1. Molecular Biology Flashcards
What is cancer?
- group of diseases characterised by unregulated cell growth and the invasion and spread of cells from the site of origin or primary site, to other sites in the body
Describe Cancer Prevention
Process of taking action to lower the risk of getting cancer
- maintaining a healthy lifestyle
- avoiding or minimising exposure to known cancer causing substances
: physical, chemical, biological
- taking medicines or vaccines to prevent cancer from developing
Describe preventable cancers with statistics (Cancer Research UK)
- 4 in 10 (42%) of cancer cases in the UK each year are linked to lifestyle factors
- in last 5 years, almost 600,000 cancer cases in the UK could have been prevented
- Cervical, mesothelioma, oral, larynx, oesophageal and lung cancers have the highest proportions of cases linked to lifestyle factors
- Prostate and testicular cancers have no established lifestyle factor links
- SMOKING is the largest single preventable cause of cancer in UK linked to estimated 19% of cancer cases in the UK each year
- Lung cancer has the highest proportion of cases linked to smoking
What lifestyle changes can reduce cancer risk?
Smoking
- largest single preventable cause of cancer in UK, linked to estimated 19% of cancer cases in UK each year
Diet
- too little fruit, vegetables and fibre
- too much red and processed meat
- linked to an estimated 9% of cancer cases in UK each year
Overweight and Obesity
- linked to estimated 5% of cancer cases in UK each year
Alcohol
- linked to estimated 4% of cancer cases in UK each year
How does smoking induce cancer?
- causes 28% of cancer deaths in UK and more than 4 in 5 cases of lung cancer
- associated with increased risk of several cancers, including lung, larynx, oesophagus, oral cavity and pharynx, bladder, pancreas, kidney, liver, stomach, bowel, cervix, leukaemia and ovarian cancers
- caused by direct effect on DNA including key genes that protect us against cancer e.g Benzene, polonium-210 along with other chemicals in cigarette smoke that inhibit DNA repair
- Scientists have found that the number of years you spend smoking affects your cancer risk even more strongly than the number of cigarettes you smoke a day
How does Alcohol induce cancer?
- risk factor for many types of cancer (including oral, pharynx, larynx, oesophagus, liver, colorectal and breast)
- cancer risk increases with amount of alcohol
- risk for several cancer types increases if the person is a heavy smoker
- caused an estimated 6% of deaths worldwide in 2012, 13% of which were due to cancer
- reducing average alcohol intake in England by around 1 unit per person per day would avoid an estimated 8% of cancer deaths (Nichols, 2012)
How does Physical inactivity (can include dietary factors and obesity) induce cancer?
- difficult to estimate the specific contribution of each of these risk factors and may underestimated the cumulative risk
- overweight and obesity are casually linked to several common cancers including oesophagus, colorectal, breast, endometrium and kidney
- taken together, raised body mass index and physical inactivity account for an attributable fraction of 19% of breast cancer mortaility, and 26% of colorectal cancer mortality
- obesity is the biggest cause of cancer after smoking. Estimated 1 in 20 cancers in the UK associated with being overweight
- Growing evidence to support reduced risk with weight loss
Describe Infective causes of Cancer
- in 2012, approximately 15% of all cancers were attributable to infectious agents such as helicobacter pylori, human papilloma virus (HPV), hepatitis B and C, and Epstein-Barr virus
- Vaccines are available for hepatitis B virus and some types of HPV and can reduce risk of liver and cervical cancers, respectively
Describe Human Papilloma Virus (HPV) with regards to cancer
- nearly all cervical cancers (99.7%) are caused by infection with a high-risk type of HPV, HPV infections are usually asymptomatic
- there are more than 100 different types of HPV
- most people will get HPV infection at some point in their lives and their bodies will get rid of it naturally without treatment but some women infected with a high-risk type of HPV won’t be able to clear it
- HPV (Types 6, 11, 16, 18) protects against 4 types of HPV (Types 16, 18, 6, 11). Between them, types 16 and 18 are the cause of most cervical cancers in the UK (More than 70%)
- Given to all girls in UK in year 8 then second dose 6-9 months later (vaccines)
Describe how Environmental Exposure induces cancer
- pollution of air, water and soil with carcinogenic chemicals contributes to the cancer burden to differing degrees depending on the geographical settings
- outdoor air pollution is classified as carcinogenic, or cancer-causing, for humans. It has been estimated that outdoor air pollution contributed to 3.2 million premature deaths worldwide in 2012 including more than 200,000 lung cancer deaths
