ANGIOGENESIS
BI3325- CANCER BIOLOGY: ADVANCES IN MECHANISMS AND TECHNIQUES
Contents
BI3325- Cancer biology: Advances in mechanisms and techniques.......................................................... 1
Contents ............................................................................................................................................. 1
Angiogenesis 1 30.10.2017 ................................................................................................. 1
Extra reading ................................................................................................................................. 10
Angiogenesis 2 31.10.2017 ............................................................................................... 11
Extra Reading ................................................................................................................................ 21
Angiogenesis 3 06.10.2017 .............................................................................................. 22
Extra reading ................................................................................................................................. 31
Angiogenesis 1
30.10.2017
Synopsis
Detail the consequences of poor vascularisation
Overview the differences between the occurrence of normal and pathological angiogenesis and
the structure of the resulting vasculature.
Briefly overview the processes involved in angiogenesis (normal and abnormal)
Describe the molecules that regulate angiogenesis, these become unbalanced in cancer
Discuss the role of HIF (hypoxia inducible factor) in promoting angiogenesis and its potential as
a therapeutic target.
Angiogenesis
Angiogenesis is the formation of new blood vessels by ‘sprouting’.Sprouting is forming from existing
vasculature. It is essential for tumour growth and facilitates metastasis. So development of a tumour
blood system is the regulating step in tumour growth. If a tumour cuts off its own blood supply then it is
not going to be able to grow. The classic model of the regulation of tumour angiogenesis is illustrated
by a scale laden with anti-angiogenic molecules on one side and pro-angiogenic molecules on the
other. Induction of the angiogenic switch depends on how heavily that balance tips in favour of pro-
angiogenesis. Pro-angiogenic gene expression is increased by physiological stimuli such as hypoxia
which results from increased tumour mass and also by oncogene activation or tumour suppressor
mutation.
Dormant lesions and premalignant lesions also initiate neovascularisation which allows them to
progress.
,The leaky vasculature facilitates the escape of cancer cells into the blood system allowing them to
transport around the body and therefore facilitating metastasis. Therefore angiogenesis is a very
important therapeutic target in cancer treatment.
Poor vascularisation causes necrosis in tumours. Cell must be within ~100-200 um of a blood vessel to
gain sufficient oxygen.This distance represents the diffusion distance of oxygen. Beyond this distance,
cell die via necrosis (dark granular staining
in left picture) due to lack of oxygen.
Necrosis is accidental or traumatic cells
death and one of the causes is hypoxia
known as a lack of oxygen. In the image on
the right the bright red areas are hypoxic:
green indicates capillaries. If the hypoxia is
sustained then the cells are irreversibly damaged and die from necrosis. Sourrounding the capillary is an
area of healthy tissue the dark regions are areas that are dying from necrosis. If a tmour needs to grow
without becoming necrotic, it has to form its own blood supply.
Histology of a Blood Vessel
Blood vessels are formed of 3 layers; endothelium, pericyte and
basement membrane.
Endothelial cell (grey)
o Basic by cell (forms endothelium)
Basement membrane (thick green line)
o Surrounds endothelium
Pericytes (yellow/green outline)
o Sit on the basement membrane
o These are undifferentiated cells by their markers
show they are related to vascular smooth
muscle
o They send survival signals to the endothelium and provide vascular support
o Can differentiated into a fibroblast, macrophage or smooth muscle
o Perivascular cells i.e. related to vascular smooth muscle
o Share basement membrane with endothelium
Normal and Abnormal Angiogenesis
Normal Angiogenesis
Angiogenesis is a normal process during periods of active growth, therefore embryogenesis.
Ambriogenesisi is purely sprouting of vessels from existing vessels. There are also periods in childhood
and adulthood were angiogenesis is needed.
, Embryogenesis:
o Primitive bv network formed from endothelial precursor cells (ECPs)
o New capillaries ‘angiogenically sprout’ from bv (blood plexus) network
o During embryonic vasculogenesis blood vessles are formed in vivo from endothelial cell
precurors or ‘angioblasts’ that assemble into a primary capillary plexus
During adulthood:
o Growth
o Female reproductive cycle- as the endometrium (highly vascularised tissue) is produced
o Wound healing- the tissue needs regenerating so a blood supply is needed
o Vasculature is usually quiescent in adults, this is one of the characteristics of tumour
blood vessels in that they fail to become quiescent
These processes are stable
Abnormal Angiogenesis
Tumours have been described as wounds that never heal. In order to facilitate angiogenesis you have to
destabalise blood vessels.
