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Page 2 of 29 Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36

ANGIOGENESIS
In general, there is an efficient vascular network that supplies blood to normal tissues. The hierarchal
architecture and growth of blood vessels are maintained by the balance between pro-apoptotic and
anti-apoptotic factors. This balance is controlled by the metabolic demands of the corresponding
tissue. Lymphatic channels on the other hand, remove metabolic waste from the interstitium. Thus, the
microstructure of the vascular network is capable of supplying adequate oxygen and nutrition to all
[1]
associated cells . During tumour progression, there is rapid proliferation of tumour tissue. When the
3
tumour reaches a critical size (1~2 mm ), tumour cells located further from the supplying blood vessel
become starved of oxygen and nutrients, leading to the impairment of tumour growth by apoptosis or
[2]
necrosis. In turn, this triggers angiogenesis, the formation of new blood vessels from existing ones .
Although tumour angiogenesis provides for tumour growth and a route for metastasis, it is not as tightly
[2]
regulated as embryonic angiogenesis .
DIFFERENCES BETWEEN BLOOD VESSELS OF NORMAL AND CANCER TISSUES
The growth of tumour blood vessels does not follow any hierarchy. It is typically heterogeneous, tortuous,
[3-5]
branches irregularly, and is enlarged circumferentially . The endothelial cells, pericytes (multifunctional
mural cells that wrap around endothelial cells) and basement membrane of tumour blood vessels are
all abnormal : endothelial cells have abnormally loose intracellular associations and focal intercellular
[3]
[6]
openings that are < 2 µm in diameter while their association with multiple layers of the vascular basement
membrane is also loose due to high interstitial pressure, leading to hyper-permeable tumour blood vessels
[7]
and vascular leakage .

Tumour blood vessels also have a reduced surface area: volume ratio. The high interstitial pressure, coupled
with a reduced surface area, impairs the delivery of oxygen, nutrients, and removal of metabolites. As such,
the tumour microenvironment is typically characterized by hypoxia and acidosis which in turn, selects for
apoptosis-resistant and metastasis competent tumour cells [Figure 1].

CELL SIGNALLING PATHWAYS IN HYPOXIA-INDUCED ANGIOGENESIS
Cell signaling pathways in hypoxia-induced angiogenesis is shown in Figure 2. HIF-1α is the founding
[8]
member of the hypoxia-induced factor (HIF) family . It regulates the genes associated with oxygen
[9]
deprivation . The HIF activity pathway is regulated by prolyl hydroxylase enzymes (PHD1-3) . PHD acts
[10]
as an oxygen sensor; in normoxia, PHD hydroxylates the proline residues of HIF-1α. The hydroxylated
HIF-1α then binds to the von Hippel-Lindau E3 ubiquitin ligase complex leading to proteasomal
degradation of HIF-1α [11,12] . Under hypoxic conditions, oxygen and cofactor 2-oxo-glutarate substrates are
[13]
depleted and PHD becomes inactivated, resulting in stabilization and intracellular accumulation of HIF-
1α. HIF-1α is then translocated into the nucleus to bind with transcriptional factor Arnt (Aryl hydrocarbon
[14]
nuclear translocator family protein) . Subsequently, a transcriptional complex is formed with p300/
CBP which binds to HREs (hypoxia response elements) in the promoters and enhancers of target genes,
leading to vasodilatation (for better delivery of oxygen), lowering of oxygen demand and upregulation of
proangiogenic factors like fibroblast growth factor (FGF), insulin-like growth factor (IGF), and vascular
[15]
endothelial growth factor (VEGF) . Vasodilatation is also caused by the upregulation of inducible nitric
oxide synthase leading to increased production of nitric oxide and relaxation of vascular smooth muscle
cells . Under hypoxic conditions, the demand for oxygen is lowered due to over expression of glucose
[16]
[17]
transporter 1 enzyme (GLUT1). GLUT1 improves the uptake of glucose and induces glycolytic enzymes
such as phosphoglycerate kinase . In turn, phosphoglycerate kinase is regulated by aldolase A and HIF-α.
[18]
[19]
Aldolase A helps in better utilization of glycolysis, tumour epithelium mesenchymal cell proliferation and
[20]
upregulation of pyruvate dehydrogenase kinase (PKD1) which inhibits mitochondrial respiration . HIF-
[21]
1α helps in cancer cell proliferation by regulating the expression of a number of proangiogenic genes like