- additionally, over 4 million people die prematurely from illness attributable to the household air pollution from cooking with solid fuels, 6% of these deaths are from lung cancer
- indoor air pollution form coal fires doubles the risk of lung cancer, particularly among non-smoking women
- exposure to carcinogens also occurs via the contamination of food, such as aflatoxins or dioxins
Describe how occupational exposure induces cancer
- more than 40 agents, mixtures and exposures circumstances in the working environment are carcinogenic to humans and are classified as occupational carcinogens
- occupational cancers are concentrated among specific groups of the working population, for whom the risk of developing a particular form of cancer may be much higher than for the general population
- it is well documented that occupational carcinogens are casually related to lung cancer, mesothelioma, and bladder cancer. For example, mesothelioma (cancer of the outer lining of the lung or chest cavity) is to a large extent caused by work-related exposure to asbestos
Describe how Radiation causes cancer
- exposure to all types of ionising radiation, from both natural and man-made sources, increases the risk of various types of malignancy including leukaemia and a number of solid tumours
- Risks increase when the exposure occurs at a young age and also when the exposure amount is higher. UV radiation, and in particular solar radiation, is carcinogenic to humans, causing all major types of skin cancer, such as basal cell carcinoma (BCC), squamous cell carcinoma(SCC) and melanoma
- Avoiding excessive exposure, use of sunscreen and protective clothing are preventive measures, UV-emitting tanning devices are now also classified as carcinogenic to humans based on their association with skin and ocular melanoma cancers
- Residential exposure can also arise from radon, a naturally radioactive gas sometime present in soil and building materials increase risk of lung cancers.
Radon levels in homes can be reduced by improving the ventilation and sealing floors and walls
What is Population Screening Programmes? Give examples of NHS population screening programmes
- Screening is process of identifying healthy people who may have an increased chance of a disease or condition
- The screening provider then offers information, further tests and treatment. This is to reduce associated problems or complications
Examples
- NHS breast screening
: all women aged 50-70
- NHS Bowel Cancer screening
: every 2 years to men and women aged 60-74
- NHS Cervical Cancer screening
: all women aged 24-49 every 3 years then 50-64 every 5 years
What is cancer?
- Uncontrolled cell division
- Unregulation growth of abnormal cells, often inappropriate locations
- Depending on the locations, decides how easy it is to treat
- Most common treatment is removal by surgery, can afford to lose some tissues such as rectal or liver however places like brain is difficult to maintain normal function
Describe hallmarks of cancer and examples of potential therapeutic methods to target them
- Sustaining proliferative signalling
- EGFR inhibitors - Evading growth suppressors
- Cyclin-dependent kinase inhibitors - Avoiding immune destruction
- Immune activating anti-CTLA4 mAb - Enabling replicative immortality
- Telomerase inhibitors - Tumour-promoting inflammation
- Selective anti-inflammatory drugs - Activating invasion & metastasis
- inhibitors of HFG/c-Met - Inducing angiogenesis
- inhibitors of VEGF signalling - Genome instability & mutation
- PARP inhibitors - Resisting cell death
- Proapoptotic BH3 mimetics - Deregulating cellular energetics
- Aerobic glycolysis inhibitors
Describe naming of tumours
- Classified according to their embryonic tissue of origin
- Can recognise >200 tumour types
- Carcinomas
: arise from epithelial cells (90% cancers) - Adenocarcinoma
: arise from glandular tissue e.g breast - Sarcomas
: arise from connective tissue & muscle - Leukaemias
: blood cell-derived sarcomas
Describe Benign tumour cells
- resemble normal cells
- tend to be localised
- often surrounded by a fibrous capsule
- usually require little treatment e.g warts
- surgical removal if appropriate
Describe Malignant tumours
- often less well differentiated than normal cells
- grow and divide more rapidly
- high nucleus to cytoplasm ratio, fewer specialised structure
- more difficult to treat, less definition
- invade surrounding tissues
- enter circulation
: seed at a distant site (metastasis)
Describe what ‘proto-oncogene’ is
- Normal function
: to control cell growth - Converted to oncogenes by gain of function mutation
: point mutation (always active)
: gene amplification (more protein)
: chromosomal translocation
What are Oncogenes?
