Table 2.
Molecular profiling of endothelial cell heterogeneity in tumor human/mouse tissue samples.
| Endothelial cell phenotype | Transcriptional profiling | Major functions/activated signaling pathways | References |
|---|---|---|---|
| Tip cells | ESM1, APLN, ADM, MMP14, ANGPTL2, INSR, PDGFB, CXCR4, PGF, KCNE3, DLL4, RAMP3, EDNRB, LXN, CD34 | Cytoskeleton remodeling, involved in VEGF signaling, EC migration, extracellular matrix formation, collagen production | (30, 46, 47) |
| Stalk cells | VWF, SELP, ACKR1, SPINT2, VEGFR2, | Known to originate from tip cells, maintains endothelial cell polarity, lumen formation | (47, 48) |
| Lymphatic ECs (LECs) and subtypes | LYVE1, CCL21, TFF3, MMRN1, ADIRF, AKAP12, FABP4, CD9, ANXA2, SNCG, GYPC, S100A10, VIM, PPF1BP1, EFEMP1, PROX1, PDPN | Secrete SEMA4C promoting metastasis | (46, 49) |
| LEC I: ACKR4, NT5E | Not known | ||
| LEC II: TNFRSF9, MARCO, IFNGR, CSF1, CXCL1-CXCL5 | Express chemokines and cytokines such as IL6, IL33, IFNGR1, IFNGR2, role in macrophage homeostasis, express neutrophil chemoattractants | ||
| LEC III : ACKR4, NT5E, LYVE1, MFAP4 | Not known | ||
| LEC IV : PDPN, LYVE1,CCL21 | Not known | ||
| LEC V:CLDN11 | Not known | ||
| LEC VI : MARCO, LYVE1, CSF1, CXCL1-CXCL5 | Express chemokines and cytokines such as IL6, IL33, IFNGR1, IFNGR2, role in macrophage homeostasis, express neutrophil chemoattractants | ||
| Endothelial progenitor cells | TIE2, FGF3, VEGRF2, CD34 | Promote vascular regeneration and repair | (50) |
| Tumor ECs | VEGF | Notch signaling | (46) |
| Arterial ECs | GJA4, GJA5, SOX17, EFNB2, DKK2, CXCL12, FBLN5, JAM2, FBLN5, CYTL1 | Involved in vascular integrity, homeostasis, and vasotonus | (46, 51) |
| Type I alveolar capillaries | EMCM, VWF (low), podoplanin, aquaporin5 | Anti-microbial defense | (46) |
| Type II alveolar capillaries | FCN3, SLC6A4, TMEM100, IL7R, BTNL9, TNFSF10, VIPR1, CD14, NOSTRIN, HIF3A, VWF | Vasoregulation | (46) |
| Postcapillary veins | VWF1, ACKR1, SELP, VCAM1 | Leukocyte recruitment, regulation of blood pressure and perfusion | (46, 52) |
| Large vein ECs | VWF, CYTL1, PI16, NOS3, LCN2, SLC38A5 | Immunomodulatory functions | (46, 51) |
| Post capillary vein ECs | ACKR1, SELP, VCAM1, CCL14, POSTN, ACTN1, PRCP, NPC2, DUSP23 | Leukocyte recruitment, tissue perfusion, and pulmonary blood pressure, involved in immune cell recruitment | (46) |
| Capillary ECs | MHC-II, MFSD2A, RGCC | Involved in antigen presentation | (46, 51) |
| Scavenging capillary | AIF1, APOC1, APOE, CCL18, CD36, CD52, CD68, CD74, CRIP1, CYBA, FCER1G, FCGR3A, FTH1, FTL, LST1, LYZ, MARCO, MNDA, MSR1, OLR1, TREM1, TYROBP | Adhesion, antigen presentation, pathogen clearance, inhibition of tumor angiogenesis | (46) |
| Proliferating ECs | TOP2A, MKI67, CCDC34, CDKN1A, CENPA, CKS1B, CKS2, EZH2, FEN1, H2AFZ, HMGB2, HMGN2, HSP90AA1, LGALS1, LIG1, LMNB1, NRM, PCNA, RRM1, SMC2, SPC24, STMN1, TUBA1B, TYMS | Basement-membrane breaching, immune cell recruitment, and semi-professional antigen presentation, tumor angiogenesis | (46, 51) |
| Breaching ECs | Tip cell markers (DLL4, CXCR4, APLN), collagen remodeling markers (COL4A1, COL4A2, COL18A), HSPG2, IGFBP3, LAMB1, MCAM, PXDN, LAMA4, NID2 | Upregulates expression of tip cell markers, initiation of vessel sprouting, involved in collagen remodeling and basement membrane degradation | (46) |
| Immature ECs | ID2, ID3, ENG, PLVAP, GSPG2, APLNR, VWA1, RBP7, GSN, MMP2, VEGF receptors (KDR, FLT1, TIE1) | Notch signaling, develop into tumor ECs | (46) |
| Capillary-arterial ECs | TGFB2, GLUL | Express both capillary and arterial markers, VEGFA, Notch signaling | (46, 53) |
| Capillary-venous ECs | TFRC, CAR4 | Express both capillary and venous markers, VEGFA, Notch signaling | (46, 53) |