Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models
Abstract
:1. Introduction
2. Role of VEGFR-1 and its Ligands in Tumor Progression
2.1. Lung Cancer
2.2. Liver Cancer
2.3. Kidney Cancer
2.4. Glioblastoma
2.5. Melanoma
2.6. Bone Cancer
2.7. Pancreatic Cancer
2.8. Cancers of the Gastrointestinal Tract
2.8.1. Oral Cancer
2.8.2. Esophageal Cancer
2.8.3. Gastric Cancer
2.8.4. Colorectal Cancer
2.9. Sex-Specific Cancers
2.9.1. Breast Cancer
2.9.2. Ovarian Cancer
2.9.3. Cervical Cancer
2.9.4. Prostate Cancer
2.10. Leukemia
3. Currently Approved Antiangiogenic Therapies and Experimental Agents Targeting VEGFR-1 or PlGF
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AKT | Protein Kinase B |
BMDCs | Bone marrow-derived cells |
BPH | Benign prostatic hyperplasia |
BRAFi | BRAF inhibitors |
ccRCC | Clear-cell renal cell carcinoma |
CNS | Central nervous system |
COX | Cyclooxygenase |
CRMP4 | Collapsin response mediator protein family 4 |
CSE | Cystathionine-γ-lyase |
DCs | Dendritic cells |
ECM | Extracellular matrix |
EMT | Epithelial/mesenchimal transition |
ERK | Extracellular signal-regulated kinase |
FAK | Focal adhesion kinase |
FGF | Fibroblast growth factor |
GAMs | Glioblastoma-associated microglia/macrophages |
GIV | Gα–Interacting Vesicle-associated protein |
H2S | Hydrogen sulfide |
HGPIN | High-grade prostate intraepithelial neoplasia |
HIF | Hypoxia-inducible factor |
HUVECs | Human umbilical vein endothelial cells |
Ig | Immunoglobulin |
IL | Interleukin |
mAb | Monoclonal antibody |
MAMs | Metastasis associated macrophages |
MAPK | Mitogen-activated protein kinases |
MCT | Monocarboxylate transporters |
miRNA | MicroRNA |
MMP | Matrix metalloproteinase |
NFkB | Nuclear factor -kB |
NK | Natural killer |
NRP | Neuropilin |
NSCLS | Non small-cell lung cancer |
ORR | Overall response rate |
OS | Overall survival |
OSCC | Oral squamous cell carcinomas |
PDGF | Platelet derived growth factor |
PFS | Progression-free survival |
PI3K | Phosphatidylinositol-3-kinase |
PKC | Protein kinase C |
PlGF | Placenta growth factor |
RANK | Receptor activator of nuclear factor kappa-Β |
RANKL | Receptor activator of nuclear factor kappa-Β ligand |
RCC | Renal cell carcinoma |
RTKs | Receptor tyrosine kinases |
SCLS | Small-cell lung cancer |
SHH | Sonic Hedgehog Homolog |
shRNA | Short hairpin RNA |
STAT3 | Signal transducer and activator of transcription 3 |
sVEGFR | Soluble vascular endothelial growth factor receptor |
TAMs | Tumor associated macrophages |
TCGA | The Cancer Genome Atlas |
TK | Tyrosine kinase |
Tregs | Regulatory T cells |
VEGF | Vascular endothelial growth factor |
VEGFR | Vascular endothelial growth factor receptor |
VHL | von Hippel–Lindau |
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Tumor Type | Metastatic Sites | VEGFR-1 Ligands | VEGFR-1 |
---|---|---|---|
Lung cancer | |||
NSCLC | Bone, brain, liver, and adrenal glands | - High VEGF-A expression in tumor specimens is associated with shorter survival time [83] | - High VEGFR-1 and VEGFR-2 expression in tumor specimens have been regarded as prognostic markers [83] |
- VEGF-A downregulation, through HIF-1α knockdown, reduces the invasiveness of a human lung carcinoma cell line [85] | - PlGF-mediated activation of VEGFR-1 is involved in macrophages polarization to TAMs [78] | ||
- VEGF-A expression is modulated by several miRNAs whose expression is decreased in tumor cell lines and tissue samples [86,87,88,89,90,91] | - VEGFR-1 is required for the infiltration by BMDCs that stimulate the growth of metastatic nodules [103] | ||
- IL-17 stimulates VEGF-A expression and angiogenesis by activating the STAT3/GIV signaling pathway [92] | |||
- Tumor-derived VEGF-A promotes its own secretion, through PI3K/AKT, STAT3, RAS/ERK signaling pathways [81] | |||
- VEGF-A165 regulates the expression of sVEGFR1-i13 splice variant of sVEGFR-1 through SOX2 and SRSF2 proteins [93] | |||
- High PlGF levels in NSCLC specimens from patients with distal metastases are associated with poor survival, increased tumor invasiveness and enhanced MMP9 expression [95] | |||
- High PlGF levels correlate with an increased ratio between the proangiogenic isoform VEGF-A165 and the antiangiogenic isoform VEGF-A165b, through induction of the splicing regulatory factor SRp40 [96] | |||