Tumourigeneic process
Unstable and dynamic process- it is unstable as there is an imbalance in the regulators
Differences between normal and tumour vasculature
Compared with normal bvs (blood vessels),
tumour bvs are:
o Irregularly shaped- can have dead
ends, have dead ends are dilated and
tortuous
o Pericytes are loosely attached or
sparsely distributed whereas in
normal tissue that are closely
attached and high in number
o Fail to stabalise properly due in part to the lack of pericyte attachment(facilitates more
sprouting)
o Dilated and don’t have any hierarchy, unlike normal tissue i.e. looks like a mess/chaotic
and disorganised
o Lack organisation and leaky due to the tissue over producing vascular endothelial
growth factor
This structure does not provide the most efficient blood flow, however it is enough to allow the tumour
to continue growing. It also reduces the effectiveness in chemotherapy getting to the tissue.
, Pericyte-Endothelial Cell Association in
Blood Vessels
In normal vessels, pericytes (red) form a
substantial covering around the
endothelial cells (green) of larger vessels
(A), a tight but sparser covering in
capillaries (B) but are less abundant and
loosely attached in tumour vessels (C). In
C the processes are just about touching
the basement membrane. This is a very
unstable vessel.
Activation of Angiogenesis in Tumours
Angiogenesis can be switched on at different/any
stages of the tumour life cycle
o Depends on tumour type and
microenvironment
It happens in two phases: avascular and vascular
Avascular phase: Dormant lesion and no
angiogenesis. They have reached a steady state
between growth and cell death
o These lesions often don’t cause clinical
symptoms and don’t seem to have any ill
effects
o This is a potential problem in screening for cancers as you do not know whether it will
turn on angiogenesis and grow rapidly or whether it will stay in this state for a long time
Therefore should you treat these if you find them?
Vascular phase: activation of angiogenesis, allowing tumour growth and spread
o The tumour has activated angiogenesis. This causes the tumour to spread and progress.
It is not clear why some avascular lesions turn on angiogenesis and others do not
BI3325- CANCER BIOLOGY: ADVANCES IN MECHANISMS AND TECHNIQUES
Contents
BI3325- Cancer biology: Advances in mechanisms and techniques.......................................................... 1
Contents ............................................................................................................................................. 1
Angiogenesis 1 30.10.2017 ................................................................................................. 1
Extra reading ................................................................................................................................. 10
Angiogenesis 2 31.10.2017 ............................................................................................... 11
Extra Reading ................................................................................................................................ 21
Angiogenesis 3 06.10.2017 .............................................................................................. 22
Extra reading ................................................................................................................................. 31
Angiogenesis 1
30.10.2017
Synopsis
Detail the consequences of poor vascularisation
Overview the differences between the occurrence of normal and pathological angiogenesis and
the structure of the resulting vasculature.
Briefly overview the processes involved in angiogenesis (normal and abnormal)
Describe the molecules that regulate angiogenesis, these become unbalanced in cancer
Discuss the role of HIF (hypoxia inducible factor) in promoting angiogenesis and its potential as
a therapeutic target.
Angiogenesis
Angiogenesis is the formation of new blood vessels by ‘sprouting’.Sprouting is forming from existing
vasculature. It is essential for tumour growth and facilitates metastasis. So development of a tumour
blood system is the regulating step in tumour growth. If a tumour cuts off its own blood supply then it is
not going to be able to grow. The classic model of the regulation of tumour angiogenesis is illustrated
by a scale laden with anti-angiogenic molecules on one side and pro-angiogenic molecules on the
other. Induction of the angiogenic switch depends on how heavily that balance tips in favour of pro-
angiogenesis. Pro-angiogenic gene expression is increased by physiological stimuli such as hypoxia
which results from increased tumour mass and also by oncogene activation or tumour suppressor
mutation.
Dormant lesions and premalignant lesions also initiate neovascularisation which allows them to
progress.
,The leaky vasculature facilitates the escape of cancer cells into the blood system allowing them to
transport around the body and therefore facilitating metastasis. Therefore angiogenesis is a very
important therapeutic target in cancer treatment.
