Cancer Pathology Flashcards
What is cancer
disease of the genome occuring as a result of unregulated cell growth
types of cancer cells
- carcinomas= epithelial cells, squamous (flat), cuboidal, columnar-85% of cancers
- sarcomas= mesoderm cells, bone, muscle
- adenocarcinomas= glandular cells e.g. breast, oesophagus, lung
10 hallmarks of cancer
- Sustaining proliferative signaling
- Evading growth suppressors
- Avoiding immune destruction
- Enable replicative immortality
- Tumour-promoting inflammation
- Activating invasion and metastasis
- Inducing angiogenesis
- Genome instability and mutation
- Resisting cell death
- Deregulating cellular energetics
sustaining proliferative signalling
1. hallmark of cancer
- aka growth signalling autonomy = lack of regulation of growth factor signalling
- normal cells require an external growth signal to divide - regulated process
- cancer cells bypass normal growth factor pathways leading to unregulated growth - hyperresponsive to growth factors
- occurs as result of acquired mutations - allows self-proliferation + inc levels of receptor proteins on cancer cells
evasion of inhibitory growth signals
2 hallmarks of cancer
- inhibitory growth signals maintain homeostasis within the tissue
- cells are not continuously dividing as a result
- cancer cells ignore these signals- enabled by acquired mutations and gene silencing which corrupts pathways
gene silencing
interruption or suppresssion of gene expression at transcriptional or translational level
avoiding immune destruction
3 hallmarks of cancer
- Immune system can recognise and remove cancer cells
- However, some are able to avoid detection by not initiating an immune response
- cancer cells hijack immune checkpoints and modulate immune response via STING5
what is an immune checkpoint
built in control mechanisms that maintain self tolerance during an immune response
Unlimited replicative potential
4 hallmarks of cancer
- normal cells have counting device (telomeres) that monitor and adjust the number of cell doublings
- once cell numbers reached finite number they enter senescence
- cancer cells maintain telomere length- replication overdrive begins - unregulated
tumour promoting inflammation
5 hallmarks of cancer
- all tumours have inflammatory immune cells - provide growth factors that promote angiogenesis and invasion - new blood vessels
- cell death by necrosis gives rise to inflammation
- necrotic cells release bioactive regulatory factors IL- 1
- inflammatory cells can release radical oxygen species that give rise to mutations
Invasion and metastasis
6 hallmarks of cancer
- Cancer cells have ability to migrate and form metastasis
- Genome mutations may affect the enzymes involved in cell-cell adhesion
Angiogenesis
7 hallmarks of cancer
- creation of blood vessel by tumour to supply oxygen and nutrients
- new blood vessels are friable leading to tumour cell escape —> metastasis
genomic instability
8 hallmarks of cancer
- alterations in DNA lead to instability
- faulty DNA repair pathways or hereditary predisposition contribute to the development of DNA alterations (mutations)
- single point and large chromosomal abnormalities can be found in tumour DNA
- accumulation of mutations over a period of time explains why cancer is more frequent in the ageing population
evasion of cell death
9 hallmarks of cancer
- normal cells undergo cell death in response to extracellular factors or physical damage
- cell death is either regulated (programmed)= apoptosis or unregulated= necrosis
- cancer cells evade death as a result of mutations within the apoptosis pathway
- caspases play central role in apoptosis therefore mutations in this family will allow cancer cells to pass through unchecked
- cell death occurs in physiological conditions e.g. menstruation and in pathological conditions e.g. DNA damage
deregulating cell energetics
10 hallmarks of cancer
- reprogramming energy metabolism
- aerobic glycolysis- used by cancer cells to redirect energy (aids growth/division)
- allows cancer cell to fuel cell growth and division
cell cycle overview
G0= resting phase
G1= cells grow larger and copy organelles
S= cells make a complete copy of DNA
G2= further cell growth
M= 4 phases of mitosis
somatic mutations
most common and aquired (not inherited) mutations
germline mutations
hereditary
basement membranes