- PlGF secreted by tumor cells induces macrophages polarization to TAMs [78] | |||
- High VEGF-B expression is associated with poor survival in patients with squamous cell carcinoma [69] | |||
SCLC | Liver | - VEGF-A levels correlate with microvessel density [98] | - |
Mesothelioma | Bone and other contiguous organs (spinal cord, pericardium, and contralateral lung) | - PlGF is overexpressed in malignant mesothelioma specimens and cell lines [100,101] | - VEGFR-1 is overexpressed in patients and in malignant mesothelioma cell lines [100,101] |
Liver | |||
Hepatocellular carcinoma | Lung, bone, lymph nodes, and adrenal glands | - High circulating VEGF-A correlates with tumor angiogenesis and reduced survival [106,107,108,109] | - VEGFR-1 activation by VEGF-B induces tumor cell migration and invasion by activating MMP9 and increasing the expression of the EMT regulator Snail; high coexpression of VEGFR-1 and MMP9 act as prognostic marker [115,116] |
- The VEGF-B186 is frequently upregulated compared to the VEGF-B167 and its expression correlates with cancer growth and invasiveness [110] | |||
- VEGF-A secretion is reduced by miR-199a-3p [111] - PlGF in vivo blockade results in normalization of tumor-associated vessels, reduced tumor nodule formation and increased survival [112,113] - VEGF-B favors molecular and morphological alterations of EMT [115] | - VEGFR-1 and VEGFR-2 expression on endothelial cells is reduced by miR-199a-3p [111] - VEGFR-1 is required for the vascularization of liver metastases from renal cell carcinoma [124] | ||
Cholangiocarcinoma | Lymph nodes, liver, and peritoneum | - PlGF inhibition, by treatment with the 5D11D4 mAb decreases tumor burden and infiltration by protumoral M2 cells in chemically-induced hepatocellular and cholangiocarcinoma in vivo models [114] - VEGF-A expression is associated with angiogenesis, metastasis and tumor recurrence [119] - High VEGF-A levels in tumor tissues correlate with a marked decrease of miR-101, a miRNA capable of downregulating VEGF-A transcript [120] | |
Gallbladder | Lymph nodes, liver, and peritoneum | - High VEGF-A levels in patients with gallbladder cancer promote angiogenesis and tumor cell proliferation/invasion [121] - VEGF-A expression correlates with poor prognosis [122] - PlGF is overexpressed and stimulates EMT through c-MYC upregulation and consequent induction of miR-19a [123] - Patients with high PlGF and miR-19a levels in the tumor show a shorter overall survival (OS) than patients with low expression [123] | - |
Renal cell carcinoma | Lung, bone, lymph nodes, liver, adrenal gland, and brain | - In clear-cell renal cell carcinoma VEGF-A overexpression is due to mutations or epigenetic inactivation of the VHL gene, in turn responsible for HIF-1α accumulation [128,129]. | - VEGFR-1 and VEGF-B expression is higher in tumor tissues compared to normal renal tissues [137] |
- 2578C/A, +936C/T and +405G/C single nucleotide polymorphisms in the VEGF gene correlate with elevated risk of developing renal cell carcinoma [133,134] - VEGF-A expression is suppressed by Dicer, an endoribonuclease downregulated in clear cell renal cell carcinoma [135] - VEGF-A protein levels are associated with tumor size, tumor grade, and metastasis at diagnosis [136] - PlGF plasma concentrations increase after treatment with the multi-targeted RTK inhibitor sunitinib [139] | - Tumor infiltration by bone-marrow derived myeloid cells expressing VEGFR-1 contributes to neovessel formation and immune escape [138] | ||
Glioblastoma | Only in 0.4–0.5% of all cases extra-cranial metastases in the spinal cord, vertebrae, lung, liver, and lymph nodes | - VEGF-A and PlGF binding to VEGFR-1 enhances migration, and ECM invasion in glioblastoma cell lines through VEGFR-1 phosphorylation at Tyr 1213 and ERK1/2 phosphorylation [145] | - In high-grade glioma specimens, VEGFR-1 is expressed at significantly higher levels than in low-grade glioma [146] |
- VEGF-A- and PlGF-mediated activation of VEGFR-1 stimulates tumor growth and angiogenesis in an in vivo preclinical glioma model [148] | - Glioblastoma cells (cell lines and tumor specimens from patients) and primary cultures of glioblastoma stem cells express VEGFR-1 [145] | ||
