Growth factors |
VEGF superfamily |
central angiogenic factors of tumor angiogenesis (Carmeliet and Jain, 2000; Potente et al., 2011). Induce genetic reprogramming of TECs, changes mode of immune cell interaction and adversely programs the TME (Albini et al., 2018; Maishi et al., 2019). Inhibits the up-regulation of leukocyte adhesion molecules (Griffioen et al., 1999; Dirkx et al., 2003; Flati et al., 2006). |
VEGF-C |
Central factor of lymphangiognesis (Hsu et al., 2019). Essential for HEV formation (Furtado et al., 2007). Overexpression fosters lymphatic metastasis (Decio et al., 2014; Wang et al., 2014; Yang et al., 2014; Goussia et al., 2018). Activated LECs by VEGF-C suppress tumor specific CD8+ T cells (Lund et al., 2012). |
PDGF, HIF1, ANGPT2, |
Central angiogenic factors of tumor angiogenesis (Carmeliet and Jain, 2000; Potente et al., 2011). |
FGF2 |
Inhibits the up-regulation of adhesion molecules (ICAM and VCAM) (Griffioen et al., 1999; Dirkx et al., 2003; Flati et al., 2006). |
bFGF |
Angiocrine factor promoting tumor cell metastasis (Maishi et al., 2019). |
EGFL7 |
Down-regulates adhesion molecules expression and fosters tumor vessel development via NOTCH signaling (Delfortrie et al., 2011; Nichol and Stuhlmann, 2012). |
TGFβ |
Angiocrine factor contributing to tumor metastasis (Maishi et al., 2019). |
Cytokines, interleukines, interferones, chemokines |
TNFα |
EC activation relies on TNFα and endothelial anergy is characterized by unresponsiveness to TNFα (De Sanctis et al., 2018; Georganaki et al., 2018). Enhances PD-L1 up-regulation on ECs (Georganaki et al., 2018) |
IFNγ |
Endothelial anergy is characterized by unresponsiveness to IFNγ (De Sanctis et al., 2018). Enhances PD-L1 upregulation on ECs (Georganaki et al., 2018). |
IL-6, IL-8 |
Secreted by activated ECs mediating immune cell trafficking (Aird, 2012; Klein, 2018). |
CXCL12/13, CCL19/21, IL-7 |
Chemokines/interleukines that are associated with the formation of HEVs and TLS (Sautès-Fridman et al., 2019). |
CCL2/18, CXCL10/11 |
Attractant chemokines down-regulated by TECs to prevent immune cell trafficking, therefore mediating immune cell anergy (Griffioen et al., 1996; Huang et al., 2015; Lambrechts et al., 2018). |
CXCL4 |
Chemokine strongly involved in leukocyte activation and endothelial rolling (Ley et al., 2007). |
Adhesion molecules |
VCAM1, ICAM1 PECAM1, E/P-selectin |
Expressed on ECs mediating leukocyte recruitments (Ley et al., 2007). Important gatekeepers of transmigration to the tumor compartment (De Sanctis et al., 2018). Multiple regulation mechanisms by tumor cells/TECs. |
Soluble adhesion molecules |
sCD146 and Endoglin inhibit TIL recruitment by competitive mechanisms and show direct VEGF-synergistic effects (Rossi et al., 2013; Stalin et al., 2016). |
Stemness factors, apoptosis-inducing/preventing molecules proteins |
FASL |
Expressed by TECs induces apoptosis in CD8+ T cells (Thommen and Schumacher, 2018). |
Stemness molecules |
TECs upregulate stem cell associated proteins (CD90, MDR1, ALP, Oct-4, and ALDH), which are associated with increased self renewal and high proliferative potential (Ohga et al., 2012; Ohmura-Kakutani et al., 2014; Hida et al., 2017) |
Immune checkpoints |
PD-L1/2, TIM3 |
Expressed by TECs and promotes T cell arrest (Georganaki et al., 2018). |
IDO1 |
Immune-regulatory molecule expressed by TECs in response to IFNγ restricting activation and inducing apoptosis of T cells (Georganaki et al., 2020). |
Antigen-presenting molecules |
MHC I, II |
Frequently expressed by ECs but lacking the co-stimulatory molecules (CD80 and CD86) (Shiao et al., 2007). MHC molecules can be down-regulated by TECs contributing to immune-evasion (Goveia et al., 2020). |
Other |
NO |
Affects leukocyte recruitment under malignant conditions (De Caterina et al., 1995). Directly suppresses effector T cells (De Sanctis et al., 2018). NO-antagonists restores T cell adhesion by up-regulation of adhesion molecules (Bouzin et al., 2007; Buckanovich et al., 2008). |
ET1 |
Associated with ICAM1 expression and decreases TIL influx (Spinella et al., 2002; Buckanovich et al., 2008). |
STING |
Highly expressed on ECs of HEVs and impacts the expression of adhesion molecules (Demaria et al., 2015; Yang et al., 2019). |
CLEVER1 |
Favors the selective influx of Treg and immuno-suppressive TAM (Nummer et al., 2007; Karikoski et al., 2014). |
Biglycan |
Preferentially expressed by high metastatic tumors and allows toll-like receptor expressing tumor cells to metastasize hematogenously (Maishi et al., 2016). |
Galectins |
Glycan-binding endogenous lectins which sustain tumor angiogenesis via autocrine and paracrine signaling (Elola et al., 2018). Directly interact with VEGFR2, bFGF, VEGFR3 and associated with resistance to anti-angiogenic therapies (Markowska et al., 2010; Markowska et al., 2011; Zhao et al., 2011; Laderach et al., 2013; Chen et al., 2016). |
Jag1 |
Expressed by TECs to generate malignant vascular niche, which is associated with aggressive course and resistance to chemotherapy (Cao et al., 2016). |
Slit2 |
Tumor-suppressive factor directly down-regulated by TECs via paracrine EphA2 signaling (Brantley-Sieders et al., 2011). |