KDR

Gene Summary

Gene:KDR; kinase insert domain receptor
Aliases: FLK1, CD309, VEGFR, VEGFR2
Location:4q12
Summary:Vascular endothelial growth factor (VEGF) is a major growth factor for endothelial cells. This gene encodes one of the two receptors of the VEGF. This receptor, known as kinase insert domain receptor, is a type III receptor tyrosine kinase. It functions as the main mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3, T-cell protein tyrosine phosphatase, etc.. Mutations of this gene are implicated in infantile capillary hemangiomas. [provided by RefSeq, May 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:vascular endothelial growth factor receptor 2
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KDR (cancer-related)

Naghizadeh S, Mohammadi A, Baradaran B, Mansoori B
Overcoming multiple drug resistance in lung cancer using siRNA targeted therapy.
Gene. 2019; 714:143972 [PubMed] Related Publications
Among cancers, lung cancer is the most morbidity and mortality disease that is remaining the fatalist. Generally, there are multiple treatment procedures for lung cancer, such as surgery, immunotherapy, radiotherapy and chemotherapy. There is, therefore, an urgent need for more specified and efficient methods for treatment of lung cancer such as RNAi, which in combination with traditional therapies could silence genes that are involved in the drug resistance. These genes may either be motivators of apoptosis inhibition, EMT and DNA repair system promoters or a member of intracellular signaling pathways, such as JAK/STAT, RAS/RAF/MEK, PI3K/AKT, NICD, B-catenin/TCF/LEF and their stimulator receptors including IGFR, EGFR, FGFR, VEGFR, CXCR4, MET, INTEGRINS, NOTCH1 and FRIZZLED, so could be considered as appropriate targets. In current review, the results of multiple studies which have employed drug application after one specific gene silencing or more than one gene from distinct pathways also simultaneous drug and RNAi usage in vitro and in vivo in lung cancer were summarized.

Jiang Q, Zhang NL, Ma DY, et al.
Efficacy and safety of apatinib plus docetaxel as the second or above line treatment in advanced nonsquamous NSCLC: A multi center prospective study.
Medicine (Baltimore). 2019; 98(26):e16065 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Some clinical trials have demonstrated that apatinib is efficacious against advanced nonsquamous NSCLC.
OBJECTIVE: This study aimed to probe efficacy and safety of apatinib plus docetaxel, as the second or above line treatment, in advanced nonsquamous NSCLC.
DESIGN: Multicenter, prospective, single arm study.
SETTING: Three teaching hospitals centers in the Sichuan.
PARTICIPANTS: Fourteen patients with stage IVA/B nonsquamous NSCLC had previously received at least 1 platinum-based chemotherapy regimen.
INTERVENTION: Patients who were enrolled between November 2016 and January 2018 were given docetaxel (75 mg/m, i.v., d1) plus oral apatinib (250 mg/d), 4 weeks as one cycle, until disease progression or intolerance to adverse events (AE).
MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival (PFS). The secondary endpoints comprised objective response rate (ORR), disease control rate (DCR), overall survival (OS), and AE incidence rate.
RESULTS: All patients carried adenocarcinoma by pathological type. The median follow-up duration was 9.76 months. Out of 14 cases, 12 were evaluable, showing ORR of 33.33%, DCR of 66.67%, DCR of 50% in cases with brain metastasis, median PFS of 2.92 months (95% CI: 1.38-4.48), and 6-month OS of 80%. Primary AEs encompassed: leukopenia in 7 cases (58.33%), hand-foot skin reaction in 5 cases (41.67%), and diarrhea in 4 cases (33.33%). Among them, grade 3 AEs were: leukopenia in 4 cases (33.33%), and hand-foot skin reaction in 1 case (8.33%). No grade 4/5 AEs were reported. Univariate and multivariate analysis were conducted respectively for PFS and OS. These factors encompassed: gender, age, gene mutations, clinical stage, ECOG scores, quantity of metastatic foci, brain metastasis, and hand-foot skin reaction. Results demonstrated zero risk factors for PFS or OS.
CONCLUSION: Apatinib plus docetaxel, as the second or above line treatment, is effective and safe against advanced nonsquamous NSCLC, with good tolerance profile.
TRIAL REGISTRATION: NCT03416231.

