Table 1.
Alternatively spliced isoforms of angiogenesis-related genes and their potential use for anti-angiogenic therapy
| 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 [52–54]. 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 [57–59]. 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]. |