- a gene which in certain circumstances can transform a cell into a tumour cell
What are Tumour Suppressor Genes?
- Genes which restrain cell growth, promote cell death and promote DNA repair
- Loss of function leads to excessive, unregulated growth of damaged cells
- Recessive genes
: both copies must be lost - Hereditary predisposition
: inheritance of one mutated copy of TSGene increases tendency of dev cancer
Describe Epigenetics
- Modifications to genomic and chromatin components/structure
- Alter gene transcription and hence protein expression
- Heritable changes
- Usually involve histone modifications, methylation
Describe molecular mechanisms of Cancer
Knudson, Vogelstein
- cancer cells usually contain 3-7 mutations
- cells undergoing a mutation must survive long enough to sustain subsequent mutations
- malignant transformation of a single cell is sufficient to give rise to a tumour
What changes occur in the body that cause cancer?
- mutations in genes
- encoding proteins involved in regulation of cell growth and cell survival
What causes the mutations?
- Chemical carcinogens (tobacco smoke, asbestos)
- Radiation ( U.V, Nuclear)
- Viruses (Human Papilloma Virus)
Describe risk factors of Cancer
- Lifestyle
- Diet
- Reproductive life
Lifestyle
- environment, job
- Smoking accounts for 40% cancer deaths 1.18 million people
- Tobacco smoke contains 81 carcinogens
- UV, radiation exposure
Diet
- Eastern diet increased risk stomach cancer over western diet, Mediterranean best
Reproductive life
- Nuns have a higher risk of breast cancer but lower risk of cervical cancer
Key points of Cancer (JUST READ)
- Cancer is a genetic disease
- Mutations occur in somatic cells
- Each cancer is a clone that arises from a single cell
- Multiple mutations are required >3
- Affects genes involved in growth control
- Proto-oncogenes and Tumour suppressor genes
Describe Human Papilloma Virus (HPV)
- Oncogenic DNA virus
: integrates viral DNA into host genome - Permanently transforms host cells
- Causes warts and other benign epithelial growths
- Causes of cervical cancer (pap smear) (vaccine)
- E5 subunit causes prolonged activation of PDGFR
- E6 and E7 inhibit pRb and p53
What are Epidermal Growth Factor Receptors?
- important proto-oncogenes involved in many cancers
- EGF important growth factor
: drives cell proliferation - Intrinsic kinase domain leading to activation of downstream signaling pathways
: Ras/ MAPK and PI3K-PKB - Mutations in receptor can cause
- Ligand independence
: constitutive dimerisation - Overexpression
: gene amplification
Describe relation between HER2 and Breast cancer
The WT HER2 gene (ErbB2) is amplified in ~25-30% of metastatic breast cancers
Cells express 10-100x more Her2 receptor
HER2+ cells associated with more aggressive tumour phenotype and reduced survival rate
- cells grow faster
- tumours are more likely to recur
- correlates with more serious prognosis
How is HER2 status detected?
IHC
- Immunohistochemistry
- staining with ab
- rating 0-3_ (latter deemed HER2)
Fish
- Fluorescent in situ hybridisation
- more sensitive than IHC
HER2-ECD ELISA
- detects cleavage product in serum
What is Herceptin (Trastuzumab) (Roche)?
- Humanised monoclonal antibody recognising HER2 (recombinant molecule constructed by inserting murine CDR into human IgG)
- Herceptin binds HER2 and blocks its activity
- Phse 1 Clinical trials
: tumours grew more slowly some disappeared, provides significant survival benefit - Originally licensed for final stage aggressive HER2+ cancer
- Now also available to early stage patients
Describe Mechanism of action of Herceptin
- decreases activation of signaling pathways
- may induce downregulation of receptor
- uncouples Src activation, increases PTEN activation
- induces cell cycle arrest, increased p27
- may increase apoptosis, decrease angiogenesis
- promotes Antibody Dependent Cellular Cytotoxicity (ADCC) (via FcR on NK cells)
Describe Ras with regards to Cancer
- activating mutations (at positions 12 or 61) present in many human tumours
: 90% pancreatic tumours
: 45% colo-rectal tumours
: 30% acute myeloid leukaemias - different mutations found in different cancers
: aa12 V G bladder, V S lung - mutations generate Ras proteins which are always active
Describe Ras as an anti-cancer target
- Ras has a fatty acid modification which tethers it to membrane
- inhibitors of this modification (farnesyl transferase inhibitors, FTI) developed
: peptidomimetics - good responses in mouse breast tumour model
- clinical trials
: disappointing, mode of action unclear - instead of adding farnesyl, geranylgeranyl fatty acid added
: K-ras still active - but potential, in treatment of leukaemias + combinations
What are the alternative anti-cancer approaches?
