Hallmarks of Cancer Flashcards
what is cancer?
- Uncontrolled proliferation of abnormal cells in a tissue
- May lead to the invasion and spread of these cells into other tissues
- Caused by genetic mutation or hijacking growth pathways by pathogens
- neoplasia - abnormal/continuous growth of cells with loss of homeostatic control
in what group of people is cancer most prevalent?
60% cancers occur in people over 60 – ageing disease
is cancer a man-made disease?
Despite being one of the world’s leading causes of death today, cancer is virtually absent in archaeological records compared to other diseases - which has given rise to the idea that cancers are mainly attributable to modern lifestyles and to people living for longer
what evidence is there for cancer in archaeological times?
An Egyptian mummy ~200BC was put through a CT scanner.
- Showed multiple lesions in the spine.
- Consistent with prostate cancer
breast cancer was treated by cauterization
whats the oldest known case of metastasis?
Prostate cancer commonly metastasizes in bone and spine
- Found metastases in 2,700‐year‐old skeleton – can see the lesions in the spine – dense lesions with holes next to them
what were the early cancers of occupational cancer?
Percival Pott discovers “occupational cancer”
- Scrotum carcinoma in chimney sweeps (chimney smoke condensates)
- Danish sweepers guild urged their members to take daily baths - reduces rate of scrotal cancer
how can chemicals cause cancer?
Gardeners who spread coal tar got skin cancer on their hands
- Coal tar causes skin cancer when painted on rabbits’ ears
- Directly implicated chemicals in cancer causation.
where does cancer arise from?
from single cells which undergo mutations and grow uncontrolled- forms a tumour
what is the cellular basis of neoplasia?
series of hits/events:
- A cell with a beneficial mutation or epigenetic change may continue to divide until a collection of identical cells or clone is formed.
- Cells from this clone may acquire new genetic and epigenetic changes which further enhance their growth and survival e.g. GOF in metastasis
Need sequential acquisition of mutations to become cancer and then become metastatic
why are organoids useful?
- cancer cell cultures grown in 2D do not recapitulate in vivo tumours - cells change over time and accumulate mutations
- organoids don’t change over time in culture
- 3 mutations induced in normal colorectal organoids alone can cause CRC e.g. p53
- 1 more addition can then induce metastasising CRC
what is the scale of cancer?
18.7 million new diagnoses in 2022
9.6 million deaths in 2022
Cancer is the second leading cause of death world wide
what are the external factors which can promote cancer?
Physical carcinogens (UV light, ionizing radiation)
Chemical carcinogens (asbestos, components of tobacco, aflatoxin arsenic)
Biological carcinogens (viruses, bacteria, parasites)
how does cancer vary across the world?
People live longer in the developed world
- Higher incidence in developed nations, but higher mortality in developing nations
- Most common cancers are lung, breast, colorectal, prostate, stomach
- Mortality most common in lung, colorectal, liver
- But this isn’t consistent worldwide
how do cancers in developing countries differ?
- more induced by infectious agents e.g. HPV = cervical cancer, HBV = liver cancer, H. pylori = gastric cancer
why do developing agents have more infection-induced cancers??
Infectious cause of cancer higher in developing countries due to:
- Lack of screening programmes e.g. for cervical cancer
- Lack of vaccines – vaccines too expensive – vaccine inequality
how can our lifestyles impact cancer incidence?
4 in 10 cancers can be prevented:
- man-made due to lifestyle e.g. smoking, diet, exercise, air pollution
what are carcinogens?
Agents which increase incidence of cancer
- Identified through epidemiological studies:
- Chemicals: benzene, formaldehyde, asbestos
- Occupations: chimney sweep, painting, coal gasification
- Metal exposure: arsenic, cadmium, chromium
- Particles and fibres: asbestos, wood dust,
- Pharmaceuticals: tamoxifen, HRT oestrogen/progesterone menopausal therapy
- Radiation:
- Biological agents: HPV, hep B helicobacter
Lifestyle factors e.g. diet
what is aflatoxin B?
