Table 1 Alternatively spliced isoforms of angiogenesis-related genes and their potential use for anti-angiogenic therapy
From: Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis
GENE | AS variant | Relevance in cancer angiogenesis |
|---|---|---|
VEGF-A | VEGF-Axxxa | Expression/function Overexpressed by a wide variety of human tumors. Pro-angiogenic function, produced by both cancer cells and ECs [46]. |
VEGF-Axxxb | Expression/function Anti-angiogenic function, generally downregulated in cancer [46]; not detected in normal or tumor ECs [47]. Examples of potential use for therapy SRPK1 inhibitors to promote AS into VEGF-Axxxb isoform [48]. Compounds blocking spliceosome machinery (Spliceostatin A, FR901464) [49, 50]. | |
VEGF receptors (VEGFRs) | sVEGFR1 | Expression/function Anti-angiogenic function, inhibits VEGF signalling in ECs [51]. Controversial role in cancer [52,53,54]. Examples of potential use for therapy Morpholino oligonucleotides to promote AS into sVEGFR1 [55]. |
sVEGFR2 | Expression/function Decreases lymphangiogenesis. Downregulated in neuroblastoma patients [56]. | |
Neuropilins (NRPs) | sNRP1 | Expression/function Soluble decoy receptor. Anti-angiogenic function [57,58,59]. Examples of potential use for therapy Overexpression of sNRP1 to prevent VEGF signalling [60]. |
NRP1-∆7 | Expression/function Altered glycosylation. Anti-angiogenic function [61]. | |
NRP1-∆E4, NRP1-∆E5 | Expression/function Altered glycosylation and endocytic trafficking [62]. | |
s9NRP2 | Expression/function Decoy function [63]. | |
Membrane-bound NRP2 variants | Expression/function Differentially activate signalling pathways [58]. | |
Fibroblasts growth factor receptors (FGFRs) | FGFRIIIb | Expression/function Expressed by epithelial tissues [64]. Pro-angiogenic function [65, 66]. Examples of potential use for therapy Anti-FGFR2-IIIb–Specific Antibody (GP369) [67]. |
FGFRIIIc | Expression/function | |
sFGFRs | Expression/function Possible decoy function [69]. | |
Deletion of auto-inhibitory domain | Expression/function Hyper-activation of the signalling pathway [69]. | |
C-term FGFRs AS variants C1, C2, C3 | Expression/function Differential impact on receptor internalization and downstream signalling. C3 implicated in oncogenesis [70]. | |
Deletion of VT motif | Expression/function Deletion affects downstream signalling [71]. | |
Vasohibins (VASHs) | VASH1A | Expression/function Anti-angiogenic-function. Expressed by ECs [72]. Examples of potential use for therapy Overexpression of VASH1A [72]. |
VASH1B | Expression/function Expressed by ECs. Promotes the normalization of tumor blood vessels [72]. Examples of potential use for therapy Overexpression of VASH1B [72]. | |
VASH2-355aa | Expression/function Expressed by ECs [73]; unknown function. | |
VASH2-290aa | Expression/function Anti-angiogenic function [73]. | |
Angiopoietins (ANGs) | ANG1–0.7, − 0.9 and − 1.3 kb | Expression/function Differentially activates TIE2 pathway [74]. |
ANG2443 | Expression/function Expressed in primary ECs and non-endothelial tumor cell lines. It antagonizes TIE2 signalling during tumorigenesis and inflammation [75]. | |
ANG2B | Expression/function Differentially activates TIE2 signalling [76]. | |
Fibronectin (FN) | EDA/EDB-FN | Expression/function Expressed during embryonic and tumor angiogenesis. EDA-FN plays a role in vascular remodelling and prevents vascular oxidative stress in diabetic conditions [77, 78]. Examples of potential use for therapy Drug delivery [79]. |
Tenascin C (TNC) | Large TNC variants | Expression/function Expressed in pathological tissues undergoing active remodelling. Favour cell migration [80]. Specific spliced variants or single AS domains are associated with different tumor types [80] types; FNIII C-bearing TNC isoform is highly expressed in brain and lung tumors, associated with tumor stroma [81]. Examples of potential use for therapy TNC antibodies to deliver cytotoxic molecules, recognizing the AS domains A1 to D of the large isoform of TNC. Aptamer TTA1 [82]. |
SLIT2 | Slit2-WT | Expression/function Expressed and released by tumor cells. Reduces EC permeability [83]. |
Slit2-ΔE15 | Expression/function Expressed and released by normal cells. Reduces EC permeability and plays a role in vessel normalization [83]. | |
PECAM1 | PECAM1-FL, Δ12, Δ13, Δ14, Δ15, Δ14&15 | Expression/function PECAM1-FL is the major form of PECAM-1 in human tissues and ECs [84, 85]. Different isoforms bear different signalling potential, thus impacting angiogenesis process [86]. |
sPECAM1 | Expression/function Possible function in regulating PECAM1-mediated cellular interactions [87]. | |
CD146 | shCD146 | Expression/function Promotes EC proliferation, migration and adhesion [88]. |
lgCD146 | Expression/function Promotes EC tube formation and stabilization [88]. | |
CD44 | CD44v6 | Expression/function Controls EC migration, sprouting and tube formation, acting as a VEGFR2 co-receptor for VEGF-A [89]. Examples of potential use for therapy CD44v6 blockage by soluble peptides [90], humanized monoclonal antibody [91], shRNA [92], miRNA [93], or antisense oligonucleotides [94]. CAR-T cells against CD44v6+ cancer cells (ClinicalTrials.gov: NCT04427449 [95]). |
Endoglin (ENG) | L-endoglin | Expression/function Interacts with TGFβ type I receptors ALK1, enhancing its-mediated pathway [96, 97]. |
S-endoglin | Expression/function Interacts with TGFβ type I receptors ALK5, stimulating ALK5 pathway. Associated with altered pulmonary angiogenesis [98]. It is induced by senescence and able to contribute to NO-dependent vascular homeostasis. | |
Insulin receptor (IR) | IR-A | Expression/function Pro-proliferative function; overexpressed in tumor vasculature [99]. |
Tissue factor (TF) | asTF | Expression/function Soluble factor, highly expressed in advanced stages of several human cancers [100, 101]. Stimulates tumor growth, angiogenesis and metastasis [102]. Examples of potential use for therapy Antibody drug conjugate of TF and monomethyl auristatin E [103]. |
flTF | Expression/function Highly expressed in several types of cancer. Involved in cancer-related thrombosis, tumor growth and metastasis [104]. Examples of potential use for therapy Anti-flTF antibody 10H10 [105]. | |
L1CAM (L1) | L1-ΔTM | Expression/function Soluble form of L1CAM, released by ECs. Promotes EC tube formation and neovascularization. Overexpressed in the ovarian cancer vasculature; associated with tumor vascularization [106]. |
L1-FL | Expression/function Highly expressed in tumor vasculature several types of cancer. Pro-angiogenic function [107]. |