Antisense oligonucleotides
- HRas, c-Raf
- got to phase II trials but show little efficacy
MEK inhibitors
- orally active CI-1040 (Phase I trials for colon cancer)
Raf inhibitors
- orally active kinase inhibitor Nexavar approved for renal carcinoma also blocks VEGFR and PDGFR
Summary of Oncogenes (JUST READ)
- understanding regulation of cell growth enables new targets to be identified
- study of pro-oncogenes informing drug development
- no therapy is likely to be 100% effective
- still need to continue research
- better prospects for combination therapies
What are Tumour Suppressor genes?
- genes which normally function to restrict growth
- recessive, loss of function mutations predispose to cancer formation
- sporadic and germline (inherited) mutations
- cancers tend to have inactivating mutations in 1 or more tumour suppressor genes
- deletions/point mutations result in no protein or a protein with altered function
What are the main classes of tumour suppressor genes?
Growth/Development suppressors
- e.g TGFb, patched 1
Cell cycle checkpoint proteins
- e.g pRb, p53
Cell cycle inhibitors
- e.g CDKI, p16
Inducers of apoptosis
- e.g Bax, p53
DNA repair enzymes
- e.g Xeroderma pigmentosa
Developmental pathways
- e.g patched (Hh pathway)
Describe Hereditary Predisposition
- Inherit germ line mutation in one allele,subsequent somatic mutation in other
APC
- precancerous intestinal polyps increased risk of colon cancer
BRCA1
- 60% probability inheriting breast cancer compared to 2% with two WT alleles
What is Retinoblastoma?
- Tumours developing in the retina
- 40% cases: inherited (cf sporadic)
- Recessive trait
- Retinal tumours early in life in one or both eyes
- Each tumour derived from a single cell (clonal)
How will loss of functions of molecules like pRb, E2F, Cyclin D, p16 contribute to cancer?
- Loss of function will remove inhibition on E2F TF so it becomes constitutively active and can drive transcription of genes required for S
phase transition - Cell growth becomes independent of GF/ cyclin D levels
- Loss of function of p16 removes the ability of a cell to halt the cell cycle in order to repair damaged DNA. Mutations are passed onto daughter cells and accumulate
- Accumulation of 3+ relevant mutations is sufficient to transform the cell
What is p53 and how is it induced?
- evolved to prevent tumour development
- usually present at low levels in cells, complexed to(due to) inhibitor protein MDM2
- stress signals inhibit MDM2 allowing activation of p53
- stabilised p53 protein levels increase
- p53 primarily acts as a transcriptional regulator
- active as a tetramer
How does p53 inhibit cell growth?
p53 activation normally inhibits cell growth by
- cell cycle arrest
- induction of apoptosis
p53 regulates expressions of
- p21 cyclin-dependent kinase inhibitor (arrest)
- MDM2 - inhibitor of p53 action (autoregulation)
- Bax - pro-apoptic protein
Describe relation between p53 and cancer
- Mutations of p53 occur in >50% human cancers
- Mutant p53 proteins more stable
- Many mutations occur in DNA binding region
- Mutant p53 molecules can interfere with wild type p53 action
- Li Fraumeni Syndrome
: inherited disorder, mutaed p53 - Affected patients
: predisposed to tumour formation
Describe p53 mutations in Lung and Liver cancer
p53 is inactivated by carcinogens
Lung cancer
- 60% human lung cancers have mutations in p53
- Benzo(a) pyrine in cigareete smoke is metabolised in liver generating a potent mutagen
- Mutagen causes G > T transversions in DNA - Hot spots in p53 R175, R248, R273
Liver cancer
- Aflatoxin (fungal metabolite) leads to G > T transversion at R249 of p53
Can p53 be a target for therapy? Give an example if there is
Advexin
- adenoviral transfer of p53 gene into tumour cells
- appears to half growth and often shrink tumour size
- well tolerated alone and in combination
Other approaches
- CDB3/PRIMA-1 stabilises mutant p53 and restores transcriptional function
- MDM2 inhibitors nutlins mimic p53
- Pifithrin suppresses endogenous p53 in normal tissue to reduce susceptibility to chemotherapy radiation induced apoptosis
What are the aims of targeted therapies?