Aflatoxin – toxin released by fungi growing on grain stores
- Eating grains with aflatoxin can increase cancer incidence
- Works synergistically with hep B = increased risk of hepatocellular carcinoma
what is the biggest risk factor for lung cancer?
Tobacco smoking associated with 16 different types of cancer
- Smoke contains 1010 particles per ml, 5000 compounds within smoke
- 70 carcinogens within those 5000 compounds
- These form DNA adducts i.e. they are covalently bonded to DNA
- Potentially this may lead to DNA damage or mutation
what are DNA adducts?
Mutations/DNA adducts:
- Forms covalent bond on nucleotides
- Adduct incorporation triggers mutation at that DNA point
how is red meat linked with colorectal cancer?
increased red meat intake increases risk of CRC
- India has low rate of colorectal cancer as they don’t eat much red meat
- In Japan, incidence has increased as red meat consumption has increased over time
- Mechanism unknown, but Harald zur Hausen proposes a cow virus is responsible
how can lifestyle factors influence cancer incidence?
Diet:
- Meat intake especially red meat.
- Reduced fibre (fruit and vegetable) intake.
- Higher intake not associated with protection from cancer
- vegetarians have 50% decrease in CRC incidence
Weight control:
- Obesity associated with adenocarcinoma, colon (men), - Post menopausal breast and endometrial cancer
Physical activity can act as preventative for colon and breast cancer
what is the most likely cause of cancer?
combination of genetics, with environmental factors e.g. lifestyle, dietary habits
how is alcohol a carcinogen?
Associated with oral, pharyngeal, larynx, oesophageal, liver, breast and colorectal cancers
- Mechanism of carcinogenesis unclear but may be related to genotoxicity of acetaldehyde. Ethanol is processed to acetaldehyde and then to acetate.
- Synergistic effect with tobacco smoking
- Heavy intake associated with hepatocellular carcinoma probably via cirrhosis.
how is ionising radiation a carcinogen?
Ionising radiation (x and g radiation):
- Can directly ionise the DNA strand
- Can strip electrons from water molecules to create reactive oxygen products/free radicals e.g. hydrogen peroxide
- These can interact with DNA resulting in base loss, single or double strand breakage
how can non-ionising radiation induce cancer?
Non-ionising radiation ultra violet light causes pyrimidine dimerisation
- Thymine bases become dimerised – crosslinking
- Causes DNA to link to unmatched base – leads to DNA breaks and damage
- Can be repaired but also may be mis-repaired leading to DNA substitution and mutation
australia has highest melanoma cases due to high UV exposure
what examples of are infectious agents of cancer?
These are associated with 16% of all cancers:
- H. Pylori – biggest infectious risk factor for gastric cancer
Viruses:
HPV – cervical cancer, head and neck cancer
Hep B and C – hepatocellular carcinoma
EBV – B, T, NK cell lymphomas, epithelial carcinoma
what is oncolytic therapy?
Oncolytic therapy – increase immunogenicity of cancer by injecting a virus into the tumour which promotes immune destruction of cancer
what are the stages of the cell cycle?
G0 = resting/quiescent cells
- cell receives external mitogen stimulus to enter cell cycle
G1: cell synthesises proteins and organelles for replication
S-phase - DNA synthesis
G2: synthesis of mitotic proteins
mitosis: cell division
what causes a cell to enter the cell cycle?
Mitogens bind to surface receptors, stimulate signalling to upregulate cyclin D and CDK4/6
what happens at late G1?
G1/S checkpoint
- cell decides whether to proceed with S phase or to exit to G0
- decision depends on magnitude of mitogenic signals
- cells become committed to cell cycle late in G1 if a large mitogen signal occurs
what is the G1/S checkpoint?
occurs late in G1
- cell will not progress if there is any DNA damage
- large mitogenic signal enables cells to pass through checkpoint and enter S-phase
what controls advancement into S-phase?