Poor vascularisation causes necrosis in tumours. Cell must be within ~100-200 um of a blood vessel to
gain sufficient oxygen.This distance represents the diffusion distance of oxygen. Beyond this distance,
cell die via necrosis (dark granular staining
in left picture) due to lack of oxygen.
Necrosis is accidental or traumatic cells
death and one of the causes is hypoxia
known as a lack of oxygen. In the image on
the right the bright red areas are hypoxic:
green indicates capillaries. If the hypoxia is
sustained then the cells are irreversibly damaged and die from necrosis. Sourrounding the capillary is an
area of healthy tissue the dark regions are areas that are dying from necrosis. If a tmour needs to grow
without becoming necrotic, it has to form its own blood supply.
Histology of a Blood Vessel
Blood vessels are formed of 3 layers; endothelium, pericyte and
basement membrane.
Endothelial cell (grey)
o Basic by cell (forms endothelium)
Basement membrane (thick green line)
o Surrounds endothelium
Pericytes (yellow/green outline)
o Sit on the basement membrane
o These are undifferentiated cells by their markers
show they are related to vascular smooth
muscle
o They send survival signals to the endothelium and provide vascular support
o Can differentiated into a fibroblast, macrophage or smooth muscle
o Perivascular cells i.e. related to vascular smooth muscle
o Share basement membrane with endothelium
Normal and Abnormal Angiogenesis
Normal Angiogenesis
Angiogenesis is a normal process during periods of active growth, therefore embryogenesis.
Ambriogenesisi is purely sprouting of vessels from existing vessels. There are also periods in childhood
and adulthood were angiogenesis is needed.
, Embryogenesis:
o Primitive bv network formed from endothelial precursor cells (ECPs)
o New capillaries ‘angiogenically sprout’ from bv (blood plexus) network
o During embryonic vasculogenesis blood vessles are formed in vivo from endothelial cell
precurors or ‘angioblasts’ that assemble into a primary capillary plexus
During adulthood:
o Growth
o Female reproductive cycle- as the endometrium (highly vascularised tissue) is produced
o Wound healing- the tissue needs regenerating so a blood supply is needed
o Vasculature is usually quiescent in adults, this is one of the characteristics of tumour
blood vessels in that they fail to become quiescent
These processes are stable
Abnormal Angiogenesis
Tumours have been described as wounds that never heal. In order to facilitate angiogenesis you have to
destabalise blood vessels.
Tumourigeneic process
Unstable and dynamic process- it is unstable as there is an imbalance in the regulators
Differences between normal and tumour vasculature
Compared with normal bvs (blood vessels),
tumour bvs are:
o Irregularly shaped- can have dead
ends, have dead ends are dilated and
tortuous
o Pericytes are loosely attached or
sparsely distributed whereas in
normal tissue that are closely
attached and high in number
o Fail to stabalise properly due in part to the lack of pericyte attachment(facilitates more
sprouting)
o Dilated and don’t have any hierarchy, unlike normal tissue i.e. looks like a mess/chaotic
and disorganised
o Lack organisation and leaky due to the tissue over producing vascular endothelial
growth factor
This structure does not provide the most efficient blood flow, however it is enough to allow the tumour
to continue growing. It also reduces the effectiveness in chemotherapy getting to the tissue.
, Pericyte-Endothelial Cell Association in
Blood Vessels
In normal vessels, pericytes (red) form a
substantial covering around the
endothelial cells (green) of larger vessels
(A), a tight but sparser covering in
capillaries (B) but are less abundant and
loosely attached in tumour vessels (C). In
C the processes are just about touching
the basement membrane. This is a very
unstable vessel.
Activation of Angiogenesis in Tumours
Angiogenesis can be switched on at different/any
stages of the tumour life cycle
o Depends on tumour type and
microenvironment
It happens in two phases: avascular and vascular
Avascular phase: Dormant lesion and no
angiogenesis. They have reached a steady state
between growth and cell death
o These lesions often don’t cause clinical
symptoms and don’t seem to have any ill
effects
o This is a potential problem in screening for cancers as you do not know whether it will
turn on angiogenesis and grow rapidly or whether it will stay in this state for a long time
Therefore should you treat these if you find them?
Vascular phase: activation of angiogenesis, allowing tumour growth and spread
o The tumour has activated angiogenesis. This causes the tumour to spread and progress.
It is not clear why some avascular lesions turn on angiogenesis and others do not
