2.6 Effect on mononuclear phagocytic system
Within tumor microenvironment, cancer cells induce monocytes to
differentiate for tumor-associated macrophages (TAMs) through recruiting
monocytes by secreting chemotactic factors such as VEGF, macrophage
chemoattractant protein-1 (MCP-1) and macrophage colony-stimulating
factor (Solinas et al., 2009). Aspirin could disrupt the crosstalk of
angiogenic cytokines between macrophages and 4T1 breast cancer cells
(Hsieh et al., 2018). Macrophages, including categorization of M1 and M2
phenotype, have the potentiality to convert the M1 into the M2
macrophages (Gordon et al., 2010; Spiller et al., 2015). M1 macrophages
secrete factors that are involved in initiating the stages of
angiogenesis, while M2 macrophages secrete factors are responsible for
later process of angiogenesis (Spiller et al., 2014). Importantly, it
has been shown that aspirin treatment raised the level of M1 marker
expression, but decreased expression of M2 marker (Hsieh et al., 2018).
Thymidine phosphorylase (TP) is a proangiogenic factor that found to be
chemotactic for ECs and to induce angiogenesis in vivo (Finnis et al.,
1993; Miyadera et al., 1995). TP is highly expressed in macrophages of
normal human tissues (Fox et al., 1995). Comparing with adjacent
uninvolved tissues, TP is often overexpressed in solid tumors, and its
expression is associated with higher microvessel count, increased tumor
invasiveness and metastasis (Takebayashi et al., 1996). It also found
that TP-expressing cancer cells secreted angiogenic factors (IL-8, bFGF
and TNFα) that stimulated endothelial cells migration and invasion
(Elamin et al., 2015). Moreover, activated macrophages are one of the
main sources for Tumor Necrosis Factor-α (TNFα), and it has been
suggested that the proangiogenic activity of macrophages is mainly
mediated by TNFα (Beutler et al., 1986; Leibovich et al., 1987). Aspirin
inhibits MCP-1 and interleukin-8 expression in TNF-alpha stimulated
HUVECs (Yang et al., 2004). Besides, THP-1 monocytes induce TP
expression by autocrine TNFα, and aspirin inhibits
TP expression in THP-1 cells by
reducing NFκB DNA-binding activity in the pathway of TNFα-induced TP
expression (GENG et al., 2003).
However, it warrants further
studies to determine the
downstream of TP signalling transduction in ECs when aspirin
antiangiogenesis.
2.7 Effect on intercellular junctions andPericytes
Disorganization of tumor vascular layers leads to
increased permeability and
leakiness, which is a common feature of tumor angiogenesis (Weis et al.,
2011). The low vascularity, abnormal morphology, and high permeability
of the tumor vessels leads to inefficient delivery of drugs and oxygen
into tumors (Jain et al., 1998). Antiangiogenic drugs would be expected
to inhibit the angiogenesis and may stop the growth of tumor tissues but
not necessarily influence existing blood vessels or cause tumor
shrinkage (Baluk et al., 2005).
VEGF, as a pro-angiogenic factor, not only plays a key role in inducing
endothelial cell migration, proliferation and differentiation, but also
can destroy tight junction proteins, thereby increasing vascular
permeability and triggering tumor metastasis (Cross et al. 2013; Azzi et
al., 2013). ASA significantly reduced the expression of VEGF in
HUVEC,hTNFered the VEGF release from endothelial cells of human primary
glioblastoma and blocked the VEGF-promoted angiogenesis (Maity et al.,
2019; Navone et al., 2018). Besides, salicylate decreased serum VEGF
levels and reduced microscopic vascular structures in animal models
(Ghezzo et al., 2004).
Moreover, three types of junctions in the endothelial monolayer have
been described: adherens, tight and gap junctions (Bazzoni et al.,
2004). The destruction of the adhesion junctions is a vital step in
inducing angiogenesis and a prerequisite for releasing EC from the
contact inhibition exerted by the association of VE-cadherin and
β-catenin (Khaidakov et al., 2010). Immunocytochemistry performing to
p120 catenin and VE-cadherin showed that adherens junctions in
VEGF-induced HUVECs tube formation are severe disrupted, but the
disruption effects is largely prevented by aspirin and salicylic acid
with preincubated in cultures (Khaidakov et al., 2012). Furthermoer,
aspirin rescues vascular permeability and up-regulates the expression of
VE-cadherin and Zonula Occludens-1 (ZO-1) in MDA-MB-231 conditioned
medium (Maity et al., 2019).
Aspirin also prevents disintegration of endothelial adheren junctions
caused by Hypoxia-reoxygenation (HR) (Khaidakov et al., 2010 ).
Pericytes play a vital role in stabilization of blood vessel
architecture and regulate vessel permeability (Bergers and Song 2005;
Ribeiro et al., 2015). It has been suggested that aspirin can recruit
pericytes from multipotent stem cells and help in binding with ECs,
which is a sign of normalization of blood vessels and reduces
permeability and leakiness through endothelial cell layer (Maity et al.,
2018). Thus, normalized tumor vasculature may reinforce drug delivery to
further solid tumors.