molecular basis of cancer Flashcards
5 general characterisitcs of cancer
- increased and uncontrolled growth
- immortality
- loss of differentiation
- invasion
- metastasis
what begins cancer
non-lethal genetic damage
- inherited or env.
- single cell and expansion from it
what are genetic requirements for CA
multi-step hits
- change must be permanent and passed on
where does heterogeneity in CA come from
tumor progression and selection for those best able to survive
2 general ways genes are altered in CA
- mutation (inherited or aquired)
2. epigenetics
4 types of mutations
- point
- deletions/insertion
- amplification.copy number alteration
- translocation
- 8 key features of molecular basis of CA
- self-sufficiency of growth signals
- insensitivity to growth-inhibitory signals
- defects in DNA repair
- evasion of apop
- limitless replicative potential
- sustained angiogenesis
- ability to invade and metastasize
- evasion of host immune system
3 types of oncogenes involves in self-sufficiency of growth signals
- oncogenes - promote cell growth in abscence of growth signals
- proto-oncogenes - non-mutated “normal” genes
- oncoprotein - product of oncegenes
what do oncogenes lead to
acceleration of normal growth patterns
5 steps to normal cell prolif that can be hijacked
- binding of GF to receptor
- transient and limited activation of GF receptor
- transmission of transduced signal
- induction and activation of nuclear regulatory factors
- entry and progression through cell cycle
5 types that oncoproteins may be
- growth factors
- GF receptors
- signal transduction molecules
- nuclear regulatory proteins
- cell cycle regulators
what is normal function, mutation, and clinical implication of Her2-neu
normally - growth factor receptor
mutation - many additional copies
clinical - many breast cancers over express and is associated with poor outcome
what is normal function, mutation, and clinical implication of Ret
normally - glial growth factor receptor in neuroendocrine cells - important for tissue migration in fetus
mutation - translocation and fusion product seen in thyroid CA, aquired point mutations
clinical - MEN type 2 and familial thyroid CA
what is normal function, mutation, and clinical implication of Ras
normally - receptor associated signal transduction molecule, normally self-limited by GTPase
mutation - mutated forms in many CA and continued signalling
clinical - testing for Ras in lung CA predicts responses
what is normal function, mutation, and clinical implication of Abl
normally - signal transduction molecule that can be activated without receptor binding
mutation - chromosomal translocation causes Bcr-Abl which is constinutively active (philly)
clinical - chronic myloid leukemia and acute lymphoblastic leukemia, target of imatinib
what is normal function, mutation, and clinical implication of Myc
normally - nuclear regulatory protein, early response gene, increase in activity
mutation - amplification or translocation
clinical - amplification seen in breat, colon and lung, translocation seen in burkitts lymphoma
what is normal function, mutation, and clinical implication of Cyclin-D
ormally - cell cycle regulator - acts with cyclin dependent kinases to move the cell through the cell cycle
mutation - amplification or translocation
clinical - amplification seen in breast, esopha. and liver CA, translocation seen in melanoma and sarcomas
- what is responsible for insensitivity to growth inhibition
tumor supressor genes (brakes) - loss of function in mutations
3 things a tumor supressor gene does
- regulate or halt cell growth
- checkpoints and brakes on cell cycle
- linked to apoptosis pathways
5 things that a tumor supressor may be
- transcription factor
- cell cycle inhibitor
- signal transduction molecule
- cell surface receptor
- regulator of cellular response to DNA damage
4 key tumor supressor genes
- Rb ( cell cycle inhib)
- Cyclin dependent kinase inhibitor (p16)
- APC (inhibitor of cell transduction)
- p53
2 main cell cycle checkpoints for DNA damage
- G1/2 (Rb, p53, ATM, ATR)- assess damage and commit to replication or not
- G2/M (p53) - reassess and repair before mitosis
what is normal function, mutation, and clinical implication of Rb
normally - cell cycle regulator
- blocks entry of cell into S phase
- bind E2F and stops transcription
- if activated then release E2F and transcription occurs
mutation - 2 hits required to mutate Rb - may be inherited or aquired
clinical - retinoblastoma
what is loss of heterozygostiy
heterozygosity does not affect cell behavior, but need both changed to get outcome
what is normal function, mutation, and clinical implication of cyclin dependent kinase inhibitor
normally - inhibits CDK to stop cell cycle at various points
clinical - mutations seen frequently in CA
what is normal function, mutation, and clinical implication of APC
normally - inhibitor of cell signal transduction by degradation of B-catenin from WNT signalling
clinical - germline mutation leads to familial adenomatous polyposis, may also be involved in sporadic colon CA via 2 hit hypothesis
POINT 3 what are defects in DNA repair
normally check DNA and repair if something is wrong
4 important DNA repair genes
- p53
- mismatch repair genes
- nucleotide excision repair genes
- homologous recombination repair genes
normal functions of p53
prevents propagation of of genetically damaged cells - quiesence, senescence, apop
how does p53 work
normally complexed to MDM2 and when cell stressed will release p53
clinical implication of p53
most common target of mutations
li fraumeni- germline mutation leads to many cancers
what are key genes in HPV
E6,7,2
how do low and high risk HPV strains differ
low risk - DNA remains in ring outside cell
high risk - integrated into cell
what is funciton of E2
supresses activity of E6 and E7
what is function of E6 and E7
E6 - binds to p53 - activates telomerase
E7- binds to Rb- displaces E2F
what is net result of HPV mutations
inactivate 2 key tumor supressor genes leadin g to cell proliferation
what is normal function, mutation, and clinical implication of mismatch repair genes
normally - correction of chance errors that occur in DNA rep
mutation - loss of mismatch leads to microinstability
clinical - sporadic colon CA and lynch syndrome - increased risk of colon and endometrial CA
what is nucleotide excision repair
- UV dameg causes pyramindine crosslinking
- these must be removed by exision
if not - xeroderma
what is homologous recombination repair
chemical crosslinking causing DNA crosslinks
- BRCA1 and 2 are part of repair pathway
what is non-homologous end-joingin pathway
- salvage pathway
- broken chromosomes joined end to end
- increase instability
- evasion of apoptosis - normal function of apoptosis
damaged cells that cannot be repaired in G1 will undergo apop
what is BCL-2
anti-apoptotic factor
- 85% of lymphoma show over expression of BCR-2
why do cells normally stop replicating
- reach hayflick limit
- progressive shortening of telomeres
- then p53 shuts down - in absence of p53 itll try and end-join
- causes instability and cell collapse
where is telomerase normally expressed
germ cells and not somatic cells
what is importance of telomerase in CA
activity present in 90%+ of CA
- why is angiogenesis needed
- provide nutrients
2. access for metast
what is normal angiogenesis
balance between angiogenic and anti-angiogenic factors
how does tumor make angio
increase angiogenic factors - eg VEGF
inhibit anti factors - p53
- what is ability to invade and metastasize
- invasion of cellular matrix
2. vascular dissemination and homing of tumor cells
4 requirements for cells to invade and met
- dissociation of neighbour cells
- degradation of ECM
- attachment of novel ECM components
- migration of tumor cells
how does CA dissociate neighbor cells
breaks in cadherins of adjacent cells
how does CA degrade ECM
may secrete proteolytic enzymes or induce other cells to do so
how does CA attach to ECM
remodelling of ECM leads to generation of novel binding sites
how does CA move
multiple genes and factors at work
what do tumor cells do in blood stream
- may clump or associate with platelets
- activate coagulation factors
- exit at distant sites
2 ways tumors pick where to go
- drainage sites
2. specific tropisms for some CA