- VEGF-A expression is higher in glioblastoma than in low-grade gliomas and plays a role in the switch to a highly vascularized tumor [31] - GAMs contribute to tumor progression and resistance to anti-VEGF-A therapy [149,150,151,152,153] | - High expression of VEGFR-1 confers metastatic traits via modulation of SHH signaling pathway [147] - Low sVEGFR-1/VEGF-A ratio correlates with high tumor aggressiveness [31] - In surgical specimens from glioblastoma patients, VEGFR-1 is expressed in GAMs [154] | ||
Melanoma | Skin, lung, brain, liver, bone, and intestine | - Expression of PlGF and VEGF-A is associated with enhanced tumor cell proliferation, migration and ECM invasion [157,158] | - Expression of VEGFR-1 correlates with tumor cell proliferation, migration and ECM invasion [157] |
- VEGF-A and PlGF release is more frequent among cell lines derived from metastatic melanoma than from primary tumor [157] - Cell lines secreting VEGF-A and expressing VEGFR-1 spontaneously migrate through matrigel-coated filters [159] - PlGF induces tumor growth, vascularization, and metastases in a preclinical in vivo model [162] - PlGF induces resistance to temozolomide through NF-κB activation [163] | - The sVEGFR-1/VEGFR-1 transcript ratio decreases in cutaneous metastases compared to primary tumors, due to decrease of sVEGFR-1 mRNA levels [36] - Upregulation of VEGFR-1 contributes to resistance toward BRAFi [161] | ||
Bone | |||
Osteosarcoma | Lungs, other bones, and lymph nodes | - Increased VEGF-A serum levels are associated with enhanced vessel density in the tumor and decreased survival [170,171,172] - VEGF-A gene polymorphisms +936C/T and –634 G/C are associated with the risk of developing osteosarcoma [173] - VEGF-A expression is promoted by HIF-1α in hypoxic conditions in osteosarcoma cells; HIF-1 and VEGF-A knockdown decreases the invasive potential of osteosarcoma cells [174] - miR-134 binds to VEGF-A transcript and attenuates tumor growth and neovessel formation [177] - miR-1 inhibits VEGF-A expression at the post-transcriptional level, by binding to its mRNA 3′-UTR [178] | - A constitutive activation of an autocrine VEGF-A/VEGFR-1 signaling pathway is reported in highly aggressive osteosarcoma [175] - VEGF-A/VEGFR-1 signaling is a target of miR-134, which binds to VEGFR-1 transcript and attenuates tumor growth and neovessel formation [177]. |
Ewing sarcoma | Lungs, bone, and bone marrow | - High levels of the VEGF-A165 isoform contribute to stimulate the osteolytic process [179,180] - VEGF-A upregulates RANKL and increases the recruitment of TAMs in the tumor [181] | - |
Chondrosarcoma | Lung and skeleton | - VEGF-A expression correlates with adiponectin expression and tumor stage [182] - VEGF-A expression is inhibited by miR-452, which in turn is downregulated by the high expression of WISP-3, stimulating angiogenesis [183] | - |
Pancreas | Liver, lung, and peritoneum; rarely bone, adrenal gland, and distant lymph nodes | - VEGF-A is expressed in ductal epithelial tumor cells, but not in ductal cells of non-transformed pancreas or chronic pancreatitis [187,188] - VEGF-A influences pancreatic tumor cells glucose metabolism: it enhances glycolysis via HIF-1α upregulation and NRP-1 involvement [189] - Increased levels of PlGF are reported in obesity-associated pancreatic cancer patients [77] - VEGF-A mRNA and protein are detected in human ductal pancreatic carcinoma cell lines [188] | - Ablation of the VEGFR-1 signaling in pancreatic ductal adenocarcinoma murine models prevents obesity-induced tumor progression [77] - VEGFR-1 and VEGFR-2 are expressed in 29% and 43% of pancreatic carcinoma tissues, respectively [188] - VEGFR-1 expression is observed in human ductal pancreatic carcinoma cell lines [188] - VEGFR-1 and VEGFR-2 coexpression has been recognized as a poor prognostic factor [190] - VEGFR-1 and VEGFR-3 expression is significantly higher in tumor cells and tumor-associated endothelial cells, while VEGFR-2 is detected only in tumor cells [191] |
Tumor Type | Metastatic Sites | VEGFR-1 Ligands | VEGFR-1 |
---|---|---|---|
