cancer bioligy - hallmarks Flashcards
what is a neoplasm
an abnormal growth of tissue which can be benign or malignant (cancerous)
cancers can be classified according to their (tissue) origins. Name the 4 subtypes
carcinomas (80% all cancers) origin epithelial cell
sarcomas orgin from the mesenchymal cells (CT, mesoderm, neurons, bone muscle), rare only 1%.
leukaemia and lymphomas origin haemotopoietic cells 7% tumours.
glio/neuroblastomas origin from neuroendodermal tissue 1.5%
> not all fit into these 4 catergories e.g melanomas, lung carcinoma
name some of the ESTABLISHED hallmarks of cancer
excessive cell proliferation
can evade the growth inhibitory signals
can evade apopotosis/cell death
are replicatively immortal
induce angiogeneisis
can undergo metastasis and invasion
where do tumour cells orignate from?
From a single progenitor cell so all tumour cells are monoclonal cell
what is VEGF - vascular endothelial growth factor. how does it work?
it is a pro-angiogenic growth factor needed to promote the formation of new blood vessels > it initiates angiogenesis
> its regulated by hypoxia and binds to tyrosine kinase receptor to drive endothelial cell proliferation. Nitrous oxide can help to dilate blood vessels and destabilize vessel allowing a tip cell to start growing
> tip cell grows towards angiogenic stimulus and stalk (endothelial) cells form behind it which then hollow out and form a tube
> tip cells meet and merge allowing blood to flow. as new vessel matures, pericytes are recruited to stabilize the vessel structure
name the cellular changes that distinguish cancer cell from a normal cell
enhanced stimulation of growth factors
hyperplastic
metaplastic
Poorly differentiated
Looks abnormal
what is the difference between a benign and malignant neoplasm?
benign are non-invasive and localised. they exhibit hyperplastic and metaplastic characteristics
malignant are invasive, can undergo metastasis and spread to other locations and form secondary tumours
what are the subtypes of carcinomas
squamous cell carcinomas - this concerns the protective nature of the endothelium
adenocarcinomas - this concerns the secretory epithelial cells (into ducts or cavities)
> lung cell has both types of cells so lung cancers of these types are common
define hyperplastic and metaplastic
hyperplastic - excessive cell number as cell proliferation is dysregulated
metaplastic - ectopic cell replacement and usually seen in epithelial transition zones (e.g. cervix or oesphagus)
what is dysplasia/dysplastic tissue?
it is the abnormal development of cells. dysplasic tissue can be said to be in a premalignant state
> abnormal shaped cells
> hyperchromatic nuclei (increased staining)
> lacks differentiaton markers
- barrets oesophagus is a good example of this where squamous -> columnar cells. increased risk of developing oesophageal carcinoma
descibe the characterisics of a malignant tumour
they can spread and invade other tissues.
they do this by breaching the basement membrane and invade the stroma and undergo cell changes to become more motile
very poorly differentiated cells as they still lack the differentiation markers
discuss the rationale for having a screening programme
allows intervention before disease progresses onto a more severe state
this would allow the correct treatment plans to be carried out -> improve quality of life for patient (maybe even extend lifespan)
describe some features of a good screening programme
non-invasive - blood urine samples
a suitable treatment is available if positive
evidence that earlier treatment has a better patient outcome
name some of the screening tests used in the uk
colonrectal (bowel cancer) uses a faecal occult blood test which is non-invasive
cervical cancer uses a liquid based cytology to detect abnormal cells/ evidence of dysplastic tissue. BUT its time intensive, requires specialist training and invasive and requires repeat testing as low sensitivity
breast cancer uses a mammography which is an x-ray of soft tissue to identify tissue irregularities
> all of these screenings have shown success in reducing the mortality of cancer. screen for polyps in the colon
what are the roles of invadopodia and Src in metastasis?
invadopodia is an actin rich protusion of the basement membrane and can help to degrade it using matrix metalloproteases, allowing cancer cell to invade other tissues
Src is a tyrosine kinase that helps to meidate the breakdown of cell:cell contacts and cell:ECM contacts
> targeting these proteins can reduce the invasive ability of cancer cells
how do cancer cells become motile?
epithelial-mesenchymal transition (EMT) is a biological process that allows a polarized epithelial cell to undergo multiple biochemical changes that enable it to assume a mesenchymal cell phenotype and give cancer cells their motile phenotype.
