17. Tumour Angiogenesis, Invasion and Metastasis Flashcards Preview

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Flashcards in 17. Tumour Angiogenesis, Invasion and Metastasis Deck (16)
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1
Q

What are some characteristics of malignant tumours?

A
GROWTH
Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available to prevent hypoxia.

INVASIVENESS
Migration of tumour cells into the surrounding stroma where they are free to 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

2
Q

What are the sequential steps of the process of metastasis?

A
  1. Transformation
  2. Angiogenesis
  3. Motility and invasion (through capillaries, venules, lymphatic vessels)
  4. Multicell aggregates (lymphocytes, platelets)
  5. Transport (embolism and circulation)
  6. Adherence (arrest in capillary beds)
  7. Extravasation into organ parenchyma
  8. Response to microenvironment
  9. Tumour cell proliferation and angiogenesis
  10. Metastasis
  11. Metastasis of metastases
3
Q

Summarise the key steps in cancer progresssion.

A
  • Extensive mutagenic and epigenetic changes followed by clonal selection
  • Angiogenesis (overcomes limitations imposed by hypoxia)
  • Epithelial to mesenchymal transition (invasive properties allowing intravasation and extravasation)
  • Colonisation of target organs (ability to expand from micrometastases)
  • Release of metastatic cells that have acquired the ability to colonise
4
Q

What is angiogenesis and vasculogenesis?

A
  • Angiogenesis is the formation of new blood vessels from pre-existing vessels
  • Vasculogenesis is the formation of new blood vessels from progenitors
5
Q

What are the different types of angiogenesis?

A
  1. Developmental/ vasculogenesis ~ organ growth
  2. Normal angiogenesis ~ wound repair, placenta during pregnancy, cycling ovary
  3. Pathological angiogenesis ~ tumour angiogenesis, ocular and inflammatory disorders
6
Q

What stimulates tumour angiogenesis?

A
  • Hypoxia is a strong stimulus for tumour angiogenesis
  • Hypoxia – low oxygen tension <1% O2
  • Increases with increasing distance from capillaries
  • Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis
7
Q

What actually prompts the formation of the new blood vessels?

A

Some tumour cells produce factors that stimulate the directional growth of endothelial cells:

  • Vascular Endothelial Growth Factor (VEGF)
  • Fibroblast Growth Factor-2 (FGF-2)
  • Transforming Growth Factor-β (TGF- β)
  • Hepatocyte growth factor/scatter factor (HGF/SF)

These factors are mainly stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases

8
Q

What are some mechanisms of tumour cell invasion?

A
  • Increased mechanical pressure caused by rapid cellular proliferation
  • Increased motility of the malignant cells (epithelial to mesenchymal transition)
  • Increased production of degradative enzymes by both tumour cells and stromal cells
9
Q

Describe the epithelial-mesenchymal transition. - what is lost/acquired?

A

LOSS OF:

  • Epithelial shape and cell polarity
  • Cytokeratin intermediate filament expression
  • Epithelial adherens junction protein (E-cadherin)

ACQUISITION OF:

  • Fibroblast-like shape and motility
  • Invasiveness
  • Vimentin intermediate filament expression
  • Mesenchymal gene expression (fibronectin, PDGF receptor, αvβ6 integrin)
  • Protease secretion (MMP-2, MMP-9)
10
Q

Describe E-cadherins.

A
  • Homotypic adhesion molecule (adhesion of cells with the same cadherin)
  • Calcium-dependent
  • Inhibits invasiveness
  • Binds β-catenin
11
Q

Describe integrins.

A
  • Heterodimers (α and β subunits)
  • Heterotypic adhesion molecule
  • Adhesion to extracellular matrix (via collagen, fibronectin, laminin)
  • Cell migration
12
Q

Describe stromal cell contribution to tumour progression.

A

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

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

Plasmin activates matrix metalloproteinases (MMPs), which permit invasion by degrading extracellular matrix (ECM) thus releasing matrix-bound angiogenic factors

13
Q

What are the steps involved in cancer dissemination?

A
  • Primary tumour formation
  • Localised invasion
  • Intrainvasion (interaction with platelets, lymphocytes and other blood components)
  • Transport through circulation
  • Arrest microvessels of various organs
  • Extrainvasion
  • Formation of micrometastasis
  • Colonisation: formaiton of a macrometastasis

The overall process is highly inefficient: tumour cells can extravasate successfully (>80%) but the last two steps are very inefficient (<0.02% of cells actually form micrometastases).

14
Q

From breast, colorectal, gastric, lung (NSCLC), pancreatic and prostatic cancer, what are the common sites of tumour metastases?

A
  • BREAST: brain, lung, liver, bone
  • COLORECTAL: liver, lung
  • GASTRIC: liver, oesophagus, lung
  • LUNG (NSCLC): brain, bone, liver, adrenal gland
  • PANCREATIC: liver, lung
  • PROSTATIC: bone
15
Q

What determines the pattern of tumour spread?

A
  1. MECHANICAL HYPOTHESIS
    Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)
  2. 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 alterations acquired during progression allow tumour cells to metastasize.
16
Q

What is Avastin and how does it work?

A

First specific anti-angiogenesis drug
in 2013 was the second biggest selling oncology product
Approved for colorectal, lung, kidney and ovarian cancers and eye diseases

Works by:

  • monoclonal antibody
  • binds to VEGF
  • prevents VEGF binding to VEGF receptors on endothelial cells

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