Oral | Hypopharynx, tongue, and lymph nodes | - VEGF-A overexpression correlates with poor prognosis [194,195] - Increased expression of VEGF-A positively correlates with disease recurrence and lymph node metastases in gingival cancer [196] | - VEGFR-1 signaling stimulates bone invasion, by promoting differentiation and activation of preosteoclasts [197] |
Esophageal | Liver, lymph nodes, lung, bone, and brain | - VEGF-A overexpression increases the risk of distant metastases and shorter OS [196] - The rs2010963 genetic polymorphism in VEGF-A correlates with worse OS [202] | - VEGFR-1 expression inversely correlates with patients’ survival [201] |
Gastric | Liver, peritoneum, lung, and bone | - High VEGF-A levels are associated with increased CRMP4 expression [207] - High VEGF-A levels are detected in both serum and plasma of gastric cancer patients [208] - PlGF promotes cell proliferation and chemotaxis through activation of PI3K/AKT and p38 MAPK signaling pathways [209] | - VEGFR-1 is associated with the formation of hematogenous metastases if co-detected with isolated tumor cells [205] |
Colorectal | Liver, peritoneum, lung, bone, and brain | - VEGF-A and VEGF-B, by stimulating VEGFR-1, induce downstream ERK-1/2 and JNK MAPK signaling pathways, increasing cell migration, invasion and proliferation [212] - PlGF expression is associated with higher cell invasion/migration [214] - PlGF is more expressed in patients with lymph node metastases, than in patients without metastases, and correlates with poor prognosis [216] - An intracrine VEGF-A/VEGFR-1 signaling mediates cancer cell survival [218] | - VEGFR-1 expression and activation promote phenotypic changes associated with tumor progression and metastases [212] - Stimulation of VEGFR-1 by VEGF-A increases cell migration and tyrosine phosphorylation of FAK, paxillin, and p130cas [213] - VEGFR-1 activation by PlGF induces invasion and migration, due to phosphorylation of p38 MAPK and upregulation of MMP9 expression [214] - VEGFR-1 blockade by the iVR1 peptide markedly inhibits tumor growth and recruitment of monocyte/macrophages at the tumor site in syngeneic and xenograft colorectal cancer models [215] - VEGFR-1 signaling, activated by intracrine VEGF-A, regulates cell migration through modulation of FAK activity [219] - VEGFR-1 expressing myeloid cells are crucial for tumor metastatic growth and angiogenesis in the liver [220] |
Tumor Type | Metastatic Sites | VEGFR-1 Ligands | VEGFR-1 |
---|---|---|---|
Breast | Bone, lung, liver, and brain | - The VEGF-A-stimulated-PKC pathway induces a pre-metastatic destabilization of pulmonary tight junctions, promoting vessel permeability and extravasation [225] - VEGF-A is involved in breast cancer liver metastases [227] - MiR-126 overexpression in human breast cancer inhibits cell proliferation by reducing VEGF-A levels [228] - Overexpression of COX-2-induced miR526b and miR655 in tumor cells upregulates VEGF-A [229] - VEGF-A signaling pathway and MMPs expression are positively regulated by cystathionine -γ-lyase, a key enzyme in the biosynthesis of the proangiogenic H2S [232] - PlGF stimulates cancer cell motility through activation of intracellular signaling cascades, including ERK1/2, and cytoskeletal remodeling [233] - PlGF favors CD34+ differentiation into tumor-mobilized bone marrow-derived CD11b+ myeloid cells [235] | - In breast cancer cells overexpression of COX-2-induced miR526b and miR655 results in upregulation of VEGFR-1 [229] - VEGFR-1 signaling, due to PlGF interaction, is associated with obesity-induced breast cancer progression [77] |
Ovary | Peritoneum, liver, lymph nodes, bone, and brain | - High expression of VEGF-A is considered a prognostic factor [239] - VEGF-A contributes to the recruitment and activation of myeloid-derived suppressor cells [242] - PlGF is overexpressed and increases MMP7 expression via downregulation of miR-543 [243] - PlGF overexpression increases ZEB2 expression in a p38 MAPK-dependent manner [245] | - sVEGFR-1 induces cell death in a murine model of ovarian cancer [246] |