made up of extracellular matrix proteins and is supporting structure for many organs and tissue
briefly summarise the extracellular matrix (ECM) and cancer metastasis
ECM directly connected to the cells it surrounds (and blood vessels). By penetrating this matrix cancer cells can move into the blood stream => around body
2 different mechanisms and patterns of metastasis
Mechanisms:
* Monoclonal
* Polyclonal
Patterns:
* Linear
* Branched
epithelial mesenchymal transition (EMT)
- cells must acquire migratory characteristics (be mobile to spread)
- EMT= conversion of closely connected epithelial cells becoming independent mesenchymal cells with the ability to move and invade their local environment
- Is a reversible process
- EMT usually occurs in embryogenesis but also occurs in cancer metastasis
In essence what does epithelial mesenchymal transition facilitate
Change of normal epithelial cell to mesenchymal cell more able to move/spread (cancer)
journey to metastasis
(as part of EMT) 5 steps
- invasion
- intravasation
- transport
- extravasation
- colonisation
followed by angiogenesis
Do all cells in the primary tumour have the ability to metastasise
no
invasion
step 1 of EMT journey to metastasis
- Induction of EMT begins with signal from tumour stroma (HGF, TGF-BETA) stimulate kinase receptors (EFGR) and trigger MAPK pathway (ligand pathway)
- multiple components involved in invasion= cell adhesion molecules, integrins (enable cells to break free becoming mobile), proteases (mark the pathway through ECM, matrix metalloproteins contribute to loss of cell junctions)
intravasation
journey to metastasis step 2
Entry of tumour cells into blood or lymphatics
- tumour cell attaches to stromal side of basement membrane
- MMPs and serin proteases help to degrade basement membrane
- tumour cell passes between the endothelial cells and off into the bloodstream (transendothelial migration) - easy as new blood vessels created for tumour are “leaky”
transport
journey to meteastasis step 3
- tumour cells in bloodstream= circulating tumour cells (CTCs)
- solo travellers vs clumps (emboli)= undirectional
- certain cancers favoured metastatic sites- first pass organ (first one downstream of tumour)
Extravasation
Journey to metastasis step 4
- exit of tumour cells from blood vessels into distant tissues
- tumour cells become trapped in capillaries
- reverse of intravasation
- endothelial side of blood vessel- degrade basement membrane- migrate into stroma
- E- selectin= calcium dependent receptor which enables attachment of cancer cell to endothelium surface of blood vessels and passage through endothelium (transendothelial migration)
colonisation
journey to metastasis step 5
- site of metastasis is determined by point of extravasation but also microenvironment
- environment must be favourable- for tumour to grow it must create new blood vessels (andiogenesis) for nutrients and oxygen
- cells can spread but not colonise- domrant (micrometastases) - period of time before angiogenesis begins
angiogenesis
formation of new blood vessels and is essential for growth/survival of cancer cells
-angiogenic switch- dependent on inhibitors and inducers
angiogenic inducers
(mostly growth factors)
- VEGF (vascular endothelial growth factor) - induces angiogenesis
- VEGF family= A-D and placental growth factorsignals transmitted via VEGF receptors 1-3
- VEGFR must be phosphorylate to become activated
- tumour cells can also stimulate nearby cells to produce VEGF and in turn promote angiogenesis
What does VEGF do
induces endothelial cell proliferation and also increases permeability and leakage
angiogenic inhibitors
just explain some of it.. not sure how much depth so just copied from pp
- Help regulate angiogenesis
- plasminogen cleaved to form angiostatin. endostatin blocks MAPK pathway thus inhibiting gene expression
-concomitant resistance- enabling growth in distant metastases - angiogenic switch controlled by hypoxia
- ** tumours create hypoxic environment** activating HIF1 alpha and beta subunit triggering VEGF
- many drugs have been developed to inhibit angiogenesis e.g. TKI AFTANIB
modalities of cancer therapies currently available
surgery, radiation, chemotherapy, immunological manipulation, novel/future modalities from advances in
knowledge of molecular biology
Briefly describe some key details/facts about chemotherapy
what is it? what does it do? what does it affect?