Mitogens/growth factors bind to surface receptors and stimulate signalling to upregulate cyclin D and CDK4/6:
- CDK4/6 phosphorylate Rb
- Rb is normally bound to E2Fs (these drive S phase)
- Phosphorylated Rb releases E2F
- E2F can transcribe S phase genes – cell progresses to S phase for DNA replication
what occurs in S-phase?
Over 6x10^9 base pairs of DNA is replicated to duplicate the 46 chromosomes – highly controlled
what are the checkpoints in S-phase?
Slow or pause DNA replication in response to damage e.g. p53 between late G1 and before S-phase
what occurs in G2 and what checkpoints are involved?
Synthesis of proteins required for mitosis
- Cells can not proceed through G2 to M until DNA replication completed
- Another checkpoint is also activated prior to mitosis if DNA damage is present
- can’t enter mitosis until passing p53 checkpoint
what occurs in mitosis? what checkpoint is in mitosis?
Mitosis encompasses 4 subphases which ultimately results in cytokinesis
prophase
metaphase
anaphase
telophase
Checkpoints prevent progression if chromatids are not aligned on mitotic spindle
what regulates the cell cycle?
Cell cycle entry and progression is regulated by a series of kinases:
Cyclin Dependent Kinases (CDK) (serine threonine kinases)
- these phosphorylate serines or threonines on target proteins
Regulatory subunits known as cyclins bind and activate CDKs
what cyclin/CDK is involved in the G1 checkpoint?
Cyclin D1 and CDK4/6
what stimulates CDK signalling?
Mitogen binds receptor e.g. cytokines, Wnt
- Phosphorylation transmits signal from receptor to upregulate cyclin D1
- Cyclin D is synthesised in response to external stimuli
- Cyclin D associates with cognate CDKs 4 and 6 to phosphorylate proteins, specifically Rb (guardian of cell cycle progression)
how do cyclins control Rb?
Limited phosphorylation of Rb by cyclin D1 relaxes inhibition of some transcription
- Allows selected gene transcription
A major transcript produced is cyclin E which associates with CDK2
This hyperphosphorylates Rb allowing its dissociation from E2F transcription factors
how do cyclins change during the cell cycle?
Different cyclins are expressed at different phases of the cell cycle.
Allows progression in one direction
how can cyclin activity be regulated?
Activity of cyclins is regulated by CDK inhibitors e.g. p15, p16, p21
- Can be induced by external stimuli such as TGF-b which inhibits cyclin D and CDK4/6 function
- DNA damage can induce expression of inhibitors
tight regulation is crucial
why is cell cycle control crucial?
There are many potential steps at which mutant gene products can disrupt cycle e.g. Ras and Raf
- The cell uses additional strategies to prevent aberrant cell cycle progress
what is p53?
the guardian of the genome
- Acts to transmit cell stress-inducing signals into anti-proliferative cellular responses
how is p53 activated?
P53 activation can occur via DNA damage, hypoxia, lack of nucleotides – cell stress activates p53
what is the role of p53?
P53 can:
- arrest cell cycle for senescence
- induce DNA repair during a cell cycle arrest
- block angiogenesis
- induce apoptosis
how does p53 resopnd to cellular stress?
- Stabilised by post-translational modification via phosphorylation
- Binds to specific DNA sequences
- Acts as a transcriptional activator or repressor of target genes
- Targets genes associated with senescence or cell cycle arrest
what are the arrest points of p53?
2 p53 checkpoints:
Late G1 before S phase
Late G2 before mitosis
what are the downstream effects of p53 activation?
- induces target genes associated with senescence or cell cycle arrest
- activate CDK inhibitors causing arrest in G1/S boundary or G2/M
- Induces DNA repair genes
- Induces regulators of apoptosis
what are the key pro-apoptotic genes/proteins and their role?
