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2. Foundations of Medicine PoD > Cancer Pathology > Flashcards

Cancer Pathology Flashcards

1
Q

What is cancer

A

disease of the genome occuring as a result of unregulated cell growth

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2
Q

types of cancer cells

A
  • carcinomas= epithelial cells, squamous (flat), cuboidal, columnar-85% of cancers
  • sarcomas= mesoderm cells, bone, muscle
  • adenocarcinomas= glandular cells e.g. breast, oesophagus, lung
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3
Q

10 hallmarks of cancer

A
  1. Sustaining proliferative signaling
  2. Evading growth suppressors
  3. Avoiding immune destruction
  4. Enable replicative immortality
  5. Tumour-promoting inflammation
  6. Activating invasion and metastasis
  7. Inducing angiogenesis
  8. Genome instability and mutation
  9. Resisting cell death
  10. Deregulating cellular energetics
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4
Q

sustaining proliferative signalling

1. hallmark of cancer

A
  • 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
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5
Q

evasion of inhibitory growth signals

2 hallmarks of cancer

A
  • 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
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6
Q

gene silencing

A

interruption or suppresssion of gene expression at transcriptional or translational level

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7
Q

avoiding immune destruction

3 hallmarks of cancer

A
  • 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
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8
Q

what is an immune checkpoint

A

built in control mechanisms that maintain self tolerance during an immune response

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9
Q

Unlimited replicative potential

4 hallmarks of cancer

A
  • 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
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10
Q

tumour promoting inflammation

5 hallmarks of cancer

A
  • 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
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11
Q

Invasion and metastasis

6 hallmarks of cancer

A
  • Cancer cells have ability to migrate and form metastasis
  • Genome mutations may affect the enzymes involved in cell-cell adhesion
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12
Q

Angiogenesis

7 hallmarks of cancer

A
  • creation of blood vessel by tumour to supply oxygen and nutrients
  • new blood vessels are friable leading to tumour cell escape —> metastasis
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13
Q

genomic instability

8 hallmarks of cancer

A
  • 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
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14
Q

evasion of cell death

9 hallmarks of cancer

A
  • 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
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15
Q

deregulating cell energetics

10 hallmarks of cancer

A
  • reprogramming energy metabolism
  • aerobic glycolysis- used by cancer cells to redirect energy (aids growth/division)
  • allows cancer cell to fuel cell growth and division
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16
Q

cell cycle overview

A

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

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17
Q

somatic mutations

A

most common and aquired (not inherited) mutations

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18
Q

germline mutations

A

hereditary

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19
Q

basement membranes

A

made up of extracellular matrix proteins and is supporting structure for many organs and tissue

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20
Q

briefly summarise the extracellular matrix (ECM) and cancer metastasis

A

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

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21
Q

2 different mechanisms and patterns of metastasis

A

Mechanisms:
* Monoclonal
* Polyclonal

Patterns:
* Linear
* Branched

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22
Q

epithelial mesenchymal transition (EMT)

A
  • 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
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23
Q

In essence what does epithelial mesenchymal transition facilitate

A

Change of normal epithelial cell to mesenchymal cell more able to move/spread (cancer)

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24
Q

journey to metastasis

(as part of EMT) 5 steps

A
  1. invasion
  2. intravasation
  3. transport
  4. extravasation
  5. colonisation

followed by angiogenesis

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25
Q

Do all cells in the primary tumour have the ability to metastasise

A

no

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26
Q

invasion

step 1 of EMT journey to metastasis

A
  • 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)
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27
Q

intravasation

journey to metastasis step 2

A

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”
28
Q

transport

journey to meteastasis step 3

A
  • 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)
29
Q

Extravasation

Journey to metastasis step 4

A
  • 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)
30
Q

colonisation

journey to metastasis step 5

A
  • 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
31
Q

angiogenesis

A

formation of new blood vessels and is essential for growth/survival of cancer cells
-angiogenic switch- dependent on inhibitors and inducers

32
Q

angiogenic inducers

(mostly growth factors)

A
  • 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
33
Q

What does VEGF do

A

induces endothelial cell proliferation and also increases permeability and leakage

34
Q

angiogenic inhibitors

just explain some of it.. not sure how much depth so just copied from pp

A
  • 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
35
Q

modalities of cancer therapies currently available

A

surgery, radiation, chemotherapy, immunological manipulation, novel/future modalities from advances in
knowledge of molecular biology

36
Q

Briefly describe some key details/facts about chemotherapy

what is it? what does it do? what does it affect?

