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B353 > L1, Tumour Growth and Development > Flashcards

L1, Tumour Growth and Development Flashcards

1
Q

What proportion of death in the UK did cancer make up in 2000 vs 2019?

A
  • 2000: ~25%
  • 2019: ~30%
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2
Q

What is cancer?

  • Outline the basic features
  • Carcinomas and their prevalence
  • Deaths worldwide, 2020
A
  • Collection of over 200 different diseases
  • Abnormally proliferating cells capable of spreading into surrounding tissue and other parts of the body
  • Carcinomas are derived from epithelial cells; >80% of cancers
  • 10 million deaths worldwide
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3
Q

Describe the trends in cancer with age:

A
  • Cancer incidence increases with age (longer life = more opportunity to acquire mutations in proto-oncogenes/tumour suppressors)
  • This is the case in almost all cancers
  • Exception: Leukeamia; peak in infancy; inherited mutations
  • See FC
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4
Q

How may a cancer karyotype differ from a normal cell?

A
  • Cancers are genetically unstable
  • Could have aneuploidy (wrong number of chromosomes)
  • Often extensive chromosomal rearrangements
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5
Q

Vogelstein model:

A
  • Model for colorectal cancer development (multi-step; clinical progression driven by acquisition of genetic changes)
    1. Normal epithelium
    <-Loss of APC
    2. Hyperplastic epithelium
    <-DNA hypomethlyation
    3. Early…IM…Late adenomas
    <- activation of K-ras….loss of 18q TSG
    <-Loss of p53
    4. Carcinoma
    5. Invasion and metastasis
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6
Q

Why are cancers hard to detect early?

A
  • Issue arises in the detection of tumours of a small size
  • Tumour must reach 10^8 cells before it can be detected via X-ray
  • Death of patient occurs by 10^12 cells; small window for detection
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7
Q

Why is vascularisation a key factor for tumour growth?

A
  • Tumour cells require a lot of nutrients since they are proliferating rapidly
  • Growth is thus limited by how far oxygen can diffuse from nearest circulation
  • Tumours will grow to a maximum of ~1mm in diameter without new blood vessel growth
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8
Q

How does angiogenesis differ in healthy vs cancerous cells?
Describe the process of ‘Angiogenic Switch’

A
  • In wound healing, angiogenesis is required but occurs in a very regulated manner
  • In cancer, however, this process is dysregulated to promote proliferation:

Angiogenic Switch
1. Perivascular detachment and vessel dilation
2. Onset of angiogenic sprouting
3 Continuous sprouting, new vessel formation + maturation, recruitment fo perivascular cells
4. Tumour vasculature (Characteristic chaotic organisation with gaps in capillary wall to permit plasma fluid -> high hydrostatic pressure)

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9
Q

Give examples of inhibitors vs activators of angiogenesis:

A

Activators: (Typically RTKs)

  • VEGF-A, -B, -C
  • FGF1, 2
  • other FGFs

Inhibitors:

  • thrombospondin-1, -2
  • interferon alpha/beta
  • angiostatin
  • endostatin
  • collagen IV fragments
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10
Q

What is metastasis? What must happen for it to take place?

A
  • Escape of cancer cells form primary site, establishment at distant secondary sites
  • ~90% cancer mortality
  • Must escape basement membrane (acellular structure comprised of extracellular matrix proteins; lamins, collagen, proteoglycan)
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11
Q

Outline the steps in metastasis:

A
  1. Local invasion (+EMT)
  2. Intravasion and transport through circulation
  3. Arrest and extravasation
  4. Colonisation
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12
Q

How does a primary tumour invade local cells and breach the basement membrane? How is this beneficial to the tumour?

A
  • Secretion of proteases (e.g. matrix metalloproteases) by tumour cells or adjacent stroma allows breach of basement membrane
  • Tumour can thus invade local stroma (no longer benign)
  • The extracellular matrix also serves as a reservoir for growth factors; degradation of basement membrane permits access and facilitates further proliferation
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13
Q

What is the EMT? (Why is it useful, what changes occur…)
Which transcription factors are involved?

A
  • EMT: Epithelial to mesenchymal transition
  • More motile and invasive phenotype adopted by tumour cells
  • More fibroblastic phenotype, more resistance to apoptosis
  • Cells repress expression of e-cadherins, upregulate expression of n-cadherin (weaker links)
  • Governed by expression of Twist, Snail (SNAI1), Slug (SNAI2)
  • Often induced in stroma (i.e. TME)
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14
Q

Why may transport through circulation threaten tumour cells?
Give a mechanism that protects cells in this scenario

A
  • Anoikis
  • Hydrodynamic stress
  • Cancer cells can interact with platelets to from microthrombi -> protects for stresses of circulatory system
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15
Q

How does extravasation take place? (Main and additional)

A
  • Cells become lodged in a microvessel and can then extravasate
  • Begins proliferating, typically involves MET
  • Alternatively: Tether and roll model facilitated by HSPGs; hijacking a process normally used for dissemination of leukocytes in wound healing
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16
Q

What factors might dictate where a particular cancer metastasises to (with a key example)? What hypothesis does this relate to?