PUMA, NOXA and BIM
- These pro-apoptotic proteins inhibit BCL2 family of anti-apoptotic proteins
what happens to cells upon DNA damage that can’t be repaired?
P53 activated:
- p53 TF upregulates pro-apoptotic genes PUMA, NOXA, BIM
- These pro-apoptotic proteins activate BAK/BAX which heterodimerise, insert mito membrane, depolarise mito via forming pores in membrane and induce apoptosis via cytochrome C release
- BAK/BAX are normally kept inactivated by anti-apoptotic protein BCL2
- Induction of pro-apoptotic proteins inhibit anti-apoptotic proteins so that BAK/BAX are activated
what are tumour suppressor genes?
e.g. p53, Rb
- these regulate cell cycle progression
- these can be inactivated in cancer via mutation
- cancer loses cell cycle arrest function
loss of Rb = retinoblastoma
loss of p53 is highly common in cancers
how important is p53 in cancer?
70% lung cancers associated with p53 mutation
P53 is the guardian of the genome
what are the main hallmarks of cancer?
Sustaining proliferation
Evading growth suppression
Resisting cell death
Replicative immortality
Induction of angiogenesis
Activating invasion and metastasis
what are the requirements for normal cell proliferation?
Diffusible growth factors (mitogenic factors)
Extracellular matrix components (substratum)
Cell–to–cell adhesion/interaction molecules
how do cancers become mitogen-independent?
Alteration of extracellular growth signals
Alteration of transcellular transducers of those signals
Alteration of intracellular circuits that transduce signals into action
how do cancers alter their extracellular growth signals?
Autocrine :
- Cancers can synthesize their own growth factors
- make mitogens which bind back onto their receptors to activate cyclin D
- Respond via expression of cognate receptors.
Platelet-derived growth factors – glioblastomas
Tumour growth factor α – sarcomas
how do cancers alter their interaction with the ECM for growth?
Signalling to/by ECM – cancers can synthesise factors that bind to receptors on cells in ECM - these cells in the ECM can then make mitogens that the cancer needs
- Normal cells supply cancer cells with growth factors.
Growth factors secreted by ECM activate SOS-Ras-Raf-MAPK pathway
how do cancers become hyperresponsive to mitogenic signals?
Cancers can over express growth factor receptors – provides large signal to drive cell cycle
EGF-R/erbB – upregulated in stomach, brain, breast tumours
HER2/neu receptor – upregulated in stomach and mammary carcinomas
how can cancers no longer depend on mitogens?
Cancer can become mitogen independent, so won’t need these pathways
- this occurs via mutations in their signalling pathways, e.g. Ras and Raf
- These proteins can help cells become independent of mitogens
what is Ras?
GTPase
- mutated in 25% of tumours
- Ras proteins are present in structurally altered forms
- Enable continual mitogenic signalling to cancer cells - constitutive activation
- Bypasses upstream regulators e.g. growth factors.
~50% of colon carcinomas have RAS (KRAS) mutations
what is Raf?
40-60% of melanomas have mutations in BRAF
BRaf is normally activated by Ras, a protein anchored to the inner leaflet of the plasma membrane
- mutation can lead to a structural alteration of Raf, leading to constitutive activation
- Enable continual mitogenic signalling to cancer cells
- Bypasses upstream regulators e.g. growth factors
what is the function of Ras in normall cells?
- When EGF interacts with EGFR – phosphorylation of EGFR
- this recruits and activates Grb2, SOS and Ras at the inner leaflet of plasma membrane - Ras-GDP is converted to Ras-GTP = activated confirmation
- Ras-GTP recruits and phosphorylates Raf to activate it
- Raf phosphorylates MEK, which phosphorylates ERK which induces proliferation
what is the role of GTPase activating proteins (GAPs)?
Catalyses removal of PO4 from Ras GTP
Returns active Ras-GTP to inactive Ras-GDP
- tightly regulates Ras signalling to prevent continual cell proliferation
how do mutations in Ras lead to mitogen-independent proliferation?
