk4, required for G1 and may lead to phosphorylation of pRB |
|
|
Term
| What are the secondary way mutant APC does dmage? |
|
Definition
cannot bind ASEF in order to prevent it decreasing E-cadherin cell-cell adhesion, causing aberrant migration where cells arent shed
No longer stabilizes spindles causing chromosomal instability |
|
|
Term
| What does HNPCC stand for, whats another name for it, what does it cause? |
|
Definition
| hereditary non-polyposis colorectal cancer, lynch syndrome, Cancer progression can go up to 3x quicker than normal and more likely to get colorectal cancers and several others |
|
|
Term
| What genes are mutated normally in HNPCC, and how does this cause disease/ |
|
Definition
| MSH2 and MLH1, Mismatch repair genes, MSH2 forms a heterodimer with MSH3/6 before binding to the mismatch, and this heterodimer is then bound by a heterodimer of MLH1 and PMS2 - without these two, cannot repair mismatches properly |
|
|
Term
| What does the lack of mismatch repair in HNPCC normally lead to for TGF beta? |
|
Definition
| Tumour cells are normally resistant to it as a consequence of mutations that inactivates its receptor - normally inhibits growth |
|
|
Term
| What are the types of brain tumours? |
|
Definition
Gliomas - astrocytomas and oligodendrocytomas
Neuronal tumours - medulloblastoma |
|
|
Term
| What are issues with most CNS tumours? |
|
Definition
| chemo mostly cant cross blood brain barrier and surgery not often an option |
|
|
Term
| Which syndromes increase the rate of medulloblastomas? |
|
Definition
Turcot's syndrome - variant of FAP
Gorlins syndrome - also affectss non-melanoma skin cancer |
|
|
Term
| How does Turcot's syndrome also raise medulloblastoma rate and does this happen sporadically? |
|
Definition
| Loss of APC, Beta-catenin stabilizes and associates with Tcf-lef, activating c-Myc, Yes in around 18% of patients |
|
|
Term
| What is Gorlin's syndrome? |
|
Definition
| Autosomal dominant, increases basal cell carcinoma and medulloblastoma rates |
|
|
Term
| What is the pathway that leads to cancer in Gorlin's syndrome? |
|
Definition
| Mutations in ptch (Shh receptor) lead to de-repression of Smo, causing release of Gli into the nucleus, acting as a transcriptional activator |
|
|
Term
| Apart from PTCH mutations what is needed for Shh subtype medulloblastoma? |
|
Definition
| P53 knockout will do it, but not seen in many tumours. Unknown what second event is needed, not LoH in PTCH - haploinsufficiency |
|
|
Term
| What is the difference between the Shh and WNT subtypes of medulloblastoma? |
|
Definition
Shh - young children, poor prognosis, many anaplastic, desmoplastic cells, PTCH1 inactivation, located within cerebellar hemispheres
WNT - Older children, highly curable, activation of CTNNB1, located in IV ventricle and dorsal brainstem surface |
|
|
Term
| What is the model for WNT medulloblastoma operation? |
|
Definition
| Activation of CTNNB1 (Beta catenin), in brainstem promotes migration and proliferation, if p53 KOed, classic MB develops |
|
|
Term
| What are the treatments for medulloblastomas? |
|
Definition
| Inhibit shh pathway - ShhAntag-691, a Smo inhibitor, showed increased apoptosis, long term survival and decrease in proliferation and elimination of tumours |
|
|
Term
| What are transit-amplifying cells and why are they relevant? |
|
Definition
| Highly proliferative cells that are daughters of stem cells, the middle steps between stem cells and fully differentiated ones, they can become cancer stem cells |
|
|
Term
| What are cancer stem cells? |
|
Definition
| Dividing cells that 'drive' the tumours, non-differentiated |
|
|
Term
| What would protect stem cells from becoming cancerous? |
|
Definition
| In areas more distant from sources of damage and protected by mucins, have drug pumps and strand retention to protect against genotoxic damage |
|
|
Term
| What would make stem cells good cancer stem cells? |
|
Definition
| Immortal and around for a long time |
|
|
Term
| Why would TA cells make good cancer stem cells |
|
Definition
|
|
Term
| How do we know some cancer stem cells are TA and some are stem cells? |
|
Definition
| Frequency of TERT/ALT mutations - if none are seen, likely stem cells as they are already immortal. Very varied amounts of mutations, some cancers have a lot, some none |
|
|
Term
| What are the four grades of Gliomas? |
|
Definition
I - benign
II - slow but non-operable
III - death in a few years
IV - Glioblastoma multiforme <5% make 5 years |
|
|
Term
| What was the experiment used to show astrocytomas originate from NSCs? |
|
Definition
TS gene surrounded by loxP sites
Nestin ( a marker for NSCs) promoter near oestrogen receptor linked Cre
Tamoxifen used to translocate Cre to nucleus to cut out TS gene
All get high grade astrocytomas - but only when done in brain stem - where NSCs are |
|
|
Term
| How do stem cells affect therapies? |
|
Definition
Slow dividing - therapies target actively replicating cells
Drug pumps
Have improved DNA repair systems so most likely to escape and make a new tumour |
|
|
Term
| What causes leukaemia symptoms? |
|
Definition
| Cells being 'crowded out' leading to reduced platelets dysfunctional white cells and a deficiency of red |
|
|
Term
| What types of leukaemia are there? |
|
Definition
Acute and Chronic
Lymphocytic (B and T cells) or Myeloid
4 combinations |
|
|
Term
| What type of leukaemia do children get? |
|
Definition
|
|
Term
| What is the most common cause of CML and how does it cause CML? |
|
Definition
| The philadelphia translocation between abl-bcr creating an abl/bcr fusion that acts as a constitutively activated tyrosine kinase that can activate the Ras pathway, Jak-STAT pathway and Myc |
|
|
Term
| What do the three variations of the philadelphia translocation cause? |
|
Definition
ALL
CML
CNL - chronic neutrophilic leukaemia |
|
|
Term
| Why do leukaemias exhibit specific translocations |
|
Definition
| They are non-random, and some cause clonal expansion - only those that give a selective advantage will spread |
|
|
Term
| What is the most well kncown treatment of the philadelphia translocation and what are the issues with it? |
|
Definition
| imatinib/Gleevec is a inhibitor of only 4 tyrosine kinases - including bcr-abl. Unless progression to blast crisis has occurred, normally succesful. Those who have reached blast crisis normally relapse due to a mutation in the bcr-abl gene that prevents Gleevec binding to catalytic cleft ( a minority just upregulated bcr-abl) - solved as we have new inhibitors now |
|
|
Term
| What are the advantages of traditional therapies such as radiotherapy, chemotherapy and surgery? |
|
Definition
V toxic to target cells
Dont need to know much about tumour
2/3 can be highly targeted |
|
|
Term
| What are disadvantages of traditional therapies such as radiotherapy, chemotherapy and surgery? |
|
Definition
Surgery can be difficult and damaging
toxicity not limited to cancer cells
causes more DNA damage - can actually restart cancer |
|
|
Term
| What are the most common types of targeted tehrapies |
|
Definition
Antibodies
Small molecule inhibitors
Angiogenesis inhibitors
Biological therapies |
|
|
Term
| Why are oncogenes better targets than TS genes? |
|
Definition
| Need to inhibit rather than restore fucntion |
|
|
Term
| What is the difference between children and adult tumours? |
|
Definition
| Childrens cells are already more proliferative |
|
|