- to identify ‘critical’ mutation
- to limit growth and invasion/spread
- to increase specificity of effects and limit side effects
- to prolong ‘quality of life’
What are the approaches of targeted therapy?
- identification of molecules/pathways dysregulated in cancer
- requires genetic profiling of the cancer
- easier to target overexpression/overactivaton that LoF
- challenge = endogenous molecules on uniquitous pathways
What is Leukaemia?
- cancer of white blood cells
- unregulated proliferation of a clone of immature blood cells
- leukaemic cells proliferate relentlessly
- squeeze normal cells out of the bone marrow
- patients with leukaemia
: blood appears mikly
How is Leukaemias classified?
- Acute or Chronic
- Divided depending on cell of origin
- Myeloid
- Lymphoid
Describe the clinical presentation of Chronic myeloid leukaemia (CML)
- Fatigue, anaemia, splenomegaly, hepatomegaly
- Elevated number of white cells in blood count
- All stages of granulocyte differentiation on blood smear
- Hypercellularity of bone marrow
- Increased ratio of myeloid to erythroid cells
- Account 20% adult leukaemias
Describe features of Chronic Myeloid Leukaemia
Three clinical phases
- initial chronic phase, fairly mild
- accelerated phase develops after 4 years
- acute leukaemic phase (Blast crisis)
- mtations throught to arise in stem or progenitor cells
- 95% of CMLs have reciprocal translocation between chromosomes 9 and 22 -t
- generates fusion between breakpoint cluster region (BCR) and Abl tyrosine kinase (BCR-ABL)
What is C-Abl and its role?
- Non-receptor protein tyrosine kinase
- Cytoplasmic and nuclear localisation
- known to be activated by DNA damage during S phase, downstream of integrin signalling
- Nuclear c-Abl interats with Rb and p53 to regulate gene transcription
- Cytoplasmic c-Abl appears to play a role in cell growth
What is STI 571 / Glivec / Gleevec TM?
- Gilvec small synthetic molecule
- Phenoaminopyrimidine derivative
- Inhibits proliferation of human CML-derived cell lines
- Inhibits CML growth in mouse model
- Blocks activity of Abl tyrosine kinase
- Also blocks PDGFbR and c-kit tyrosine kinases
What is GIST and how is it treated by Glivec?
- Gastro-intestinal stromal tumours
- driven by constitutive c-kit receptor activity
- receptor blocked by Glivec
Targeted Therapy (JUST READ)
- Cancer is a multifactorial process
: successful therapy often involves several different approaches - Many cancers involve the constitutive activation of a tyrosin kinase
- small molecule inhibitors and monoclonal antibodies which block activation of kinase activity have been used successfully to treat many patients
(JUST READ) STEM CELLS IN CANCER
Cancer is a disease of proliferating cells
- but most mature cells dont proliferate
Tumours are often heterogeneous in terms of cellular differentiation
- but cancers are clonal (arise from a single cell)
Cancer is caused by the accumulation of mutations in a single cell (clonal disease)
- but most cells have a finite lifetime and don’t live long enough to acquire 3+ mutations
Only a small number of tumours cells can recolonise
- Why and how do they get the appropriate growth signals at the secondary site
What is a Stem cell?