Mutations in KRAS lead to conformational changes to be constitutively active
- Ras-GAP cannot activate GTPase function
- Ras permanently active in Ras-GTP form
– no mitogens needed as is can continuously signal alone and upregulate Cyclin D
how can Raf become independent of Ras?
Raf mutations can also induce a constitutively active confirmation, so becomes independent of Ras
- Can activate MEK and ERK alone without Ras input
what is the normal structure of inactive Raf?
Normally, inactive Raf is minimally phosphorylated and closed conformation
- stabilised by 14-3-3 proteins
what happens to the structure of Raf when it is phosphorylated by Ras?
Ras-GTP phosphorylates Raf, so Raf opens up to become active:
- Displacement of N-terminal inhibitory loops
- Phosphorylation of activation loops between serine and threonine to be maintained in open confirmation
- Raf can then be active to phosphorylate downstream MEK
how can mutations lead to a constitutive activation of Raf?
Many mutations occur in the activation loop and P loop, at the phosphorylation sites in kinase domain
- these mutations in the serine or threonine mean they are no longer need to be phosphorylated and maintain Raf in a permanent, open, active confirmation
- leads to constitutive activity as Raf cannot close
what can excessive proliferative signalling induce?
cellular senescence:
- Excessively elevated signaling by oncoproteins such as Ras and Raf can provoke counteracting responses from cells, specifically the induction of cell senescence and/or apoptosis by p53.
- Intrinsic cellular defence mechanisms designed to eliminate cells experiencing excessive levels of signaling.
- In order to sustain active growth, cancer cells must circumvent the powerful programmes that negatively regulate cell proliferation - evasion of growth suppression
what are the roles of Rb and p53?
RB and TP53 govern decisions of cells to proliferate
or activate senescence and apoptosis.
RB transduces extracellular (mostly) growth-inhibitory signals.
TP53 receives and transduces signals from within the cell.
how do healthy cells inhibit excessive growth?
In healthy cells, anti-proliferative signals operate to maintain cellular quiescence and tissue homeostasis
- Soluble growth factors (ie TGFβ) are upregulated
- Immobilised inhibitors embedded in the ECM or other cells
most anti-proliferative responses are funneled through Rb
how do anti-proliferative signals block proliferation?
2 ways:
Cells forced out of active proliferative cycle into quiescent state (G0)
Induced to permanently relinquish their proliferative potential (post mitotic state)
what is the role of TGFb?
TGF-beta is best known for its antiproliferative effects and evasion by cancer cells:
- TGFb prevents phosphorylation of Rb
- TGFb prevents progress from G1 to S
- TGFb triggers CDKi synthesis e.g. p15, p21
what happens to TGFb in cancer?
Downregulation of TGF-β receptors
Mutant, dysfunctional receptors
Loss of function mutations in TGF-β pathways (rare)
Smad4 is often mutated so TGF-β signal is not transduced
(common in colorectal cancer)
how does TGFb function in normal cells?
Normal cells have upregulation of TGFb to stop cell cycle by upregulating CDKi:
- TGFb binds to surface receptor tyrosine kinase
- Recruits SMAD2/3 which are phosphorylated
- This recruits SMAD4
- SMAD complex enters nucleus as TF to upregulate expression of CDKis
how is TGFb signalling impaired in cancers?
In tumour:
- TGFb expression induces phosphorylation of SMAD2/3
- But mutated SMAD4 is phosphorylated, which interacts with SMAD2/3
- Complex translocates to nucleus and can complex with other TFs like p300 - phosphorylated SMAD4 is unable to bind to CDKi DNA promoter, no transcription of CDKi
what triggers apoptosis?
Apoptosis is triggered in response to various physiologic stresses:
- Signaling imbalances resulting from elevated oncogene signalling e.g. elevated Ras/Raf signalling
- DNA damage associated with hyperproliferation = triggers p53
how do cancers affect apoptosis?
