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[MBD] NoNa > Tumour Angiogenesis Invasion and Metastasis > Flashcards

Tumour Angiogenesis Invasion and Metastasis Flashcards

1
Q

What are the characteristics of malignant tumours ?

A

Growth
Unlimited growth - if there is an adequate blood supply. Grows in size + proliferates in number

Invasiveness
Migration of tumour cells from primary site of origin into the surrounding stroma/ECM where they break free and disseminate via vascular or lymphatic channels to distant organs

Metastasis
Spread of tumour cells from the primary site to form secondary tumours at other sites in the body

Loss of apoptosis
Angiogenesis = enhanced blood supply of tumours

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2
Q

Summarise the key steps in cancer progression/metastasis formation

A

1.Transformation
Extensive mutagenic and epigenetic changes followed by clonal selection. Single cell acquires oncogenes/lost tumour suppressor genes = proliferates to form clones.

2.Angiogenesis
New blood vessel formation (overcomes limitations imposed by hypoxia)
Tumour receives Limited oxygen + nutrients.
Nearby capillary forms new blood vessels towards the tumour = more oxygen + nutrients = tumour can expand further.

3.Motility and invasion
Epithelial to mesenchymal transition (acquire invasive properties that allow intravasation into circulation and extravasation from circulation to tissues)
Move through circulation, through the lungs, arrest in lungs/Arrest in distant capillary beds through adhesion molecules on cell surface = extravasation = move out of circulation into local tissue environment, where they will form a new tumour/micrometastases = colonisation

4.Metastais
Colonisation of target organs (ability to expand from micro metastases). Tumour cells colonise a distant organ site.

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3
Q

Outline angiogenesis and the different types of angiogenesis.

A

Angiogenesis = Formation of new blood vessels from pre-existing vessels

1.Developmental/Vasculogenesis
(Organ growth). no pre-existing vessels in developing embryo.

2.Normal angiogenesis
(Wound repair, placenta during pregnancy , ovarian cycle)

3.Pathologocial angiogenesis
(Tumour angiogenesis, ocular disorders, inflammatory disorders). increased blood vessel network makes the tumour more aggressive

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4
Q

What is Vasculogenesis?

A

Vasculogenesis = Formation of new blood vessels from progenitor cells.
endothelial cell progenitors, precursor cells that then form a capillary network

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5
Q

Outline Neovascularisation of tumours

A

The natural formation of new blood vessels

Numerous blood vessels have infiltrated into the tumour tissue

Tumours will generally not grow beyond a size of about 1-2mm without their own blood supply - limited diffusion of oxygen. Tumour then initiates a process to acquire a new network of blood vessels from pre-existing capillaries in that tissue

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6
Q

Outline Tumour Angiogenesis

A

a) small tumour eventually gets to a large enough size when delivery of oxygen and nutrients from nearby capillaries (diffusion) become limiting
b) Tumour switches on expression of angiogenic genes/factors that initiate new blood vessel growth. Stimulus = tumour upregulates angiogenic factors (cytokines + proteins) that allow for new blood vessel growth . Growth factors that act on endothelial cells within a vessel that allow vessel to form a new sprout. + Chemotactic factors allow cells within blood vessels to grow towards the tumour.
c) New network of blood vessels grows in and around the tumour = ⬆ oxygen and nutrients = ⬆ growth + provides a route for cells to shed off and spread.(Metastasis). become motile + invasive

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7
Q

Outline what tumour hypoxia is

A

Tumour hypoxia = strong stimulus for tumour angiogenesis. Causes ⬆ in GFs released from the tumour + angiogenic genes

Hypoxia = low oxygen tension <1% O2

Increases with increasing distance from capillaries
Gets to a certain size + distance away from blood vessel.

Activates transcription of genes involved in angiogenesis , tumour cell migration and metastasis

The oxygen-deprived cells will release growth factors:
Vascular endothelial growth factor (VEGF) = most important GF for new blood vessel formation
Glucose transporter 1( GLUT-1) - glucose uptake. oxygen lack = energy from non-oxphos.
Urokinase plasminogen activator receptor (u-PAR) - invasion + metastasis
Plasminogen activator inhibitor (PAI-1)

Blood vessel endothelial cells, smooth muscle cells, pericytes form a new network of vessels, sprouting off from capillary

slide 6

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8
Q

What are the angiogenic factors ?