> cell loses polarity, loss of cellular adhesion molecules such as E-cadherin, cytoskelton changes and increase in mesenchymal markers such as N-cadherin
SNAIL and TWIST are transcription factors that regulate gene expression so are overexpressed in cancer cells
give an overview of the metastasis process
microenvironment of tumour cell is key influential factor in its metastatic ability.
intravasion -> circulate -> extravasion -> colonise and undergo angiogenesis
> only 1 in 10,000 cells will set up a secondary tumour
name some of the EMERGING hallmarks of cancer
alterations in energy metabolism and avoiding immune destruction also contribute to cancer formation
THEY also have enabling characteristics such as genome instability and tumour promoting inflammation which help to drive tumour growth
how do cancer cells deregulate cellular bioenergetics? Can we use this to detect neoplasms?
~ wahrburg effect
GLUCOSE - - > PYRUVATE
instead of oxidative phosphorylation or anaerobic glycolysis. Cancer cells undergo aerobic glycoloysis why? Cancer cells grow very rapidly and are frequently hypoxic as a result. this means they are unable to perform OP.
aerobic glycolysis is preferred as precursors for other biosynthetic pathways are produced and 4ATP instead of 2ATP molecules per glucose molecule are produced
radio-label glucose and use it to locate tumour growth
what is the wahrberg effect?
used to describe an increase in glucose uptake and lactose production (glycolysis), even in the presence of oxygen (krebs cycle -> OxPhos). this is seen in cancer cells
to kill cancer cells they need to be deprived of glucose and oxygen
how can cancer cells evade immune surveliance?
normally T-cells recognise antigens on csncer cells and intiate apoptosis via intrinsic (caspase) or extricnisc (death receptor) routes
cancer cells can downregulate expression of these antigens and antigen-presenting molecules and over express immune checkpoint proteins + antiapoptopic (BCL-2X) proteins to evade the immune surveillance
how is tumour inflammation an enabling characteristic of cancer?
secretion of cytokines attract tumour associated macrophages. they in turn secrete additional cytokines, ROS and growth factors that activate transcription factors involved in cell proliferation and angiogenesis
ROS can also induce DNA damage and may result in mutations forming
> obesity linked to increased risk of gastric cancer as there is chronic inflammation ongoing
what is an organotropism
way to describe the tendancy of primary cancer cells to metastasize to specific organs and tissues
usually proximal to primary site (follows direction of blood flow) but can be distal too (often optimum environments are matched as seen in kidney thyroid nodule metastasis)
depends on the cross talk between cell and microenvirnoment (seed and soil hypothesis)
why are people taking immunosupressive drugs more at risk of developing cancer?
this reduces the tumour supressive effects of the immune system and increase the liklihood that of the cancer cells evading immune cell surveillance
can do this by downregualting antigen presenting molecules and antigens and overexpress immune checkpoints
why are mutations considered an enabling characteristic of cancer growth?
accumulation of mutations support carcinogenesis as there can be a cumulative effect of tumour supressor genes switching off and oncogeness switching on
> illustrated by colonorectal cancer where polyps form in epithelial lining, APC (growth inhibitory protein/ TSgene) is switched off = excessive cell proliferation as seen by polyps
and then Ras oncogene can be switched on and then a furthur mutation of p53 TSgene is turned off -> metastatic tumour
what is a driver mutation and what is a passenger mutation?
driver mutations are mutations that give rise to cncer cells/ give them a growth or cell survival advantage
> study by sanger institue shows the number of driver mutations vary between cancers ~ 11 for intestinal, 4 breast and liver
passenger mutations do not give any advantages to the cell
the environment is a risk factor for cancer so can you name some specific carcinogens in the environment?