Apoptosis is attenuated by cancers so that p53 doesn’t induce cancer death:
- Seen in high grade malignancies
- Seen in chemotherapy-resistant cancers which are resistant to cell death
what does DNA damage normally induce in cells?
DNA damage leads to upregulation of p53
- p53 upregulates BH3-only pro-apoptotic initiators (BIM, PUMA, NOXA)
- these inhibit anti-apoptotic BCL-2 and activate BAX
what does apoptosis depend on? how does this impact cancer evasion?
Apoptosis activation is based on the balance of pro-apoptotic and anti-apoptotic factors
- anti-apoptotic = Bcl2, Bcl-xl, Bcl-w, Mcl-1, A1
- pro-apoptotic = PUMA, NOXA, BIM, which induce BAK/BAX
Evasion of apoptosis is complex
- Can’t just upregulate anti-apoptotic proteins, as these are balanced by pro-apoptotic protein upregulation
- lots of interaction
what is the process of the intrinsic apoptotic pathway?
Anti-apoptotic proteins bind to the pro-apoptotic, triggering proteins (BAX and BAK), repressing their function
Bax and Bak are embedded in the mitochondrial walls
Release of anti-apoptotic proteins from BAK and BAX enables their function
BAK and BAX disrupt mitochondrial wall integrity, resulting in cytochrome release.
Cytochrome c activates a cascade of caspases that induce cellular changes associated with apoptosis.
how do BH3-only proteins function?
e.g. BIM, NOXA, PUMA
BAK and BAX share protein-protein interaction domains (BH3 motifs) with anti-apoptotic proteins.
- INHIBITION OF APOPTOSIS.
BH3-only proteins sense cell abnormality, i.e, DNA damage, lack of cytokines, growth factor withdrawal
BH3-only proteins act by:
Interfering with the anti-apoptotic proteins
Directly activating BAK and BAX
how does damage/stress upregulate BH3-only proteins?
P53 senses severe DNA damage and induces/upregulates:
- Noxa
- PUMA (p53 upregulated modulator of apoptosis)
- BIM
Insufficient growth factor signalling (IL-3 in lymphocytes, Igf1/2 in epithelial cells) upregulates BIM
Hyperactive signalling by oncoproteins (Ras, Raf, cMyc) triggers BIM and other BH3-only proteins
how do cancers evade apoptosis?
Cancers have mutations which inactivate p53 – failure to upregulate PUMA, NOXA, BIM, so cannot induce apoptosis upon DNA damage
- Leads to increased expression of anti-apoptotic proteins due to lack of p53
Epigenetic silencing of PUMA, BIM, BAX
Some viral infections can induce CpG methylation of promoters of pro-apoptotic proteins so that they are no longer expressed
how are normal cells limited in their growth and division?
Normal cells have a limited number of growth and division cycles
This limitation associated with two distinct barriers:
- Senescence; irreversible entrance into nonproliferative but viable state
- Crisis; leads to cell death
what regulates normal cells to stop growth and enter senescence?
This division limitation is associated with telomere length of the chromosomes
what are telomeres?
Telomeres are hexanucleotide repeats that protect the ends of chromosomes
- telomeres on ends of chromosomes are in limited number – every replication, there is loss of a telomere – after all telomeres are lost, cell senesces - limits replicative capacity
- Function to prevent chromosomes form fusing to each other
- telomere loss means chromosome ends can join, leading to apoptosis
how to cancers gain telomeres to enable replicative immortality?
- Cancers upregulate telomerase
- telomerase is a specialised DNA polymerase
- adds telomeres to chromosome ends – enables continuous replication
what is telomerase?
- Specialised DNA polymerase
- Adds telomere repeat segments to the ends of telomeric DNA
- Almost absent in non-immortalised cells
- Expressed in human cancers to maintain telomere length
- Expression of telomerase is correlated with resistance to senescence and crisis/apoptosis
what are the functions of telomerase?
