Background
Different forms of tumor angiogenesis
Mechanisms of tumor VM formation
Epithelial-mesenchymal transition and VM
Tumor microenvironment and VM
Cancer stem cells
Tumor-associated macrophages
Tumor-associated fibroblasts
Hypoxia
Key molecules and signaling pathways in tumor VM formation
EphA2
FAK
PI3K
MMPs
Notch
Non-coding RNAs, as emerging regulators in tumor VM formation
MiRNA | Cancer type | Target | Function characteristic | Effect of VM formation | Reference |
---|---|---|---|---|---|
miRNA-27b | Ovarian cancer | VE-cadherin | inhibits ovarian cancer cell migration and VM via binding to the 3′-untranslated region(3′UTR) of VE-cadherin mRNA | Suppress | [98] |
miRNA-584-3P | Glioma | ROCK1 | Disturbs hypoxia-induced ROCK1-dependent stress fiber formation | Suppress | [87] |
MiRNA-let-7f | Glioma | POSTN | Disturbs the POSTN-dependent migration | Suppress | [86] |
miR141 | Glioma | EphA2 | Inhibits EphA2 expression | Suppress | [88] |
miR-27a-3p | Hepatocellular carcinoma | VE-cadherin | Targets the 3′-UTR of VE-cadherin, and suppresses EMT signaling | Suppress | [92] |
miR-193b | Breast cancer | DDAH1 | Regulates MDA-MB-231 cells migration and VM formation via targeting DDAH1 | Suppress | [97] |
miR-125a/let-7e | Breast cancer | IL-6, IL-6R, STAT3 | Suppresses IL-6-induced adhesion of monocytes to ECs and VM formation | Suppress | [96] |
miR-200a | Ovarian cancer | EphA2 | Inhibits EphA2 expression | Suppress | [99] |
miR-490-3p | Clear cell renal cell carcinoma | Vimentin | - | Suppress | [28] |
miR-745 | Ovarian cancer | VEGFR/AKT1/SRC-α | Decreases the levels of VEGFA, AKT1, and SRC-α transducers and exerts a negative regulation of VEGFA by specific binding to its 3'UTR | Suppress | [74] |
miR-9 | Glioma | Stathmin (STMN1) | targets the 3′-UTR of STMN1 | Suppress | [75] |
miR-186 | Prostate cancer | Twist1 | - | Suppress | [84] |
miR-101 | Hepatocellular carcinoma | TGF-β1, Smad2 | Targets TGF-ΒR1 and Smad2 to attenuate TGF-β signaling transduction in tumor cells and blocks SDF1 signaling | Suppress | [93] |
miR-124 | Cervical cancer | Amotl1 | Represses VM, migration, and invasion in HeLa and C33A cells by regulating AmotL1’s 3'untranslated region (3'UTR) | Suppress | [85] |
LncRNA | Cancer type | Cancer cell lines | miRNA | Signaling pathway | Effect of VM formation | Reference |
---|---|---|---|---|---|---|
MALAT1 | Gastric cancer | BGC823 SGC7901 | miR-376a | ERK/MMP FAK/paxillin pathway | Promote | |
MALAT1 | Lung cancer | H1299 H292 | miR-145-5p | lncRNA-MALAT1/miR-145-5p/NEDD9 pathway | Promote | [70] |
LINC00339 | Glioma | U87 U251 | miR-539-5P | miR-539-5P/Twist1/MMPs pathway | Promote | [89] |
LncRNA n339260 | Hepatocellular carcinoma | HepG2 | - | TGF-β pathway | Promote | [68] |
LncRNA HOXA-AS2 | Glioma | U87 U251 | miR-373 | miR-373/EGFR pathway | Promote | [90] |
LncRNA TP73-AS1 | Triple negative breast cancer | MDA-MB-231 | miR-490-3P | miR-490-3p/Twist1 pathway | Promote | [94] |
LINC00312 | Lung adenocarcino-ma | H1299 PC-9 | - | YBX1/AKT/TGF-β pathway | Promote | [26] |
SNHG20 | Glioma | U87 U251 | - | ZRANB2/SNHG20/FOXK1 pathway | Promote | [73] |
Clinical significance of VM in cancer
Pharmacological agents | Cancer type | Molecule target | Drug action | Referrence |
---|---|---|---|---|
Brucine | Triple-negative breast cancer | EphA2/MMP-2/MMP-9 | Suppresses VM by disrupting F-actin cytoskeleton and microtubule structure | [111] |
R8 modified epirubicin-dihydroartemisinin liposomes | Non-small-cell lung cancer | VE-cadherin/TGF-β/MMP-2/HIF-1 | Suppresses VM channels and tumor metastasis by downregulating the levels of VE-cad, TGF-β, MMP-2 and HIF-α | [115] |
Ginsenoside Rg3 | Pancreatic cancer | VE-cadherin/EphA2/MMP-2/MMP-9 | Downregulates the levels of VE-cad, EphA2, MMP-2 and MMP-9 to inhibit the formation of VM | [116] |
Dequalinium (DQA) modified paclitaxel plus ligustrazine micelles | Non-small-cell lung cancer | VEGF/MMP-2/ TGF-β/E-cadherin | Destroies VM channels and down regulate the expression of VEGF, MMP-2, TGF-β and E-cadherin | [122] |
Favone isoxanthohumol | Breast cancer | IFN-γ/IL-4/IL-6 Jak/Stat signaling | Blocks IFN-γ/IL-4/IL-6 Jak/Stat signaling and TGF-β signaling to inhibits VM formation | [112] |
Dunorubicin and dioscin codelivery liposomes | Non-small-cell lung cancer | MMP-2/VE-cadherin TGF-β/HIF-1α | Inhibits VM formation by down regulating the levels of MMP-2, VE-cadherin, TGF-β and HIF-1α | [117] |
Melittin | Liver cancer | HIF-1α/Akt | Inhibits hypoxia-induced VM formation and EMT by suppressing HIF-α/Akt pathway | [118] |
Tivantinib (TivB) | Melanoma | Vnculin/RhoC | Disrupts VM channels by targeting vinculin and RhoC | [114] |
PARP inhibition | Melanoma | VE-cadherin | Inhibits reduced pro-metastatic markers | [110] |
Thalidomide | Melanoma | VEGF/NF-ΚB/MMP-2/MMP-9 | Regulates vasculogenic factors to inhibit VM channel and mosaic vessels formation | [119] |
Trastuzumab | HER2-positive breast cancer | VEGF | Suppresses VM in HER2-positive BCCs | [113] |
Rapamycin | Ovarian cancer | VEGF/mTOR | As HIF-α inhibitor to prevent VM | [120] |
Resveratrol | Melanoma | VEGF-R1/VEGF-R2 | Suppresses VM formation | [121] |
Niclosamide | Oral cancer | miR-124/STAT3 | Inhibits VM formation through downregulation of the expression of VM-related genes VEGFA, MMP2, ROCK1, and Cdc42 | [123] |
Celastrus orbiculatus extrac (COE) | Hepathocellular carcinima | Notch1 signaling | Inhibits VM formation by downregulating Notch 1 signaling | [83] |
Luteolin | Gastric cancer | Notch 1/VEGF | Inhibits VM formation through suppressing VEGF secretion dependent on Notch1 expression | [69] |