- compound targeting DNA, RNA and proteins
- Aim to force cells into apoptosis
- Is non-specific to cancer cells so all rapidly dividing cells are affected —> side effects (hair/nausea)
How can chemothereputic drugs be delivered, and what is important to consider
- IV or Oral
- frequency of administration (target cancer cells at most venerable but give normal cells time to recover)
3 “types” of chemotherapy we can give
depending of desired treatment outcome
- Neoadjuvant (before surgery)
- Adjuvant (reduce risk of returning)
- Disease control Palliative (control for as long as possible)
3 main types of chemotherapy
- alkylating agents and platinum drugs= form DNA adducts blocking DNA replication (all phases of cell cycle)
- antimetabolites= structurally mimic essential molecules required for cell division (S phase)
- organic drugs= vinca alkaloids/taxanes/anthracyclines
each work at different points in the cell cycle
explain organic drugs in more detail (name all 3 and describe each’s action)
type of chemotherapy
- vinca alkaloids = bind to tubulin and prevent microtubule assembly in spindle formation
- taxanes = bind to beta tubulin subunit inhibiting depolymerisation and disrupting mitotic spindle - “freeze” spindle at this stage
- anthracyclines = microbial antibiotic targets topiosomerase II
give some side effects of chemotherapy
nausea/vomiting, alopecia, mucositis, pulmonary fibrosis, cadiotoxicity, local reaction, renal failure, myelosuppression, phlebitis, diarrhoea, cystitis, sterility, myalgia, neuropathy
must manage these side effects to dec risk of treatment interruptions
3 personalised systemic therapies
(specific treatments for individuals with certain genes etc.)
- hormonal therapies - anti-oestrogen, aromatase inhibitors
- targeted therapies - EGFR, VEGF, CDK 4/6
- immunotherapy - PD 1, PD -L1, CTLA - 4
Explain hormonal therapy (type of personalised systemic therapy) in more detail
give example with breast cancer
cancers linked to hormones
- breast cancer= oestrogen promotes cell proliferation within breast tissue=> incchance of mutation
- breast cancer drugs= anti- oestrogen=> tamoxipen: binds to oestrogen receptor, aromatase inhibitors=> letrozole: block conversion to androgens to oestrogen
targeted therapy (type of personalised systemic therapy) - give key example
EGF Receptor signalling pathway
- how growth signals are transmitted from outside the cell to inside –> leads to proliferation
EGF receptor inhibitors
targeted tratment (personalised systemic therapy)
tyrosine kinase inhibitors - targets tumours which express EGF receptors => blocks binding to them
-1st generation= gefitnib and erlotinib (reversiable so :( bad)
-2nd generation= afatanib
-3rd generation= osimertinib
-side effects= diarrhoea/dry skin/rash/hypertension/liver dysfunction
CDK 4/6 inhibitors
targeted therapy (personalised systemic therapy)? - remember cyclin D
cyclin dependent kinase inhibitors
-cyclins and cyclin dependent kinases control passage of cells through each phase of cell cycle
-cyclin D + CDK 4/6 pushes cells out of G0-> G1
-cyclin D regulates cyclin E= pushes cells from G1-> S phase
-inhibitors block progression of cells through cell cycle
haematopoetic stem cells
An immature cell that can develop into all types of blood cells, including white blood cells, red blood cells, and platelets (B and T cells mostly)
immunotherapy-immune checkpoints
- immune checkpoints ensure that self tolerance is maintained
- activated by receptor ligand binding (PD-1 to PD-L1)
- immune checkpoint inhibitors= removal of brakes of the immune system allowing increase T cell activity
immunotherapy- therapeutic agents
maybe just dont bother with this stuff - a lot and not sure if is a LO
-pembrolizumab= IgG4 monoclonal antibody
-targeted at PD 1 checkpoint blocking binding to PD -L1 and PD-L2