A

Tumour cells produce factors :

  • Vascular Endothelial growth factor (VEGF)
  • Fibroblast Growth factor 2(FGF2)
  • Placental growth factor (PIGF)
  • Angiopoietin 2(Ang 2)

These factors are secreted by tumour cells/are stored bound to components of the extracellular matrix + may be released by enzymes called matrix metalloproteinases: (also important to invade cells+TumAng):
Matrix Metalloproteinase 2 (MMP-2)

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9
Q

How do these angiogenic factors then work ?

A

-Tumour releases VEGGF + Ang-2 and bind to receptors on the blood vessel (endothelial cells)
+ other angiogenic growth factors

The biological processes involved in sprouting angiogenesis:

  • Proliferation
  • Migration
  • Invasion. endothelial cells lining blood vessels move into ECM (MMPs)
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10
Q

Outline the vascular endothelial growth factor (VEGF) signalling

A

(SLIDE 12)

VEGF binds to VEGF-R2 on endothelial cells

❶VEGF/VEGF-R2 dimerises (RTyrKin = phosphorylate downstream substrates) at the plasma membrane and recruits cofactors❷ which subsequently phosphorylates/activates 3 major signal transduction pathways ❸ in endothelial cell that increase angiogenesis

Ultimately, VEGF activates cell growth, cell survival, vascular permeability, gene expression and cell proliferation

All of these pathways are essential for angiogenesis - allow endothelial cells to activate to form new vessels

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11
Q

Mechanisms of tumour cell motility & invasion

A
  • Increased mechanical pressure on surrounding environment caused by rapid cellular proliferation.
  • Increased motility of the malignant cells (epithelial to mesenchymal transition of cells)
  • Increased production of degradative enzymes by both tumour cells and stromal cells. to degrade ECM to invade into local tissue space
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12
Q

Outline the Epithelilal-Mesenchymal Transition (EMT)

A

Phenotypic switch of the cells - epithelial cell acquires mesenchymal-type characteristics (motile+invasive properties)

Loss of (epithelial phenotype) :

  • Epithelial shape and cell polarity (beta-catenin,claudin-1) - cell-cell adhesion molecules
  • Cytokeratin intermediate filament expression
  • Epithelial adherens junction proteins(E-cadherin) = cell-cell adhesion molecules

Acquisition of (mesenchymal phenotype):
•Fibroblast-like shape and motility
•Invasiveness
•Vimentin intermediate filament expression
•Mesenchymal gene expression (fibronectin, PDGF receptor, αvβ6 integrin)
•Protease secretion (MMP-2, MMP-9)

  • Downregulate genes/proteins regulating epithelial shape. epithelial cell monolayer.
  • Upregulate genes/proteins regulating mesenchymal shape (fibroblasts). elongated fibroblast extensions, motile, invade = tumour cells
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13
Q

Describe the E-Cadherins

A

E-Cadherins = Cell adhesion molecules expressed in epithelial cells
Form homotypic dimers (two cells are adhered to each other )
Homotypic adhesion molecule dimer (adhesion of 2 diff. cells which both have E-cadherin)
Ca2+-dependent
Inhibits invasiveness
Intracellular domain binds beta-catenin

Cell-cell adhesion (E-cadherin) = contact inhibition = epithelial monolayer
Contact inhibition prevents cells from proliferating further

slide 15

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14
Q

What happens if there is a mutation on E-cadherin ?

A

Cancer cell = mutated/downregulate E-cadherin = loss of contact inhibition = disrupted cell-cell adhesion = no monolayer = proliferation is not inhibited = tumour mass

Disrupted cell-cell adhesion
Mutation/loss of E-cadherin

Loss of contact inhibition cells grow on top of each other
Cells become motile + invasive - release enzymes to invade ECM

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15
Q

Describe a normal cell - Containing E-cadherin

A

Low density
Proliferation
Cell adhesion
Contact inhibition and monolayer of normal cells

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16
Q

What is contact inhibition ?