radiation - ionizing, UV
benzopyrene - cigarette smoke
aromatic amines - from our diet
how do carcinogens increase risk of cancer
carcinogens can damage DNA and introduce mutations
or elicit a DNA damage response but the repair mechanisms are faulty –> introduce mutations which then accumulate in the cell
adenocarcinomas are derived from which cell A protective epithelial cell B peripheral never cell C connective tissue cells D secretory epithelial cell
OPTION D
protective epithelial cells form squamous cell carcinomas
> 80% all tumours are carcinomas
why do epithlial tumours make up the majority of cancerS?
they are exposed to the environment and many carcinogens (UV radiation)
epithelial cells also have a high turnover and are continuously dividing and replicating so more likely for mutations to ocuur and mistakes to happen during DNA replication
in females, why do all cells of a tumour have the same inactive X-chromosome?
tumour cells are monoclonal so arise from a single progenitor cell so the same X-chromosome is inactivated
during metastasis, cells undergo Epithelial-Mesenchymal transition where there is:
A increase in cell polarity
B loss of cell adhesion
C down regulation of SNAIL and TWIST TFs
D decrease in N-cadherin expression
E decrease in cell adhesion and N-cadherin expression
OPTON B
snail and twist are upregulated as they activate genes making cell more motile so it loses cell adhesion
loss of E-cadherin and gain in N-cadherin as that is a mesenchymal marker
HPV is an oncogenic virus that is a risk factor for cancer. Describe how an infection can lead to cancer
HPV (DNA tumour virus) can produce oncoproteins to degrade the tumour supressor protein Retinoblastoma so it no longer respresses the TF E2F
Therefore, there is a continuous activation of the cell cycle
> there are also retroviruses e.g. HTLV-1 that has been implicated in leukaemia and they encode mutated forms of gene
how do bacterial agents increase risk of cancer incidents
they can cause chronic INFLAMMATION which helps to promote tumourgenesis - h.pylori is implicated in gastric cancer
also bacteria can hijack cell signallng proteins involved in cell proliferation and survival
what do antioxidants do
substances that can prevent or slow damage to cells caused by free radicals
endogenous reactions and normal metabolism in our body create ROS which can be combated with antioxidants present in the blood - not in the tunica i
how do oestrogen receptors promote tumourgenesis?
I think EVICEDNCE OR DIAGRAM OF THIS
*normal* metabolism of oestrogen produces metabolites that can be processed with p450 to produce estradiols which are then detoxified. but in (breast) cancer, estradiols and quinone products accumulate and they can form adducts with the DNA and also be a source of superoxide radicals -> introduce mutations into DNA
why is ioninising radiation a carcinogen?
ionizing radiation can directly ionise DNA and displace electrons or indirectly damage DNA molecules through the creation of ROS
why is UV radiation a carcinogen?
UV radiation can induce the formation of CPD and 6-4 photoproducts that distort and kink the DNA structure,
This means that DNA polymerase may misread bases and incorporate mutations into DNA
> p53 tumour supressor gene is the most commonly affected
describe the general mechanism of chemical carcinogens
[the chemical ] is an electrophilic molecule will interact with DNA nucleophilic sites - the pyrimidne and purine ring.
forming ADDUCTS with DNA and can lead to depurinations and deletions/ missense mutations
give examples of direct and indeicrect chemical carcinogens
direct carcinigens are uncommon but can include dimethly sulphate and nitrgoren mutard
indirect carcinogens are generally water soluble and unreactive but get processed in our body by cytochrome450 to create the electrophilic centre. Examples include polycyclic aromatic hydrocarbons (PAHs) (cigarette smoke) & aromatic or heterocyclic amines (cooked meats)
what is a protooncogene? How does it become an ocongene. what is ists relevance in cancer biology?