Cervix | Lung, bone, liver, and brain | - Serum VEGF-A is a promising prognostic biomarker [249] - VEGF-A is highly expressed in specimens from patients with post-radiotherapy relapsed/persistent cancer [250] - VEGF-A is coexpressed with a metabolism-related protein (MCT4 isoform) [251] - PlGF induces EMT, promoting migration and metastases, through activation of the ERK/MAPK signaling pathway [252] - VEGF-A in culture supernatants from cervical cancer cell lines induces an M2-like phenotype [254] | - High VEGFR-1 expression is associated with distant metastases, poor OS and PFS [248] - VEGFR-1 is highly expressed in specimens from patients with post-radiotherapy relapsed/persistent cancer [250] |
Prostate | Bone, lymph nodes, lung, liver, brain | - VEGF-A expression and tumor invasiveness are favored by an acidic environment, through increased MMP9 secretion [256] - VEGF-A expression is higher in prostate cancer samples than in BPH and HGPIN samples [259] - VEGF-A decreases the expression of miR-130b and abrogates its antiangiogenic effect [261] - VEGF-A is upregulated by androgens [262] - VEGF-A inhibits the maturation and activity of DCs [264] | - VEGFR-1 expression is higher in prostate cancer samples than in BPH and HGPIN samples [259] |
Name | Target | Mechanism of Action | In Vivo Antitumor Activity | Ref. |
---|---|---|---|---|
IMC-18F1/ Icrucumab | Human VEGFR-1 | Competitive: prevention of VEGF-A, VEGF-B and PlGF binding to VEGFR-1 | Suppression of tumor growth, by increasing apoptosis and decreasing cell proliferation in human breast cancer xenografts | [287] |
D16F7 | Human VEGFR-1 | Non-competitive: down-modulation of VEGFR-1 signaling without inhibition of VEGF-A or PlGF binding | Decrease of tumor growth and tumor-associated angiogenesis and increase of animal survival in heterotopic and orthotopic glioblastoma murine models | [148] |
Inhibition of tumor growth, tumor infiltration by monocytes/macrophages and bone invasion by cancer cells in a syngeneic murine melanoma model | [160] | |||
KM1730/ KM1732 | Human VEGFR-1 | Competitive: blockade of VEGFR-1 interaction with VEGF-A | - | [288,289] |
TB-403 (RO5323441) | Human PlGF | Interaction with the receptor-binding site of PlGF | Inhibition of primary tumor growth and spinal metastases in medulloblastoma murine models | [53] |
Tumor growth inhibition in hepatocarcinoma and renal cancer murine models | [291] | |||
16D3 | Human PlGF | Interaction with the receptor-binding site of PlGF | Tumor growth inhibition in colorectal and pancreatic cancer xenograft models | [112,215] |
ClinicalTrials.gov Identifier Code | Phase and Status | Agent | Combined Drugs and Comparators | Tumor Type | Ref. |
---|---|---|---|---|---|
NCT01234402 | II, Completed | IMC-18F1/ Icrucumab | Icrucumab + capecitabine Vs Ramucirumab + capecitabine or capecitabine | Breast cancer (previously treated, stage III/IV) | [293] |
NCT01282463 | II, Completed | IMC-18F1/ Icrucumab | Icrucumab + docetaxel Vs Docetaxel + ramucirumab or docetaxel | Locally advanced or metastatic carcinoma of the urinary tract | [294] |
NCT01111604 | II, completed | IMC-18F1/ Icrucumab | Icrucumab + mFOLFOX-6 Vs mFOLFOX-6 + ramucirumab or mFOLFOX-6 | Metastatic colorectal cancer after progression during first-line chemotherapy | [295] |
NCT00782002 | I, Completed | IMC-18F1/ Icrucumab | - | Advanced/ refractory solid tumors | www.ClinicalTrials.gov |
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Ceci, C.; Atzori, M.G.; Lacal, P.M.; Graziani, G. Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models. Int. J. Mol. Sci. 2020, 21, 1388. https://doi.org/10.3390/ijms21041388
Ceci C, Atzori MG, Lacal PM, Graziani G. Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models. International Journal of Molecular Sciences. 2020; 21(4):1388. https://doi.org/10.3390/ijms21041388
Chicago/Turabian StyleCeci, Claudia, Maria Grazia Atzori, Pedro Miguel Lacal, and Grazia Graziani. 2020. "Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models" International Journal of Molecular Sciences 21, no. 4: 1388. https://doi.org/10.3390/ijms21041388
APA StyleCeci, C., Atzori, M. G., Lacal, P. M., & Graziani, G. (2020). Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models. International Journal of Molecular Sciences, 21(4), 1388. https://doi.org/10.3390/ijms21041388