A

When cells binds to another cell (via E-cadherin dimerisation), there is a signal for them to not migrate /invade

17
Q

Cancer cells secrete …………. that allow for cell ………
………. cells also contribute to cancer cell ………..

A

enzymes (matrix metalloproteinases)
invasion
Stromal cells

18
Q

How do stromal cell contribute to tumour progression ?

A

Factors released by stomal cells (macrophages , mast cells , fibroblasts ) include angiogenic factors, growth factors, cytokines, proteases

Example : Urokinas-type plasminogen activator (uPA)activated by tumour cells -resulting in plasmin production

Plasmin activates matric metalloproteases (MMPS) which permit invasion by degrading extracellular matrix (ECM) and releasing matric-bound angiogenic factors such as transforming growth fasctors-beta 1.

19
Q

Outline the mechanism of action of Urokinase-type plasminogen activator (uPA)

A

Protease -Pro-uPA which will bind to a Urokinase plasminogen activator receptor on cancer cells. It will then activate it to active uPA which can activate plasminogen to plasmin which can also activate downstream enzymes such as pro-MMPs to MMPS which can break down ECM allowing cancer cell to move.
They can also activate latent growth factors
Latent TGF-beta 1 to TGF-B1 (activated)

see slide 16 for my explanation

20
Q

Outline the steps involved in Cancer Dissemination

A

Primary tumour formation, Angiogenesis
Localised motility + invasion
Intravasation
Transport through circulation - systemic vasculature
Arrest in micro vessels of various organs
Extravasation
Formation of a micrometastasis within organ
Colonisation - formation of a macrometastasis, Angiogenesis

21
Q

What are the sites of tumour metastasis ?

A 
Breast - Liver, lung, brain, bone 
Colorectal - Liver, lung
Gastric - Oesophagus, liver, lung
Lung - Adrenal gland, brain, liver 
Pancreatic - liver, lung
Prostate - bone
22
Q

What are the 2 hypotheses of the pattern of tumour spread?

A

Mechanical Hypothesis:
Tumour moves to a local organ
Blood/lymphatic systems - from 1 organ to another
entrapment in capillary beds(20-30 um)

Seed and Soil Hypothesis:
Specific adhesions between tumour cells and endothelial cells in the target organ, creating a favourable environment in the target organ for colonisation
Genetic alteration acquired during progression allow tumour cells to metastasize. acquire mutations whilst circulating, allowing cells to colonise certain distant organs

23
Q

What is the Angiogenesis hypothesis ?

A

Tumour growth is dependent on new blood vessel growth (angiogenesis)
If a tumour could be held indefinitely in the non-vascularised dormant state, it is possible that metastases will not arise.
Inhibit the surrounding vasculature of tumour to keep tumour in inhibited state = cannot metastasise
-Target tumour vasculature rather than the tumour itself
-Both the tumour and its vasculature are valid therapeutic targets

e.g. Kidney cancer /renal cell carcinoma is a highly angiogenic, highly metastatic tumour. - VEGF drives metastasis. Inhibited VEGF.

  • Tumour angiogenesis inhibitors - factors in invasion + metastasis of tumours
  • Targeted therapy to angiogenic factors e.g. VEGF
24
Q

Outline Avastin and what it can be used to treat .

A
  • This is the first anti-angiogenesis drug
  • Specific drug, binds to VEGF
  • Approved for colorectal ,lung ,kidney and ovarian cancers , eye diseases (abnormal angiogenesis in eye diseases = inhibit VEGF)
25
Q

What is the mechanism of action of Avastin?

A

Avastin = anti-VEGF antibody , it binds to VEGF which has been secreted by the tumour.
Avastin prevents VEGF protein binding to the ligand binding site on the receptor of endothelial cell.
= No dimerization (of TyrKinR), No downstream phosphorylation.
=VEGF signal transmission inhibition = no downstream pathway activation
= ↓ in angiogenesis, progression, metastasis and survival of tumour

[MBD] NoNa (28 decks)

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