Zang W, Bian H, Huang X, et al.
Traditional Chinese Medicine (TCM)
Anticancer Res. 2019; 39(6):2739-2747 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs).
MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a.
RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-β. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control.
CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.

Gao Y, Qian H, Tang X, et al.
Superparamagnetic iron oxide nanoparticle-mediated expression of
Int J Nanomedicine. 2019; 14:2719-2731 [PubMed] Free Access to Full Article Related Publications

Rusak A, Jablonska K, Piotrowska A, et al.
Correlation of Expression of CHI3L1 and Nogo-A and their Role in Angiogenesis in Invasive Ductal Breast Carcinoma.
Anticancer Res. 2019; 39(5):2341-2350 [PubMed] Related Publications
BACKGROUND/AIM: Chitinase 3 like 1 (CHI3L1) is a secretion glycoprotein. Elevated levels of this protein are observed in cancer diseases. The biological role of CHI3L1 is not yet fully known, but the connection between CHI3L1 and angiogenesis has been shown. Recent reports also describe the association of Nogo isoforms and Nogo-B receptor (NgBR) with a proliferative potential, cancer cell invasiveness, and angiogenesis. The aim of this study was to evaluate the levels of CHI3L1, Nogo-A, Nogo-A/B, and NgBR and correlate them with clinical-pathological data, to study their role in angiogenesis in invasive ductal breast carcinoma (IDC).
MATERIALS AND METHODS: A total of 77 IDC cases were used in the study. Immunohistochemistry was used to determine the level of expression of CHI3L1, Nogo-A, Nogo-A/B, NgBR and vascular endothelial growth factors (VEGFA, VEGFC and VEGFD). The obtained results were subjected to statistical analysis including clinicalpathological data.
RESULTS: A statistically significant positive correlation of CHI3L1 and Nogo-A expression (r=0.474, p>0.0001) and a positive correlation of Nogo-A and VEGFC expression (r=0.280, p=0.013) were found.
CONCLUSION: CHI3L1 and Nogo-A are important in angiogenesis in IDC.

Liang W, Zheng Y, Zhang J, Sun X
Multiscale modeling reveals angiogenesis-induced drug resistance in brain tumors and predicts a synergistic drug combination targeting EGFR and VEGFR pathways.
BMC Bioinformatics. 2019; 20(Suppl 7):203 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Experimental studies have demonstrated that both the extracellular vasculature or microenvironment and intracellular molecular network (e.g., epidermal growth factor receptor (EGFR) signaling pathway) are important for brain tumor growth. Additionally, some drugs have been developed to inhibit EGFR signaling pathways. However, how angiogenesis affects the response of tumor cells to drug treatment has rarely been mechanistically studied. Therefore, a multiscale model is required to investigate such complex biological systems that contain interactions and feedback among multiple levels.
RESULTS: In this study, we developed a single cell-based multiscale spatiotemporal model to simulate vascular tumor growth and the drug response based on the vascular endothelial growth factor receptor (VEGFR) signaling pathway, the EGFR signaling pathway and the cell cycle as well as several microenvironmental factors that determine cell fate switches in a temporal and spatial context. By incorporating the EGFRI treatment effect, the model showed an interesting phenomenon in which the survival rate of tumor cells decreased in the early stage but rebounded in a later stage, revealing the emergence of drug resistance. Moreover, we revealed the critical role of angiogenesis in acquired drug resistance, since inhibiting blood vessel growth using a VEGFR inhibitor prevented the recovery of the survival rate of tumor cells in the later stage. We further investigated the optimal timing of combining VEGFR inhibition with EGFR inhibition and predicted that the drug combination targeting both the EGFR pathway and VEGFR pathway has a synergistic effect. The experimental data validated the prediction of drug synergy, confirming the effectiveness of our model. In addition, the combination of EGFR and VEGFR genes showed clinical relevance in glioma patients.
CONCLUSIONS: The developed multiscale model revealed angiogenesis-induced drug resistance mechanisms of brain tumors to EGFRI treatment and predicted a synergistic drug combination targeting both EGFR and VEGFR pathways with optimal combination timing. This study explored the mechanistic and functional mechanisms of the angiogenesis underlying tumor growth and drug resistance, which advances our understanding of novel mechanisms of drug resistance and provides implications for designing more effective cancer therapies.