protoncogenes work to promote cell survival/proliferation and inhibitit apoptosis
In cancer, oncogenes are GOF dominant mutations of protoncogenes resulting in excess cell proliferation
what mutations can result in an oncogene forming?
so a GOF dominant mutation results in oncogene forming
this can happen through gene amplification, chromosome rearrangements and also just mutations in the DNA bases causing protein to be overproduced
also chromosome rearrangements can create fusion proteins as seen in chronic myeloid leukemia
what are tumor suppressor gene, examples ? How can they lead to cancers?
essentially the opposite of protoncogene so inhibit cell proliferation and promote apoptosis by inhibiting cyclin dependant kinases (CDK)
in cancer, there is LOF recessive mutation (in both alleles) resulting in excess cell proliferation and survival
> p53, retinoblastoma gene, p10
what mutations can result in an TS forming?
so a LOF recessive mutation results in tumour supressor gene forming.
this can happen through gene or whole chromosome deletions, chromosome rearragement, mutations in the DNA bases = nonfunctional protein or epigenetic silencing
> Mutations in genes coding for chromatin-remodelling complexes e.g. SWI/SNF so TS gene switch off
why are tumour supressor genes the most commonly mutated genes in cancer (p53) instead of protonocgenes and caretaker genes
well TS genes are formed from a recessive mutation so a person can have a predisposition to the disease
> seen in Hereditary retinoblastoma (loss of Rb TS gene results in childhood retinal tumours and other tumours later in life)
> Familial adenomatous polyposis (FAP) (loss of APC gene – formation of colon polyps which if untreated could develop into malignant colon cancer
what are caretaker genes? How are these genes relevant to cancer?
these encode proteins to repair or prevent DNA damage
in cancer, there can be LOF recessive mutation which will downregulate rate of DNA repair -> mutation accumulation
what mutations can result in an caretaker cancerous gene forming?
What would the result of this?
so a LOF recessive mutation results in carcinogenic caretaker gene forming.
this can happen through gene or whole chromosome deletions, mutations in the DNA bases = nonfunctional protein or epigenetic silencing ~ methylations
this would result in different DNA repair mechanisms becoming faulty or less efficient
DNA mismatch repair, Nucleotide excision repair
Double stranded DNA breaks
why are bacteria and viruses (infectious agents) considered carcinogenic/ increase cancer risk # specific example
> HPV can encodeoncogenic viral proteins that block tumour suppressor gene of Rb facilitating excess cell proliferation
HLTV-1 retrovirus can encode mutated versions of genes, disrupting function of gene and promote tumorgenesis
bacteria such as H.pylori can cause chronic inflammation and then promote cancer formation
which is false?
A driver and passenger mutations do not cooperate to drive cancer
B activation of oncogenes and loss of TS gene are both needed for tumor development
C cancer cells all show the same basic genetic homogeneity
D carcinogens are solely responsible creating DNA mutations
E Tumour mass can show heterogeneity
OPTION D IS FALSE
carcinginogens can create DNA damage (interrupt the DNA repair mechanisms)
But, DNA mutations can occur spontaneously, during DNA replication, error in damage repair
or you can just have a genetic predisposition in the first instance
which intermediate is NOT formed during radiolysis?(reaction between ionizing radiation and water) A hydrogen peroxide h2o2 B superoxide radical C hydroxyl radical HO• D water
radiolysis - the dissociation of a molecule following ionizing radiation
WATER IS NOT FORMED
h2o2 most unstable and most reactive. HO• least reactive but most stable so more problematic
exposure to benzopyrene is most commonly associated with which cancer? A lung cancer B breast cancer C leukemia D colorectal cancer
lung cancer- as its found in cigarette smoke, its a polycyclic aromatic hydrocarbon and can form adducts with DNA , promote G-> T transversions and this can lead to errors in DNA and introduce mutation into DNA.
which is true?