A
  • Similar/favourable conditions to tissue of origin (‘Seed and soil’ hypothesis)
  • Circulation (i.e. path taken
    e.g. Panreatic primary tumours -> Liver (majority; first stop after colon in system)
    -> Lungs (minority)
17
Q

Describe the TNM system for cancer characterisation

A
  • T: Size of tumour (T1 (small) to T4)
  • N: Local Spread to lymph nodes (N0-3)
  • M: Metastasis (0 or 1)
18
Q

How are lymph nodes relevant to cancer progression?

A
  • Often used to detect whether a cancer has spread
  • Act as ‘sentinels’; is fluid draining from the tumour into a particular node?)
19
Q

How might a cancer be imaged?

A
  • CT/PET scan
  • Typically use radioimaging; labelling areas of high glucose uptake for example
    -> Warburg effect (high glucose uptake by cancer cells)
  • 18-Fluorine labelled FDG commonly used in PET scanning
20
Q

Give the original 6 hallmarks of cancer:
(Hannahan and Weinberg)

A
  1. Sustained proliferative signalling
  2. Evading growth suppressors
  3. Activating invasions and metastasis
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. Resisting Cell death
21
Q

What 4 updates were added to the hallmarks of cancer in 2011:
(Hannahan and Weinberg)

A
  1. Avoiding immune destruction
  2. Tumour-promoting inflammation
  3. Genome instability and mutation
  4. Deregulating cellular energetics
22
Q

+ What is anoikis and how is it carried out?

A
  • Programmed cell death induced upon detachment form E-C matrix (Greek for ‘homelessness’)
  • Critical for preventing adherent-independent cell growth and attachment to inappropriate matrix -> prevents colonisation
  • Pathways for anoikis converge in caspase activation and subsequent activation of endonucleases, DNA fragmentation and cell death
23
Q

+ How do cancer cells resist anoikis?

A
  • EMT: Confers anoikis resistance (as well as anchorage-independent growth)
  • Further mechanisms for resistance: change in integrins’ repertoire -> can grow in different niches, alongside various hallmark molecular features
  • Tumour microenvironment also contributes to anoikis resistance in bystander cancer cells -> modulates matrix stiffness, enhances oxidative stress, pro-survival soluble factors, EMT etc
24
Q

+ What two forms do anti-angiogenic therapies take?

A
  • Antibodies
  • Tyrosine kinase inhibitors
  • Whilst a few of these drugs have been approved for use, they generally provide limited success; short term relief and only modest survival benefits -> see broad variety in mechanisms for angiogenesis both in healthy and cancerous tissue
25
Q

+ What two ways can tumours become vascularised?

A
  • Co-option of pre-existing vasculature
  • Inducing new vessel formation
26
Q

+ Outline 3 mechanisms for formation of new blood vessels in cancer:

A
  • Intussuscpetive angiogenesis (new vasculature where a pre-existing vessel splits in two)
  • Vasculogenic mimicry (vessel-like structures formed by tumour cells; more common in aggressively growing tumours)
  • Transdifferentiation of cancer cells (Cancer cells -> CSCs -> Epithelial cells near vasculature)
  • Neo-vascularisation in normal tissues and tumours occurs through one or more of various mechanisms
27
Q

+ Angiogenesis is involved in what 3 processes in healthy tissues?

A
  • Development
  • Menstrual cycle
  • Wound healing
28
Q

+ Vasculature organisation in healthy vs cancerous tissues:

A
  • Tightly controlled in all cases of healthy tissues -> ordered division of ‘vascular tree’
  • Conversely, in tumours the organisation is chaotic with lacking maturation, heterogeneity in sizes of similar types of vasculatures, unregulated bloodflow etc -> areas of persisting or intermittent hypoxia
  • Partial detachment of pericytes and uneven distribution of basement membrane -> fragility and risk of hemhorrage
29
Q

+ Alternative routes for the tumour cell to invade beyond tissue of origin

A
  • Whilst blood-borne cancers (hematogenous) are most common, cancers can also travel via the nervous system or along the basal side of endothelial cells
  • They can travel through the lymphatic system
  • They can travel along coelomic cavities
30
Q

+ Broad types of mutation in development of cancer:

A
  • Driver
  • Passenger
  • Hitchhiker
31
Q

+ Are developmental and cancerous EMT equivalent?

A
  • Whilst they share many features, they are not equivalent at a molecular level

B353 (15 decks)

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