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Molecular Basis of Disease > 23- Tumour Angiogenesis, Metastasis and Invasion > Flashcards

23- Tumour Angiogenesis, Metastasis and Invasion Flashcards

1
Q

what are the three main characteristics of malignant tumours?

A

unlimited growth, invasiveness, metastasis

unlimited growth as long as there’s adequate blood supply, no changes in growth signals

invasiveness - migration of tumour cells, spreading through blood or lymphatic vessels to distant organs

metastasis - spread of tumour cells from primary site to form secondary tumours/ metastatic deposits

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2
Q

list the four steps in (malignant) cancer progression

A

transformation
angiogenesis
motility and invasion
metastasis

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3
Q

describe the four steps in (malignant) cancer progression

A
  1. transformation
    - extensive mutagenic/ epigenetic changes in a cell that activate oncogenes and/or lose function of TS genes allow the cell to transform
    - transformed cell proliferates into a growing clonal cell population, forming the primary tumour
  2. angiogenesis
    - new blood vessels form from existing blood vessels, removing limitation on tumour growth with better nutrient & oxygen supply to the tumour
  3. motility and invasion
    - local blood vessels are invaded, inducing an epithelial to mesenchymal switch
    - tumour cells invade, intravasate and circulate as single cells or clumps
    - may lodge in distant organs or microcapillaries
  4. metastasis
    - extravasation, goes from a micrometastasis to macrometastasis, colonisation of target organs
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4
Q

define angiogenesis

A

the formation of new blood vessels from pre-existing vessels

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5
Q

define vasculogenesis

A

formation of new blood vessels from progenitors - e.g. formation of circulatory system in embryo

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6
Q

what type of angiogenesis occurs in association with tumours?

A

pathological angiogenesis

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7
Q

why is neovascularisation of tumours required?

A

tumours won’t grow beyond 1-2mm3 before their growth is limited

need their own blood supply for tumour growth

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8
Q

what are the 5 steps in tumour angiogenesis?

A
  1. formation of the initial small tumour
  2. initiation of the angiogenic response following hypoxia stimulus
  3. directional growth of new blood vessels
  4. formation of vascular network enhancing oxygen and nutrient supply
  5. increased tumour growth and metastasis
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9
Q

describe the tumour angiogenesis process

A
  1. formation of the small tumour
    - small tumour proliferates, reaches a size (1-2mm3) where oxygen & nutrient supply from nearby capillaries becomes limited
    - hypoxia sets in, acts as a stimulus to induce tumour angiogenesis
  2. initiation of angiogenic response
    - TFs sensitive to oxygen levels and angiogenic genes are upregulated
    - angiogenic factors are released from the tumour to stimulate blood vessel growth
  3. directional growth of new blood vessels
    - nearby capillaries respond to angiogenic factors which create a chemokine gradient, attract blood vessel cells to sprout towards the tumour directionally
  4. formation of vascular network
    - blood vessel networks forms within and around the tumour, enhances oxygen & nutrient supply
  5. enhanced vasculature increases tumour growth, allows tumour cells to shed off and metastasise
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10
Q

summarise the process of tumour angiogenesis

A

small tumour proliferates and grows

size limitation due to inadequate oxygen and nutrient supply - hypoxia sets in

hypoxia stimulus activates angiogenic gene activation & tumour release of angiogenic factors

new blood vessel growth, directional due to chemokine gradient from vessel cells to tumour

enhanced oxygen and nutrient supply with increased vasculature

increased tumour growth and potential for metastasis

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11
Q

define hypoxia

A

low oxygen tension, below 1% oxygen

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12
Q

what is VEGF?

A

vascular endothelial growth factor

an angiogenic factor secreted by tumour cells in hypoxic conditions, stimulates growth of new vessels

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13
Q

name genes and factors upregulated by tumour hypoxic conditions

A

genes:
VEGF
glucose transporter 1
urokinase plasminogen activator receptor
plasminogen activator inhibitor 1

factors:
vascular endothelial growth factor/ VEGF
fibroblast growth factor 2/ FGF 2
placental growth factor/ PIGF
angiopoietin 2/ Ang 2

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14
Q

what is an angiogenic factor?

A

factor produced by tumour cells that stimulate the directional growth of endothelial cells during angiogenesis

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15
Q

what is MMP-2?