- adds telomeres to ends of chromosomes
- Signal amplification from Wnt pathway
- telomerase upregulates Wnt, which activates cyclin D and CDK4/6 to drive cell cycle
- Enhancement of cell proliferation and/or resistance to apoptosis
- Involvement in DNA damage repair
why is angiogenesis important for cancer?
Tumour cells require neovasculature for:
Sustenance: nutrients, oxygen
Removal of metabolic waste and CO2
large tumour is hypoxic in the middle, so needs blood vessels to reach its core
this enables cancers to deal with a high proliferation rate
how is angiogenesis controlled?
Angiogenesis is controlled by a balance of pro- and anti-angiogenic factors:
VEGF-A:
- Orchestrate new blood vessel growth
- Upregulated by hypoxia and oncogene signalling
- New vasculature requires endothelial cells and sprouting of new vessels
Fibroblast growth factor (FGF)
- Sustain tumour angiogenesis when chronically upregulated
what activates pro-angiogenic factors?
Ras mutations can up-regulate expression of VEGF
- Oncogene expression
hypoxia
Innate immune cells (macrophages, neutrophils, mast cells, myeloid progenitors) can infiltrate pre-malignant lesions and tumours and secrete VEGF
- Help maintain ongoing angiogenesis
what is metastasis?
Primary tumours may spawn cells which can invade adjacent tissues
- These can migrate and form distant tumours
what enables cancers to metastsise?
Ability of carcinomas to metastasise is associated with:
Change of cell shape
Changes in attachment to surrounding cells and extracellular matrix
- induced by EMT
what is the structure of epithelial cells? how does this inhibit cancer migration?
Epithelial cells are polarised, contain cell adhesion molecules, attached to basement membrane and ECM
- for cancers to move, they need to become detached from ECM and neighbouring cells for migration
how are cell adhesion molecules changed in cancer?
LOSS of E-Cadherin
- Key cell–cell adhesion molecule
- maintains polarity and quiescence
- Adherens junctions
- Assembly of epithelial cell sheets
- loss enables cells to detach
Upregulation of N-Cadherin
- N-cad normally active during embryogenesis to enable movement of cells for tissue generation
- Can be upregulated in chronic inflammation and cancer – enables migration of cells
what is the invasion-metastasis cascade?
local invasion: cancer starts in epithelium, can invade tissue
Cancer moves into blood vessels and lymphatics (intravasation)
Circulates to distant sites and extravasates out of blood
Forms micrometastases (small cancer nodules)
– establish new TME to form metastatic tumour and macropscopic lesion
what is epithelial-to-mesenchymal transition (EMT)?
EMT is a developmental programme important in embryonic morphogenesis and wound healing.
Can be triggered transiently or stably
crucial in cancer metastasis
what are the features of EMT?
- Loss of adherens junctions and polarisation – E-cad loss
- Associated conversion from a polygonal or epithelial to a spindly/fibroblastic morphology - mesenchymal
- Expression of matrix-degrading enzymes
- Increased motility
- Heightened resistance to apoptosis
- upregulation of MMPs to degrade attachment between epithelial cell and ECM - enables detachment
how do epithelial cells change in EMT?
Epithelial cells change shape to mesenchymal, spindly form for migration – can move through blood vessels via N-cad upregulation
- loss of polarity so change shape
what do cancers need to do when they reach their metastatic site?
When reaching metastatic sites, they need to recondition stromal cells in the area to establish a tumour
how do cancers initiate a metastatic tumour?
Stromal cells contribute to invasion and metastasis.
Mesenchymal stem cells secrete CCL5/RANTES (chemokines) in response to signals released by cancer cells.
- CCL5 acts on the cancer cells to stimulate invasive behaviour.
Macrophages foster local invasion:
- Supply matrix-degrading enzymes such as MMPs and cysteine cathepsin proteases - degrades ECM
- Supply epidermal growth factor (EGF) to enable intravasation.