- pluripotent cells that can differentiate into many different cell types
- unspecialised cells that can reproduce themselves and/or generate more specialised cells indefinitely (Self-renewal)
- intermediate cells known as precursors or progenitor cells
- resulting specialised cells often cannot divide
: carry out specialised function - terminal differentiation generally irreversible
- change in cell state transcriptionally regulated
Describe adult stem cells
- small number of residual stem cells identified in adult tissues
- include blood, intestine, skin, muscle, liver, brain
- in bone marrow, stem cells required for normal cell turnover
- in liver and muscle, stem cells involved in healing
- only present in very small numbers, proliferaton normally suppresssed
- Difficult to identify and isolate
Are stem cells involved in cancer?
- if undifferentiated or partially differentiated stem cells are implanted into tissues they can, in some cases, form tumours
- for a differentiated cell to form a tumour it must dedifferentiate and reacquire ability to proliferate
- alternatively, the mutations may occur in the tissue stem cells
- these proliferate rapidly, undergo some degree of differentiation and metastasise more easily
How is stem cells and cancer related?
- Stem cells are long lived an self renew giving more opportunity for mutations to accumulate
- The asymmetric division of stem cells may account for the heterogeneity of the tumour mass
- Adult stem cells are present at very low numbers in tissues but have been shown to have the ability to recolonise
- Many of the signalling pathways involved in self renewal have been shown to be mutated in cancer cells
Descrobe Cancer Stem Cell Hypothesis
- Expansion of the normal stem cell niche permits the expansion of cancer stem cells that arose from normal stem cells
- Cancer stem cells that arose from normal stem cells adapt to a different niche allowing their expansion
- Cancer stem cells that arose from normal stem cells become niche-independent, and self-renewal is cell-autonomous
- Shift in the programmed declined in replication potential. Cancer stem cells arising from a progenitor cells
What are Wnt and Hh pathways?
Wnt
- signalling pathways of which a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors
(Wnt stands for Wingless/integrated)
Hh
- signalling pathways that transmits information to embryonic cells required for proper cell differentiation.
What are Telomerases?
- tandem repeats found on the ends of chromosomes and aid chromosomal replication
- Because the DNA polymerases cannot copy right to the end of the chromosomes, the telomeres shorten on each cell division
- When this telomeres get too short they are eventually recognised as damaged DNA and p53 is activated to induce senescence or even apoptosis
- Telomerases are reverse transcriptase enzymes containing an RNA template to add TTAGGG repeats to chromosome ends
- Telomerases are found in rapidly dividing and germ line cells, most somatic cells lack telomerases
How are Telomerases and cancer related?
- Tumour cells express telomerases and so are able to repair chromosomes so extending cell life
- Telomerase and N-myc levels indicative of prognosis (high is poor)
- Potential target for anti cancer therapy
- Telomerase antisense or telomerase with mutated RNA template
JUST READ
- STEM CELLS
- Stem cells cause cancer they can keep growing
- Characteristics of stem cells
: ability to keep growing, partial differentiation make them likely candidates for initiation of cancer - Stem cell long lived so can accumulate mutations, maybe only cells which can recolonise, express telomerases to extend lifespan
- Explain cancer stem cell hypothesis in terms of changes to niche cells, mutations in Wnt/Hh dev pathways
What is Metastasis?
- Secondary cancer
- ability of cancer cells to escape from the primary tumour via the blood and lymphatic system and to grow in a secondary site
- 90% of cancer mortaility is related to advanced, metastatic disease
- ~45-46% of cancers are diagnosed at stage III or IV
Describe the metastatic cascade
- Primary tumour growth (proliferation)
- Angiogenesis
- Detachment and invasion into the surrounding tissue towards the vessels
- Intravasation into lymphatics/capillaries
- Survival in the circulation
- Arrest in new/secondary organ (small capillaries, adhesion to vessel wall)
- Extravasation into the secondary tissue
- Establishment of microenvironment
: death
: dormant
: proliferating
What is Angiogenesis?
: where and when does it happen?
- growth of new blood bessels
- Blood vessels bring oxygen and nutrients to cells while carrying away CO2 and cellular waste
- Angiogenesis is involved in formation, maturation and differentiation of blood vessels from pre-existing vessels.
Define Neoangiogenesis.
- angiogenesis observed in physiological and pathological conditions including growth, injury, inflammation and cancer
How does tumour cells grow more quickly compared to normal cells?