-in a normal immune response T cells activated and can attack tumour cells
-tumour evasion and T cell deactivation= some tumours can evade immune system through PD-1 pathway, PD-L1 and 2 ligands on tumours can bind with PD1 receptors on T cells to inactivate them
-cell reactivation with pembrolizumab= binds to PD-1 receptor and blocks its interaction with PDL1 and 2 ligands which helps restore immune response
side effects of immunotherapy
- colitis= diarrhoea
- pneumonitis
- hypophysitis/thyroid dysfunction/diabetes
- dermatiti
- hepatitis
- nephritis
- neurological
toxicities manageable with treatment brakes/steroids
what 2 theraputic options do we have in cancer and give examples of each
Prevention:
* environment/behaviour change
* diet
* screening (e.g. cervical/breast cancer)
* genetics (e.g. in CRC is autosomal dominant or BRCA1/2 in breast cancer)
* medication/vaccination
Treatment:
* surgery
* radiotherapy
* systemic therapy
* immunotherapy
theraputic options of cancer treatment: staging
Need to know location (examining/radiology or imaging) and what kind of cancer (pathology/cytology)
“local” cancer therapies
surgery and radiotherapy - but surgery need anatomical clearance
Local cancer therapy: radiotherapy
give a few small details/facts about it (e.g. anatomical…)
- Needs anatomical coverage
- can treat inoperable lesions
- Can make surgery possible
- Can maintain function and/or appearance
5 R’s of radiotherapy
- Radiosensitivity
- Repair
- Re-population
- Re-oxygenation
- Re-assortment (kill canncer cells in sensitive phase of proliferation)
Do we only do radiotherapy by itself
No, it can be combined with chemotherapy
What does radiotherapy have an important role in other than killing cancer cells
palliation (improve symptoms)
Briefly explain systemic treatment of cancer as a theraputic option of treatment
Beneficial for widespread disease but can also have widespread toxicity (now micture of chemotherapy and now targeted agents)
targeted agents have the potential to be very specific:
* hormone therapy: tamoxifen and ER+ve breast cancer
* targeted a tumour mutation: EGFR mutations and TKI agents
Indications for use of systemic therapies
- curative
- adjuvant
- neoadjuvant
- palliative
What is good about targeted cancer therapies
very effective in people with that mutation/receptor/gene so allows for a pateint-specific treatment plan and more likely to cure cancer than a more generic therapy/cure
Give some non-specific and specific immune therapies
theraputic options
Non-specific:
* innate (macrophages and NK cells)
* Programmed cell death pathway (PD-1) - uses immune system to attack foreign cancer cells
Specific:
* monoclonal antibodies
* chimeric antigen receptor (CAR) T-cells (artificial T-cell receptors, using retroviral vectors to give a specific cell killing function directed against cancer cells)
Mechanisms of checkpoint blockade
theraputic options
Don’t kill cancer cells directly but allow immune system to do so
PD-1 and PDL-1 antagonists
Block message from tumour cells saying they’re normal and allows for invasion/attack by immune system
Monoclonal antiboides (specific immune therapy as part of theraputic options for cancer treatment)
Not just confined to cancer but also used in inflammatory diseases
how will theraputic options bring about improvements
- surgical techniques: reduced morbidity
- Radiotherapy: technical combination with systemic treatment
- Systemic treatment: more targeted therapies
- Immunotherapies: monoclonal antibodies, innate immune system, programmed cell death pathway, CAR T-cell therapy
what is of vital importance in cancer therapy
staging
what is important in the actions of anti-cancer therapies
Not sure about this, but is LO - maybe google???
cell turnover and kinetics