A

matrix metalloproteinase 2

enzyme involved in tumour migration, degrades tissue and extracellular matrix, allows tumour to keep moving and invading

can also release angiogenic factors

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16
Q

describe the signalling pathway of VEGF as an angiogenic factor in promoting directional angiogenesis

A

VEGF is released by tumour cells as an angiogenic factor, induced by hypoxia

VEGF binds to VEGF-R2 receptor on endothelial cells and dimerises, recruits co-factors

activates three major signalling pathways:
- Ras-MEK pathway
- DAG-IP3 pathway
- PI3K pathway

pathways collectively activate processes needed for angiogenesis - cell survival, vascular permeability, gene expression, cell proliferation

endothelial cells undergo changes - suppress apoptosis, enhance gene expression and proliferation, increase vascular permeability

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17
Q

what three major signalling pathways are activated by the VEGF/VEGF-R2 signalling pathway?

A

Ras-MEK pathway
DAG-IP3 pathway
PI3K pathway

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18
Q

what four major changes do endothelial cells undergo, activated by the VEGF/VEGF-R2 signalling pathway?

A

suppress apoptosis/ promote cell survival
enhance gene expression
enhance cell proliferation
increase vascular permeability

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19
Q

what three factors affect tumour cells that enhance tumour motility and invasion?

A
  1. increased mechanical pressure from rapid cell proliferation = increase tumour cell invasiveness
  2. increased motility of malignant cells from epithelial to mesenchymal transition = epithelial cells acquire mesenchymal characteristics
  3. increased production of degradative enzymes - e.g. MMPs - by tumour and stromal cells = facilitates tumour invasiveness
20
Q

cause of the EMT transition in cancer cells? what purpose does it serve in encouraging cancer development?

A

cause: cancer cells undergo EMT and lose epithelial characteristics due to changes in oncogenes and TS genes

purpose: lose their compact epithelial shape, transition into fibroblast-like mesenchymal phenotype, increasing tumour motility and invasiveness

21
Q

what epithelial characteristics are lost by cancer cells? list three

A

epithelial cell shape and polarity

cytokeratin intermediate filament expression decreased

epithelial adherens junction protein – E-cadherin – is downregulated

22
Q

what mesenchymal cell characteristics are acquired by cancer cells? list at least 4

A

fibroblast-like shape and motility = increases invasiveness

Vimentin intermediate filament expression

mesenchymal gene expression – fibronectin, PDGF receptor, αvβ6 integrin

increased protease expression – MMP-2 and MMP-9 = promote tissue remodelling

23
Q

what is E-cadherin?

A

a homotypic adhesion molecule exhibited by epithelial cells, maintains cell-cell adhesion through Ca2+ dependent interactions

keeps tight junctions between cells by binding to cells and other molecules through extracellular and intracellular domains, maintaining contact inhibition

24
Q

in terms of the epithelial-mesenchymal transition, how does E-cadherin affect cancer?

A

epithelial cells exhibit E-cadherin as an adhesion molecule that prevents proliferation and invasion of cells in close proximity

epithelial to mesenchymal cell transition results in loss of E-cadherin

this removes the contact inhibition on cancer cells = results in uncontrolled proliferation and increased motility

25
Q

what factors are released by stromal cells (macrophages, mast cells, fibroblasts) to contribute to tumour progression? list at least four

A

angiogenic factors
growth factors
cytokines
proteases = including urokinase-type plasminogen activator (uPA)

26
Q

describe the role of uPA in the plasminogen activation system during tumour progression

A

local stromal cells release uPA = binds to receptors on cancer cells

tumour cells activate uPA = leads to the conversion of plasminogen to plasmin, a proteolytic enzyme.

27
Q

how does plasmin contribute to tumour invasiveness?

A

plasmin is activated by uPA - degrades the extracellular matrix

plasmin also activates MMPs in the tumour microenvironment which:
- further degrade extrac. matrix components
- release latent growth factors
- release matrix-bound angiogenic factors - e.g. TGF-beta1/ transforming growth factor-beta 1

28
Q

what is the overall impact of the plasminogen activation system on tumour progression?