Zhang Q, Lu S, Li T, et al.
ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway.
J Exp Clin Cancer Res. 2019; 38(1):173 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear.
METHODS: The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model.
RESULTS: ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs.
CONCLUSIONS: Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway.
TRIAL REGISTRATION: Retrospectively registered.

Wang T, Xing Y, Meng Q, et al.
Mammalian Eps15 homology domain 1 potentiates angiogenesis of non-small cell lung cancer by regulating β2AR signaling.
J Exp Clin Cancer Res. 2019; 38(1):174 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Non-small cell lung cancer (NSCLC) is a devastating disease with a heterogeneous prognosis, and the molecular mechanisms underlying tumor progression remain elusive. Mammalian Eps15 homology domain 1 (EHD1) plays a promotive role in tumor progression, but its role in cancer angiogenesis remains unknown. This study thus explored the role of EHD1 in angiogenesis in NSCLC.
METHODS: The changes in angiogenesis were evaluated through human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation assays. The impact of EHD1 on β2-adrenoceptor (β2AR) signaling was evaluated by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and enzyme-linked immunosorbent assay (ELISA). The interaction between EHD1 and β2AR was confirmed by immunofluorescence (IF) and coimmunoprecipitation (Co-IP) experiments, and confocal microscopy immunofluorescence studies revealed that β2AR colocalized with the recycling endosome marker Rab11, which indicated β2AR endocytosis. Xenograft tumor models were used to investigate the role of EHD1 in NSCLC tumor growth.
RESULTS: The microarray analysis revealed that EHD1 was significantly correlated with tumor angiogenesis, and loss- and gain-of-function experiments demonstrated that EHD1 potentiates HUVEC proliferation, migration and tube formation. EHD1 knockdown inhibited β2AR signaling activity, and EHD1 upregulation promoted vascular endothelial growth factor A (VEGFA) and β2AR expression. Interestingly, EHD1 interacted with β2AR and played a novel and critical role in β2AR endocytic recycling to prevent receptor degradation. Aberrant VEGFA or β2AR expression significantly affected EHD1-mediated tumor angiogenesis. The proangiogenic role of EHD1 was confirmed in xenograft tumor models, and immunohistochemistry (IHC) analysis confirmed that EHD1 expression was positively correlated with VEGFA expression, microvessel density (MVD) and β2AR expression in patient specimens.
CONCLUSION: Collectively, the data obtained in this study suggest that EHD1 plays a critical role in NSCLC angiogenesis via β2AR signaling and highlight a potential target for antiangiogenic therapy.

Wu G, Niu M, Qin J, et al.
Inactivation of Rab27B-dependent signaling pathway by calycosin inhibits migration and invasion of ER-negative breast cancer cells.
Gene. 2019; 709:48-55 [PubMed] Related Publications
Previous studies report the upregulation of the secretory Rab27B small GTPase in human breast cancer, which could promote invasive growth and metastasis in estrogen receptor (ER)-positive breast cancer cells. However, there is limited evidence for its role in ER-negative breast cancer, along with the signaling pathways. Consistent with previous studies, we here confirmed that Rab27B is upregulated in breast tumor tissue in comparison with normal breast tissue. In addition, in ER-negative breast cancer cell line MDA-MB-231, when the levels of Rab27B expression were further elevated by transduction with recombinant lentivirus vector, migration and invasion assays demonstrated that cell migration and invasion was significantly stimulated. Moreover, Rab27B overexpression increased levels of β-catenin, followed by upregulation of vascular endothelial growth factor (VEGF). Our findings reveal a key function for the Rab27B-mediated modulation of β-catenin and VEGF in ER-negative breast cancer cell metastasis. Notably, the suppressed expression of Rab27B, β-catenin and VEGF was found in calycosin-treated MDA-MB-231 cells, accompanied with decreased invasive and migratory potential of these cells. What's more, these inhibitory effects of calycosin were all attenuated by Rab27B overexpression. The results demonstrated that calycosin-induced inhibition of migration and invasion in ER-negative breast cancer cells may be associated with the inactivation of Rab27B-dependent signaling, and suggest that antagonism of this pathway by calycosin may offer alternative therapeutic strategy for the aggressive breast cancer.

