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Dastidar et al. Vessel Plus 2020;4:14 I http://dx.doi.org/10.20517/2574-1209.2019.36 Page 3 of 29

A

B

Figure 1. Schematic representation of the physiological differences between normal blood vessels (A) and the tumour vasculature (B)

VEGF, Ang-1, Tie 2, platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), monocyte
chemoattractant protein-1 (MCP-1), IGF and epidermal growth factor (EDGF). These HIF regulated factors
bind to corresponding receptors on the cell membranes of pericytes and increase vascular permeability,
endothelial cell proliferation, sprouting, migration, adhesion, and tube formation. The angiogenic factors,
their corresponding receptors, and functions are shown in Table 1. Vascular permeability is increased due
to overexpression of VEGF [22-25] . In endothelial cells and pericytes, Ang-1 (angiopoietin-1) is induced by
hypoxia. It is a Tie-2 receptor agonist which recruits pericytes to mature vessels and promotes tumour
[22]
angiogenesis . Despite active angiogenesis, the tumour microenvironments still have hypoxic domains
that lead to sustained stabilization of HIF-α. HIF-α then promotes cap-dependent translation of selective
mRNAs for angiogenesis through up-regulation of translational factor eIF4E1. In contrast, 4E-BP1 is a
translation initiation repressor that sequesters eIF4E1 and is thus a tumour supressor protein. The activity
of translational factor eIF4E1 is also controlled by pathways such as Ras and PI3K/AKT. These pathways act
by inhibiting 4E-BP1 and increasing the expression of eIF4E1.

The inducible enzyme cyclooxygenase-2 (COX-2) is also an important mediator of angiogenesis and tumor
growth. It induces matrix metalloproteinases that have traditionally been associated with the degradation
and turnover of most of the components of the extracellular matrix (ECM). Plasminogen activator inhibitor
type 1 (PAI-1) though has the opposite effect of remodeling the ECM by regulating plasmin.

BARRIERS TO TARGETED DELIVERY OF THERAPEUTIC AGENTS TO TUMOUR
Spatial and temporal heterogeneities in blood supply
Vascular morphology and blood flow rate govern the movement of blood-borne particles through tumour
vasculature. Depending on the tumour type, location and growth rate, the architecture of the tumour