A retroviruses major cause of cancer in humans
B protooncogenes are altered form of normal gene
C gene amplification can be oncogenic
D tumorgenesis does not occur via epigenetic modification
OPTION C IS TRUE
retrovirus are implicated in leukemia in humans but it affects animals more. and also leukimia makes up nly 7% tumours
majority of human cancer are carcinoma due to mutations in p53`
GOF mutation of which gene will help to bypass restriction point controls A cyclin D B P16 C Rb (retinoblastoma) D p53 E PTEN
some of these are TS genes. some of these are kinases and phostpahta
OPTION A
- GOF associated with protooncogenes and cylin D is the only proto-oncogene here
what are the roles of CDK and cyclins in the cell?
can you name some examples?
Cyclins regulate cyclin-dependent kinases (serine threonine kinases)
they are involved in the cell cycle and act to regulate it
> they are all in effect proto-oncogenes as they help to drive cell proliferation processes
there are specific cyclins for each stage of the cell cycle and they peak in number and get degraded as we move from each stage
examples include CyclinD+CDK4/6 CyclinE+CDK2
what can CDK activity be influenced by?
CDK can be inhibited by binding to CDK inhibitors p15, p16 p21 p27
phosphorylation and phosphorylation
binding to its specific cylin!
in the cell cycle, there are cell cycle checkpoint regulators. DEscribe one regulator and mechansim of action
Rb is the main regulator for G1->S phase. It is bound to TF E2F.
E2F becomes active when Rb becomes phosphorylated by CDK4/6
how does CDK4/6 become activated? well when cyclin D binds to it and inhibitor p16 dissociated
TF is now free from Rb and can transcribe proteins needed for DNA replication, allowing cell cycle to progress
what happens in cancer that affects the cell cycle?
there is a deregulation of checkpoint markers
Overexpression of the proto-oncogene for cyclin D
Loss of TS genes for p16 CDK inhibitor
Loss of TS gene for RB
>HPV can also encode oncoproteon E7 to degrade Rb
what is p53?
it is the most important TS gene.
It is a transcription factor and can transcribe genes to put the cell cycle in arrest if the DNA becomes damaged giving time for DNA repair or can initiate apoptosis if DNA cannot be repair (facilitates DNA repair so thats why it isn’t a caretaker gene)
what is a common muttion in p53 gene
commonly a SNP in the gene. Hotspots in the DNA binding domain of the TF so p53 cannot perform its function
so the p53, the trancription factor cannot bind to the promoter of DNA and initiate trancription therefore the DNA stays damaged and does not undego apoptosis
Also 50% of 053 mutations are due to methylation. How interesting
where are cylins and cyclin dependent kinases found in a cell?
they are both found in the cytoplasm. The kinases are always in the inactivated form and usually bound to a repressor protein
once bound to their specific complementary cyclin, they become activated and can phosphorylate target protein and enable next phase of cell cycle to continue
once cyclin is degraded, the CDK returns to its inactivated form
what is p53? describe what itdoes
it is the most important TS gene. it is a transcription factor and can initiate the DNA damage response by promoting apoptosis and transcribe genes to put cell cycle into G1 or G2 cell cycle arrest
> increase in p21 and p27 CDK inhibitors
this allows TIME to fix the DNA. if it cannot be repaired. apoptosis will be initiated
why is p53 a TS gene instead of a caretaker gene
it facilitates DNA damage repair but p53 isn’t actually directly involved in the process of repairing DNA so it merely suppress tumours
what is a common mutation in cancers
p53 is the most commonly mutated gene in cancer as a mutated p53 will allow cells with DNA damage to survivive
most commonly a SNP mutation in p53 at the DNA binding domain so p53 cannot bind to the promoter of the genes and transcribe genes involved in DNA damage repair, cell cycle arrest or apoptosis
describe the general mechanism of a growth factor receptor
> these are tyrosine receptor kinases
ligan binds to extracellular domain which results in receptor mediated dimerisations and activates the receptor
trans auto-phosphorylation of the tyrosine residues on intracellular region.
