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.