Describe hypoxic conditions that drive neo-angiogenesis
- Tumour cells grow more quickly than normal cells and outgrow their source of oxygen and nutrients
- In order to grow, tumours need to attract new blood vessels to provide necessary energy
Hypoxic conditions for neo-angiogenesis
- not enough oxygen
- HIF-1a (hypoxia inducible factor 1a)
- expression of VEGF (vascular endothelial growth factor)
Angiogensis is controlled by angiogenic growth factors/ cytokines and inhibitors
Name some endogenous activators and inhibitors
Endogenous activators
- VEGFs (Vascular endothelial growth factor)
- FGFs (Fibroblast growth factors)
- PIGF (Placental growth factor)
- PDGF (Platelet-Derived Growth Factor)
- TGF (transforming growth factor)
Endogenous inhibitors
- Endostatin
- Thrombospondin (TSP) 1 and 2
- IFN-a
- IL-b
- Angiostatin
What are the characteristics of tumour angiogensis?
- uncontrolled expression of pro-angiogenic factors
- disorganised vascular structure
- low integrity vessels -> can collapse -> hypoxia
- low adhesion and pericyte coverage
- distorted and different flow characteristics
- increased microvasculature permeability (leaky)
Describe anti-angiogenic therapy in cancer
- inhibits production of angiogenic proteins
- neutralises angiogenic proteins
- inhibits receptors for angiogenic protein or induces endothelial cell apoptosis
What is Bevacizumab (Avastin)?
- humanised monoclonal anti-VEGF-A antibody
: neutralises VEGF-A - Only approved for advanced, metastatic disease
Describe the Anti-angiogenic therapies
Monoclonal antibodies
- Bevacizumab (anti-VEGFA antibody), approved
- Ramucirumab (anti-VEGFR-2 antibody), in development
- Cetuximab (anti-EGFR), volociximab (anti-integrin-avb1), MEDI3617 (anti-Ang2) and GAL-G2 (anti FGF2) = mainly developed to overcome VEGF resistance
Decoy receptors
- Ziv-aflibercept (Zaltrap) = binds to VEGF-A, VEGF-B and PIGF)
Receptor tyrosine kinase inhibitors
- Sorafenib, Sunitinib (multi-kinase inhibitors, including VEGFR, approved)
In order to acquire motility and invasiveness, carcinoma cells must change their phenotype from a more epithelial mesenchymal phenotype -> EMT (epithelial to mesenchymal transition)
Describe characteristics of Epithelial cells and Mesenchymals
Epithelial cells
- cytokeratin expression
- adherence junction (E-cadherin)
- epithelial cell polarisation
- epithelial markers, E-cadherin, b-catenin
Mesenchymal
- fibroblast-like shape
- increased motility and invasiveness
- secretion of protease (MMPs)
- mesenchymal markers: N-cadherin, vimentin
Theories for site-specific metastasis
Define the following theories
- First pass organ
- Seed and Soil hypothesis
First pass organ
- tumour cells are carried through bloodstream and recolonise in next organ they encounter (e.g lung from breast)
Seed and Soil hypothesis
- provision of a fertile environment which supports the growth of the tumour cells
Name 5 therapies of metastatis diseases and the aim of these therapies
- Radiotherapy
- Chemotherapy
- Targeted therapy
- Hormonal therapy
- Surgery
- control further metastasis
- control the growth of both the primary and secondary tumours
- relieve the symptoms experienced by the patient
Describe the following methods that target the metastatic cascade
- Seeding
- Dormancy
- Metastatic colonisation
- Targeting established metastasis
- Immunotherapy
- Pembrolizumab and nivolumab
Seeding
- invasion, extravasion, EMT
- targeting tumour-tumour, tumour-ECM adhesion molecules, proteases (MMPs), Plasticity programs such as EMT
Dormancy
- to keep cancer cells in the harmless dormant state
- to reactivate dormant cells to increase their susceptibility to anti-proliferative drugs
- to eradicate dormant cancer cells
Metastatic colonisation
- in addition to mutational events, tumour cells alter multiple signalling pathways in order to colonise a foreign organ + cross-talk with the microenvironment
Targeting established metastasis
- drugs must kill tumour cells (cytotoxic) rather than just being cytostatic (stops, slows growth)
- immunotherapy
: a monoclonal antibody that blocks CTLA4
: enhanced the effector T cell subpopulation while downregulating a suppressor T cell subpopulation