Alonso-Gordoa T, García-Bermejo ML, Grande E, et al.
Targeting Tyrosine kinases in Renal Cell Carcinoma: "New Bullets against Old Guys".
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal cell carcinoma (RCC) development and progression has been a key milestone in the management of this type of tumor. The discovery of Von Hippel Lindau (

Chen J, Chen J, He F, et al.
Design of a Targeted Sequencing Assay to Detect Rare Mutations in Circulating Tumor DNA.
Genet Test Mol Biomarkers. 2019; 23(4):264-269 [PubMed] Related Publications
BACKGROUND: Qualitative and quantitative detection of circulating tumor DNA (ctDNA) is a liquid biopsy technology used for early cancer diagnosis. However, the plasma ctDNA content is extremely low, so it is difficult to detect somatic mutations of tumors using conventional sequencing methods. Target region sequencing (TRS) technology, through enrichment of the target genomic region followed by next generation sequencing, overcomes this challenge and has been widely used in ctDNA sequencing.
METHODS: We designed a ctDNA sequencing panel to capture 128 tumor genes, and tested the performance of the panel by running TRS for ctDNA of a clear cell renal cell carcinoma (ccRCC) patient and 12 breast cancer patients.
RESULTS: TRS using the new ctDNA panel at more than 500 × coverage depth achieved almost the same accuracy as traditional whole-exome sequencing (WES). PBRM1 p.L641V was detected in the plasma sample of the ccRCC patient with an allele frequency of 0.2%. The ctDNA of 12 breast cancer patients was sequenced at a depth of 500-fold, achieving 99.89% coverage; 34 genes were detected with mutations, including the drug target genes BRCA2, PTEN, TP53, APC, KDR, and NOTCH2.
CONCLUSIONS: This TRS new ctDNA panel can be used to detect mutations in cell-free DNA from multiple types of cancer.

Kubatka P, Uramova S, Kello M, et al.
Anticancer Activities of
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of

Yun JW, Bae YK, Cho SY, et al.
Elucidation of Novel Therapeutic Targets for Acute Myeloid Leukemias with
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
The

Liu JB, Jian T, Yue C, et al.
Chemo-resistant Gastric Cancer Associated Gene Expression Signature: Bioinformatics Analysis Based on Gene Expression Omnibus.
Anticancer Res. 2019; 39(4):1689-1698 [PubMed] Related Publications
BACKGROUND/AIM: This study aimed to identify biomarkers for predicting the prognosis of advanced gastric cancer patients who received docetaxel, cisplatin, and S-1 (DCS).
MATERIALS AND METHODS: Gene expression profiles were obtained from the Gene Expression Omnibus database (GSE31811). Gene-Ontology-enrichment and KEGG-pathway analysis were used for evaluating the biological functions of differentially-expressed genes. Protein-protein interaction (PPI) network and Kaplan-Meier survival analyses were employed to assess the prognostic values of hub genes.
RESULTS: A total of 1,486 differentially expressed genes (DEGs) were identified, including 13 up-regulated and 1,473 down-regulated genes. KEGG pathways such as metabolic pathways, cell adhesion molecules (CAMs), PI3K-Akt signaling pathway and pathways in cancer were significantly represented. In the PPI network, the top ten hub genes ranked by degree were GNG7, PLCB1, CALML5, FGFR4, GRB2, JAK3, ADCY7, ADCY9, GNAS and KDR. Five DEGs, including ANTXR1, EFNA5, GAMT, E2F2 and NRCAM, were associated with relapse-free survival and overall survival.
CONCLUSION: ANTXR1, EFNA5, GAMT, E2F2 and NRCAM are potential biomarkers and therapeutic targets for DCS treatment in GC.