this activated dimer can then activate relay proteins that can dock onto the kinase
describe the actions of HPV oncoproteins
- oncoprotien E7 can degrade the retinoblastoma TS protein which then results in dyregulated cell cycle as E2F TF is free to transcribe genes involved in cell proliferation and survival
- oncoprotien E5 can activate PDGFReceptor which can then drive cell proliferation (particularly in wound healing)
what is an important GF thats inplicated in cancers
Epidermal GFR (EGFR) as its associated with differentiation of epithelial cells and as we know, carcinomas make up 80% of human cancers
more mutations in EGFR is associated with increased ability for cancer cells to metastasize and resistant to treatment so poorer patient outcome/survival and also advanced disease progression
name some patways that EGFR is invovled in
RAS/RAF MAPK pathway - cell proliferation
STAT transcription factor
P13K and PKB - inhibits apoptosis
» all pathways needed for normal epithelial cdll function and miatenence
describe how EGFR signalling can be maintained # normally
phosphatase activity can shut down signal cascade but mainly regulated by receptor degradation
> activated tyrosine kinase recruits target proteins and simultaneously recruits Cbl - a ubiquitin ligase to shut down the signalling pathway = TIGHT CONTROL
> Cbl ubiquinates tryrosine residues stimulating process of receptor internationalization and directs recprot into endocytotic pathway
> receptor is degraded by hydrolytic enzymes in lysosome
this is DIFFERENT as usually the receptor gets recycled so to get more EGFR it has to be transcribed which would take LONGER!
what happens to EGFR signalling in cancer? // what causes (downstream) signalling to be dyregulated
mutations in signal transduction molecules like pi3K, Ras,Raf so they are permanently so stimulate the cell cycle and drive oncogenesis
> but this means drugs that target the EGFR receptor (tarceva) will no be effective as the mutation is below tarceva binding domain
what happens to EGFR molecule in cancer ?
- increase in ligand (EGF) production due to OE. via autocrine stimulation from cancer cells
- increase in EGFR due to OE/gene amplification/mutation or a strong promoter (defects in p53 maybe)
decrease in Cbl activity will also contribute to increase in EGFR expression - constitutively active EGFR (so same amount but always on). in glioblastomas, there is EGFR||| deletion variant which results in most of ligand binding domain of receptor missing = permanently active -> Pi3/PKB pathway is o``n…cell proliferation and survival
> quite hard to treat as cells are resistant to treatment as cell survival, proliferation and motility increase
cancer cells can evade apoptosis. which route is the most commnonly mutated?
the intrinsic/mitochondrial route is most commonly disrupted in cancer compared to extrinsic route
> intrinsic route would be stimulated by cells showing dna damage during the cell cycle stages
mutations in p53 are common so will prevent intition of apopotosis== disruption and evasion of apoptosis
how can cancers evade apoptosis (molecular changes)
promoted by RTk i dont get
cancer cells can OE antiapoptopic molecules BCL-x/2 - this can happen by chromosome translocation of BCL gene with a strong promoter
LOF of proantiapoptopic molecule p53, bax,bad
> > all results in excess cell survival and proliferation promoted by receptor tyrosine kinases
which of the following os the molecular target of the drug TARCEVA
A extracellular domain of EGFR
B tyrosine kinase domain of EGFR
C EGF the ligand for EGFR
D transmembrane domain of EGFR
OPTION B
tarceva competes with ATP (phosphorylation) for the active intracellular tyrosine kinase domain of EGFR
blocking downstream signalling actions, preventing cell proliferation and promoting apoptosis of damaged cells restoring normal cellular function
What are the classic/cardinal signs of inflammation
PRISH - these are localised to sight of injury
- pain due to relase of chemical mediators like histoonde and bradykinin
Redness and swelling and heat due to vasodilation increasing blood flow to areas
Also helps with immune recruitment
What is LAD-1
Leukocyte adhesion deficiency autosomal recessive where the adhesion molecule intergrinB2 is deficient
So we cannot recruit immune cells from circulation so we are susceptible to more recurrent bacterial infection