A
  • 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)
37
Q

How can chemothereputic drugs be delivered, and what is important to consider

A
  • IV or Oral
  • frequency of administration (target cancer cells at most venerable but give normal cells time to recover)
38
Q

3 “types” of chemotherapy we can give

depending of desired treatment outcome

A
  • Neoadjuvant (before surgery)
  • Adjuvant (reduce risk of returning)
  • Disease control Palliative (control for as long as possible)
39
Q

3 main types of chemotherapy

A
  • 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

40
Q

explain organic drugs in more detail (name all 3 and describe each’s action)

type of chemotherapy

A
  • 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
41
Q

give some side effects of chemotherapy

A

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

42
Q

3 personalised systemic therapies

(specific treatments for individuals with certain genes etc.)

A
  • hormonal therapies - anti-oestrogen, aromatase inhibitors
  • targeted therapies - EGFR, VEGF, CDK 4/6
  • immunotherapy - PD 1, PD -L1, CTLA - 4
43
Q

Explain hormonal therapy (type of personalised systemic therapy) in more detail

give example with breast cancer

A

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
44
Q

targeted therapy (type of personalised systemic therapy) - give key example

A

EGF Receptor signalling pathway

  • how growth signals are transmitted from outside the cell to inside –> leads to proliferation
45
Q

EGF receptor inhibitors

targeted tratment (personalised systemic therapy)

A

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

46
Q

CDK 4/6 inhibitors

targeted therapy (personalised systemic therapy)? - remember cyclin D

A

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

47
Q

haematopoetic stem cells

A

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)

48
Q

immunotherapy-immune checkpoints

A
  • 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
49
Q

immunotherapy- therapeutic agents

maybe just dont bother with this stuff - a lot and not sure if is a LO

A

-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

50
Q

side effects of immunotherapy

A
  • colitis= diarrhoea
  • pneumonitis
  • hypophysitis/thyroid dysfunction/diabetes
  • dermatiti
  • hepatitis
  • nephritis
  • neurological

toxicities manageable with treatment brakes/steroids

51
Q

what 2 theraputic options do we have in cancer and give examples of each

A

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

52
Q

theraputic options of cancer treatment: staging

A

Need to know location (examining/radiology or imaging) and what kind of cancer (pathology/cytology)

53
Q

“local” cancer therapies

A

surgery and radiotherapy - but surgery need anatomical clearance

54
Q

Local cancer therapy: radiotherapy

give a few small details/facts about it (e.g. anatomical…)

A
  • Needs anatomical coverage
  • can treat inoperable lesions
  • Can make surgery possible
  • Can maintain function and/or appearance
55
Q

5 R’s of radiotherapy

A
  • Radiosensitivity
  • Repair
  • Re-population
  • Re-oxygenation
  • Re-assortment (kill canncer cells in sensitive phase of proliferation)
56
Q

Do we only do radiotherapy by itself

A

No, it can be combined with chemotherapy

57
Q

What does radiotherapy have an important role in other than killing cancer cells

A

palliation (improve symptoms)

58
Q

Briefly explain systemic treatment of cancer as a theraputic option of treatment

A

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

59
Q

Indications for use of systemic therapies

A
  • curative
  • adjuvant
  • neoadjuvant
  • palliative
60
Q

What is good about targeted cancer therapies

A

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

61
Q

Give some non-specific and specific immune therapies

theraputic options

A

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)

62
Q

Mechanisms of checkpoint blockade

theraputic options

A

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

63
Q

Monoclonal antiboides (specific immune therapy as part of theraputic options for cancer treatment)

A

Not just confined to cancer but also used in inflammatory diseases

64
Q

how will theraputic options bring about improvements

A
  • 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
65
Q

what is of vital importance in cancer therapy

A

staging

66
Q

what is important in the actions of anti-cancer therapies

Not sure about this, but is LO - maybe google???

A

cell turnover and kinetics

2. Foundations of Medicine PoD (28 decks)

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