Davis PJ, Lin HY, Hercbergs AA, et al.
How thyroid hormone works depends upon cell type, receptor type, and hormone analogue: implications in cancer growth.
Discov Med. 2019; 27(147):111-117 [PubMed] Related Publications
The classical molecular mechanism of thyroid hormone involves the intranuclear interaction of 3,5,3'-triiodo-L-thyronine (T3) with thyroid hormone-specific nuclear proteins and consequent specific gene expression. This mechanism prevails in normal cells. What we emphasize here is that how thyroid hormone acts depends upon the types of cell or cell-like structure, e.g., platelet, under consideration, and that cancer cells, dividing endothelial cells, phagocytes, and platelets respond to the liganding of L-thyroxine (T4) by plasma membrane integrin αvβ3. In intact tumor cells, T4 at the integrin can modulate the transcription of a substantial number of specific genes relevant to cancer cell proliferation, cell metabolism, and cancer cell anti-apoptosis defense. T4 may also regulate the interactions of the integrin in the endothelial cell plasma membrane with adjacent vascular growth factor receptors, modulating angiogenesis. T4 activates platelets via αvβ3 transferred from the megakaryocyte. It is also possible that, in addition to T4, reverse T3 (rT3) may have actions in cancer cells at the thyroid hormone receptor on αvβ3.

Li J, Guo L, Chai L, Ai Z
Comprehensive Analysis of Driver Genes in Personal Genomes of Clear Cell Renal Cell Carcinoma.
Technol Cancer Res Treat. 2019; 18:1533033819830966 [PubMed] Free Access to Full Article Related Publications
AIM: To characterize personal driver genes in clear cell renal cell carcinoma independent of somatic mutation frequencies.
METHODS: Personal cancer driver genes were predicted by Integrated CAncer GEnome Score in 417 patients with clear cell renal cell carcinoma using 26 786 somatic mutations from The Cancer Genome Atlas, followed by an integrated investigation on personal driver genes.
RESULTS: A total of 233 personal driver genes were determined by Integrated CAncer GEnome Score. The coexpression network analysis found 5 coexpressed modules. The blue module was significantly negatively correlated with all 5 clinical features, including cancer stage, lymph node metastasis, distant metastasis, age, and survival status (death). CTNNB1, TGFBR2, KDR, FLT1, and INSR were the hub genes in the blue module. The expression of 79 personal driver genes was significantly associated with clinical outcomes of patients with clear cell renal cell carcinoma.
CONCLUSIONS: The set of personal driver genes sheds insights into the tumorigenesis of clear cell renal cell carcinoma and paves the way for developing personalized medicine for clear cell renal cell carcinoma.

Fang Y, Sun B, Wang J, Wang Y
miR-622 inhibits angiogenesis by suppressing the CXCR4-VEGFA axis in colorectal cancer.
Gene. 2019; 699:37-42 [PubMed] Related Publications
Angiogenesis is essential for tumor metastasis. Our previous study has revealed that miR-622 inhibits colorectal cancer (CRC) metastasis. Here, we aimed to explore the effects and potential molecular mechanisms of action of miR-622 on angiogenesis. We found that overexpression of miR-622 inhibited CRC angiogenesis in vitro, according to suppression of proliferation, migration, tube formation, and invasiveness of human umbilical vein endothelial cells (HUVECs) treated with a tumor cell-conditioned medium derived from Caco-2 or HT-29 cells. Likewise, enhanced miR-622 expression suppressed CRC angiogenesis in vivo as determined by the measurement of Ki67 and VEGFA levels and microvessel density (by immunostaining). CXCR4, encoding a positive regulator of vascular endothelial growth factor A (VEGFA), was shown to be a direct target of miR-622. Overexpression of CXCR4 attenuated the inhibition of VEGFA expression by miR-622 and reversed the loss of tumor angiogenesis caused by miR-622. Taken together, these data show that miR-622 inhibits CRC angiogenesis by suppressing the CXCR4-VEGFA signaling axis, which represents a promising target for developing a new therapeutic strategy against CRC.