A

promotes the degradation of the extracellular matrix
enhances cancer cell invasiveness
facilitates tumour progression and metastasis

29
Q

describe the plasminogen activation system and its contribution to tumour progression

A

local stromal cells release uPA = binds to its receptors on cancer cells

tumour cells activate uPA = converts plasminogen into active plasmin, a proteolytic enzyme

plasmin activates MMPs in the tumour microenvironment

MMPs have 3 main actions:
- degrade extrac. matrix components
- release latent growth factors
- release matrix bound angiogenic factors such as TGF-B1

facilitate tumour progression and metastasis through enhancing invasion and motility

30
Q

why is the process of cancer dissemination inefficient?

A

tumour cells can extravasate successfully (>80%)

however forming a micrometastasis and colonising to form a macrometastasis is inefficient (<0.02%)

31
Q

list the steps in cancer dissemination from the formation of the initial tumour

A

localised invasion of primary tumour
intravasation
arrest in microvessels
extravasation
micrometastatic formation
angiogenesis of micrometastasis, becomes a clinically significant macrometastasis

32
Q

what are the key steps in cancer dissemination?

A
  1. localised invasion = primary tumour forms and develops a blood supply through angiogenesis
  2. intravasation = tumour cells enter the bloodstream and circulate
  3. arrest in microvessels = influenced by the microenvironment or perhaps the diameter of the capillary, tumour cells arrest in the microvessels of various organs
  4. extravasation = tumour cells exit bloodstream, invade surrounding tissue
  5. micrometastasis forms in new tissue = inefficient process
  6. angiogenesis of micrometastasis = micrometastasis establishes blood supply for further growth, progresses into a clinically significant metastasis
33
Q

list the four factors/reasons that determine the pattern of tumour spread

A

vascular properties of organs/tissues
anatomical features of blood/lymph vessels
seed and soil hypothesis
genetic alterations

34
Q

describe the vascular properties that may influence the pattern of tumour spread?

A

different endothelial cells in microvessels of organs, size and characteristic of blood vessels

  • different endothelial cells in various organs have distinct properties that attract tumour cells
  • features of blood vessels - e.g., size, characteristics - influence the pattern of tumour spread.
35
Q

describe the anatomical considerations/ features of blood and lymph vessels that may influence the pattern of tumour spread?

A

tumour cells (20-30μm) may get entrapped in capillary beds (approx. 8μm)

anatomical features of blood and lymphatic systems determine the pattern of tumour spread

36
Q

describe how the seed and soil hypothesis may influence the pattern of tumour spread?

A

specific adhesions between tumour cells and endothelial cells in the target organ create a favourable microenvironment for colonisation

37
Q

describe the genetic alterations that may influence the pattern of tumour spread?

A

specific genetic changes acquired during tumour progression enable cells to metastasise = changes result in a preference for a specific organ or organs during metastatic spread

38
Q

example of breast cancer and its preferential metastatic pattern?

A

breast cancers often preferentially metastasise to bone, brain, lung, and/or liver

39
Q

what are the targeted approaches in cancer therapy for angiogenesis, cell motility, and invasion? how successful have they been?

A

angiogenesis = targeted therapies against angiogenic factors - e.g. Avastin for VEGF - have successfully inhibited tumour angiogenesis

cell motility = targeting cell-cell adhesion molecules involved in cell motility, less successful

invasion = targeting MMPs to reduce invasion, less successful

40
Q

what is the angiogenesis hypothesis of 1971? what does this imply in terms of targeted therapy for tumours?

A

suggests that tumour growth depends on the formation of new blood vessels, and stopping angiogenesis could prevent metastases

both the tumour and microvascular compartments could be valid therapeutic targets - targeting the tumour and/or blood vessels supporting its growth

41
Q

what is Avastin? what cancers does it specifically treat?

A

first specific anti-angiogenesis drug

a monoclonal antibody used in the treatment of colorectal, lung, kidney, and ovarian cancers, as well as eye diseases

42
Q

mechanism of action of Avastin?

A

Avastin binds to VEGF, prevents its binding to VEGF-R2 receptors on endothelial cells

decreases circulating VEGF from the tumour, inhibiting tumour angiogenesis and metastasis.

43
Q

LO: Describe the sequential process of metastasis and common sites of metastatic spread

A
44
Q

LO: Define angiogenesis and its role in tumour expansion

A
45
Q

LO: Explain epithelial to mesenchymal transition in tumour cells and the role of adhesion molecules

A
46
Q

LO: Explain how proteases facilitate tumour cell invasiveness

A
47
Q

LO: Understand how targeted therapies can slow tumour progression

A

Molecular Basis of Disease (20 decks)

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