Tumour Angiogenesis, Invasion & Metastasis

Question 1

Describe growth as a characteristic of malignant tumours

Answer 1

Growth

Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available

Question 2

Describe invasiveness as a characteristic of malignant tumours

Answer 2

Invasiveness

Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs

Question 3

Describe metastasis as a characteristic of malignant tumours

Answer 3

Metastasis

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

Question 4

Summarise the key steps in cancer progression

Answer 4

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

Question 5

What is angiogenesis

Answer 5

Angiogenesis is the formation of new blood vessels from pre-existing vessels

Question 6

What is vasculogenesis

Answer 6

Vasculogenesis is the formation of new blood vessels from progenitors

Question 7

List then describe effects of the types of angiogenesis

Answer 7

Developmental/ vasculogenesis = organ growth

Normal
angiogenesis = wound repair
placenta during pregnancy
cycling ovary

Pathological angiogenesis = tumour angiogenesis
ocular and
inflammatory disorders

Question 8

Describe tumour size limit

Answer 8

Tumours will generally not grow beyond a size of about 1-2mm3 without their own blood supply

Question 9

Describe the process of angiogenesis

Answer 9

Small tumour releases angiogenic factors
Which leads to a sprouting capillary which in turn leads to a growing tumour due to the release of nutrients from blood and metastatic spread through the tumour

Question 10

Define tumour hypoxia

Answer 10

Hypoxia is a strong stimulus for tumour angiogenesis

Hypoxia – low oxygen tension <1% O2

Question 11

Describe link between tumour hypoxia and distance from capillary

Answer 11

Increases with increasing distance from capillaries

Question 12

Describe effect of tumour hypoxia

Answer 12

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

Question 13

List 4 angiogenic factors

Answer 13

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)

Question 14

Describe secretion of angiogenic factors

Answer 14

These factors are secreted by tumour cells or are stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases

Question 15

Describe mechanisms of tumour cell motility and invasion

Answer 15

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

Question 16

What is lost in epithelial-mesenchymal transition

Answer 16

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

Question 17

What is acquired in epithelial-mesenchymal transition

Answer 17

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)

Question 18

Describe the use of E-cadherins

Answer 18

E-Cadherins:

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

Question 19

Describe the use of integrins

Answer 19

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

Question 20

Explain effect of factors released by stromal cells by giving an example

Answer 20

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

Question 21

Explain effect of plasmin

Answer 21

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

Question 22

Describe cancer dissemination

Answer 22

Primary tumour formation → localized invasion → intravasation (interaction w/platelets, lymphocytes + other blood components) → transport through circulation → arrest in microvessels of various organs → extravasion → formation of metastasis →colonization - formation of macrometastasis

Question 23

List sites of tumour metastasis

Answer 23

Breast
Colorectal
Gastric
Lung (non-small cell)
Pancreatic cell
Prostate

Question 24

Describe mechanical hypothesis

Answer 24

The ‘mechanical’ hypothesis states that metastasis is likely to occur at sites based on the pattern of blood flow

Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)

Question 25

Describe seed and soil hypothesis

Answer 25

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

The seed and soil hypothesis states that metastatic tumor cells will metastasize to a site where the local microenvironment is favorable

Question 26

Describe the success in targeting tumour angiogenesis to inhibit cancer

Answer 26

Tumour angiogenesis

Success with targeted therapy to angiogenic factors like vascular endothelial growth factor

Question 27

Describe the success in targeting cell motility to inhibit cancer

Answer 27

Cell motility

No success with targeting cell-cell adhesion molecules or integrins

Question 28

Describe the success in targeting invasion to inhibit cancer

Answer 28

Invasion

All clinical trials with matrix metalloproteinases have been unsuccessful in reducing tumour burden!

Question 29

Describe folmans’s work in the angiogenesis hypothesis

Answer 29

1971 – Angiogenesis hypothesis
Tumour growth dependent on new blood vessel growth
“If a tumor could be held indefinitely in the non-vascularized dormant state….it is possible that metastases will not arise”
Paradigm shift in cancer therapy
- Both the tumour and microvascular compartment are valid therapeutic targets

Question 30

What is avastin - used for what?

Answer 30

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

Question 31

Describe avastin’s mechanism

Answer 31

A monoclonal antibody
Which binds to VEGF
Prevents VEGF binding to VEGF receptors on endothelial cells
Leads to VEGF-signal transmission inhibition
= so no angiogenesis, progression, metastasis or survival