Lian L, Li XL, Xu MD, et al.
VEGFR2 promotes tumorigenesis and metastasis in a pro-angiogenic-independent way in gastric cancer.
BMC Cancer. 2019; 19(1):183 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: VEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. However, little work has been carried out concerning the pro-malignancy functions of VEGFR2 that are independent of its pro-angiogenesis effects in gastric cancer. Here, we demonstrated that VEGFR2 up-regulation in gastric cancer tissues was a prognostic marker for poor disease-free survival and overall survival of gastric cancer patients.
METHODS: Immunohistochemistry was used to detect VEGFR2 and VTN expressions in specimens. Kaplan-Meier curves were constructed for survival analysis. Stably knockdown cell lines and overexpression cell lines were constructed by small interfering RNA and plasmids transfection. Real-time PCR and Western blot were used to confirm the expressions of target genes at both RNA and protein levels. Cell proliferation was measured by using Cell Counting Kit-8 and xenograft models. Microarray and bioinformatic analysis were also performed to identify the relationship between Vitronectin (VTN) and VEGFR2.
RESULTS: When overexpressed in gastric cancer cells, VEGFR2 increased cellular proliferation and invasion in vitro and tumor formation in xenograft models. By using integrating microarray and bioinformatic analysis, we identifiedVTN as a downstream of VEGFR2 pathway. In gain- and loss-of function analysis in gastric cancer cells, VTN was further verified in consistent with VEGFR2 in expression levels and in regulating cell growth and motility in vitro and in vivo. Moreover, in gastric cancer samples, VTN was as also revealed as a poor prognostic factor.
CONCLUSIONS: Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects.
IMPLICATIONS: Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects, which may provide a new and valuable target for design of therapies for intervention and a new cognitive perspective for the anti-angiogenesis therapies.

Zhang L, Luo B, Dang YW, et al.
The clinical significance of endothelin receptor type B in hepatocellular carcinoma and its potential molecular mechanism.
Exp Mol Pathol. 2019; 107:141-157 [PubMed] Related Publications
OBJECTIVE: To explore the clinical significance and potential molecular mechanism of endothelin receptor type B (EDNRB) in hepatocellular carcinoma (HCC).
METHODS: Immunohistochemistry was used to detect EDNRB protein expression level in 67 HCC paraffin embedded tissues and adjacent tissues. Correlations between EDNRB expression level and clinicopathologic parameters were analyzed in our study. The expression level and clinical significance of EDNRB in HCC were also evaluated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The cBioPortal for Cancer Genomics was employed to analyze the EDNRB related genes, and Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network were conducted for those EDNRB related genes.
RESULTS: Lower expression level of EDNRB in HCC was verified by immunohistochemistry than adjacent tissues (P < 0.0001). The expression level of EDNRB in HCC tissues was lower than normal control liver tissues based on TCGA and GEO data (standard mean difference [SMD] = -1.48, 95% [confidence interval] CI: -1.63-(-1.33), P
CONCLUSION: Our study provides novel findings and insights on the molecular pathogenesis of HCC from EDNRB view.

Shen J, Li L, Yang T, et al.
Drug Sensitivity Screening and Targeted Pathway Analysis Reveal a Multi-Driver Proliferative Mechanism and Suggest a Strategy of Combination Targeted Therapy for Colorectal Cancer Cells.
Molecules. 2019; 24(3) [PubMed] Free Access to Full Article Related Publications
Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC

Teufel M, Seidel H, Köchert K, et al.
Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma.
Gastroenterology. 2019; 156(6):1731-1741 [PubMed] Related Publications
BACKGROUND & AIMS: In a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib.
METHODS: We obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model.
RESULTS: Decreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders.
CONCLUSION: We identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. ClinicalTrials.gov number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221.

Gurdal H, Tuglu MM, Bostanabad SY, Dalkiliç B
Partial agonistic effect of cetuximab on epidermal growth factor receptor and Src kinase activation in triple‑negative breast cancer cell lines.
Int J Oncol. 2019; 54(4):1345-1356 [PubMed] Related Publications
Cetuximab is a monoclonal antibody developed to inhibit the binding of growth factors and the subsequent activation of epidermal growth factor receptor (EGFR). Triple‑negative breast cancer (TNBC) is resistant to cetuximab treatment. The aim of the present study was to examine the partial agonistic properties of cetuximab, which not only blocks ligand binding, but also partially triggers EGFR activation, which may lead to cetuximab resistance in TNBC. The phosphorylation of growth factor receptors and their signalling pathways were evaluated by determining the phosphorylation of EGFR, insulin‑like growth factor receptor (IGF‑1R), vascular endothelial growth factor receptor (VEGFR)‑2, Src kinase, phosphoinositide‑3‑kinase (PI3K), extracellular signal‑regulated kinase (ERK1/2) and serine/threonine‑specific protein kinase (Akt) and the degradation of EGFR, and by assessing the morphology and proliferation of MDA‑MB‑231 and MDA‑MB‑468 cells. Cetuximab treatment led to the phosphorylation of EGFR, VEGFR‑2, IGF‑1R and downstream signalling molecules, Src kinase and PI3K in these cells, as well as Akt in the MDA‑MB‑231 cells. The cetuximab‑mediated phosphorylation of IGF‑1R, VEGFR‑2 and Akt was inhibited by the EGFR kinase inhibitor, AG1478, and the Src kinase inhibitor, PP2. Cetuximab treatment led to the degradation of EGFR. The cetuximab‑induced phosphorylation and EGFR degradation were less prominent compared with those induced by EGF. Cetuximab partially inhibited EGF‑mediated responses. Cetuximab, similar with EGF, altered cellular morphology in a serum‑free medium. In both cell lines, the Src kinase inhibitor enhanced the cetuximab‑induced anti‑proliferative response. These results indicate that cetuximab exerts a partial agonistic effect on EGFR, which activates Src kinase and subsequently transactivates IGF‑1R and VEGFR‑2. This partial agonistic property is likely one of the mechanisms underlying the resistance of TNBC to cetuximab.

Zhang C, Liang Y, Ma MH, et al.
KRT15, INHBA, MATN3, and AGT are aberrantly methylated and differentially expressed in gastric cancer and associated with prognosis.
Pathol Res Pract. 2019; 215(5):893-899 [PubMed] Related Publications
AIM: The present study aims to identify aberrantly methylated and differentially expressed genes (DEGs) in gastric cancer (GC) and explore their potential role in the carcinogenesis and development of GC.
METHODS: The original RNA-Seq, clinical information and Illumina Human Methylation 27 Chip data associated with GC were downloaded from The Cancer Genome Atlas (TCGA) database using the gdc-client tool. The DEGs and aberrantly methylated genes (AMGs) were screened with edgeR and limma package in R, respectively. The cut-off criteria for DEG identification were P < 0.05 and fold change (FC) >2.0, and for AMG identification were P < 0.05 and |t|>2.0. Genes which were both DEGs and AMGs were considered to be regulated by aberrant DNA methylation in GC. The common genes were used for further functional enrichment analysis in the categories of cellular component, molecular function, biological process and biological pathway.
RESULTS: In total 465 genes including 336 down-regulated genes with hyper-methylation (DGs-Hyper) and 129 up-regulated genes with hypo-methylation (UGs-Hypo) were identified. Cellular component analysis showed that these genes were mainly expressed in the cytoplasm and plasma membrane. Molecular function and biological process analysis indicated that the genes primarily participate in cell communication, signal transduction, cell growth/maintenance and function as transcription factors, receptor, cell adhesion molecules, and transmembrane receptor protein tyrosine kinases. Biological pathway analysis revealed that the genes are involved in some crucial pathways including epithelial-to-mesenchymal transition, IL3-mediated signaling, mTOR signaling, VEGF/VEGFR and c-Met signaling. KRT15, INHBA, MATN3, and AGT are significantly associated with the prognosis of GC patients.
CONCLUSION: Our study identified several DEGs regulated by aberrant DNA methylation in GC. The mechanism of DNA methylation in the carcinogenesis and development of GC could be further explored in these genes, especially KRT15, INHBA, MATN3, and AGT.

Niland S, Eble JA
Neuropilins in the Context of Tumor Vasculature.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. This review highlights the diverse neuropilin ligands and interacting partners on endothelial cells, which are relevant in the context of the tumor vasculature and the tumor microenvironment. In addition to tumor cells, the latter contains cancer-associated fibroblasts, immune cells, and endothelial cells. Based on the prevalent neuropilin-mediated interactions, the suitability of various neuropilin-targeted substances for influencing tumor angiogenesis as a possible building block of a tumor therapy is discussed.

Kokabu T, Mori T, Matsushima H, et al.
Antitumor effect of XCT790, an ERRα inverse agonist, on ERα-negative endometrial cancer cells.
Cell Oncol (Dordr). 2019; 42(2):223-235 [PubMed] Related Publications
PURPOSE: The estrogen-related receptor (ERR) α is structurally similar to classical estrogen receptors (ERs), but is considered to be an orphan nuclear receptor. We previously found that ERRα regulates uterine endometrial cancer progression. Here, we investigated the efficacy of XCT790, a selective inverse agonist of ERRα, on endometrial cancer cells in vitro and in vivo.
METHODS: HEC-1A and KLE, ERα-negative endometrial cancer cells exhibiting high ERRα expression levels, and HEC-1A cell-derived xenograft model mice were treated with XCT790. Transcriptional activity and cell proliferation were examined using luciferase, WST-8 and colony formation assays, respectively. Cell cycle progression was evaluated using flow cytometry, immunofluorescence cytochemistry and Western blotting. Apoptosis was evaluated using a caspase-3/7 activity assay.
RESULTS: We found that XCT790 significantly inhibited ERRα-induced in vitro transcriptional activity, including that of the vascular endothelial growth factor (VEGF) gene, in a concentration-dependent manner (p < 0.05). We also found that XCT790 suppressed colony formation and cell proliferation in a concentration and time-dependent manner (p < 0.01) without cytotoxicity, and induced apoptosis (p < 0.01). XCT790 was found to cause cell cycle arrest at the mitotic phase. Akt and mTOR phosphorylation was found to be inhibited by XCT790, but PI3K levels were not found to be significantly affected. Combination therapy of XCT790 with paclitaxel elicited a synergistic inhibitory effect. Additionally, we found that XCT790 significantly inhibited in vivo tumor growth and angiogenesis, and induced apoptosis without a reduction in body weight, in xenograft models (p < 0.01).
CONCLUSIONS: From our data we conclude that XCT790 has an anti-tumor effect on endometrial cancer cells in vitro and in vivo. As such, it may serve as a novel therapeutic agent for endometrial cancer.

Villanova T, Gesmundo I, Audrito V, et al.
Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma.
Proc Natl Acad Sci U S A. 2019; 116(6):2226-2231 [PubMed] Free Access to Full Article Related Publications
Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

Liu X, Xu X, Deng W, et al.
CCL18 enhances migration, invasion and EMT by binding CCR8 in bladder cancer cells.
Mol Med Rep. 2019; 19(3):1678-1686 [PubMed] Free Access to Full Article Related Publications
Increased expression of CCL18 has been observed in various malignancies and in the urine samples of patients with bladder cancer (BC). However, the roles of CCL18 in the development, progression and metastasis of BC remain unclear. The present study demonstrated that CCL18 expression was significantly associated with advanced clinical stages of BC. Furthermore, exogenous CCL18 promoted cell invasion and migration, and induced cell epithelial‑mesenchymal transition (EMT) in BC cells. Western blotting demonstrated that E‑cadherin, an epithelial marker, was decreased, whereas matrix metalloproteinase (MMP)‑2 and vascular endothelial growth factor (VEGF)‑C were increased in CCL18‑treated cells. Blocking CCR8 via a small molecule inhibitor or short hairpin (sh)RNA mitigated the decrease in E‑cadherin, and increase in MMP‑2 and VEGF‑C, caused by human recombinant (r)CCL18. CCR8 knockdown by shRNA reversed rCCL18‑induced cancer cell invasion, migration and EMT. In conclusion, these data suggested that CCL18 may promote migration, invasion and EMT by binding CCR8 in BC cells. Inhibition of CCL18 activity by blocking CCR8 could be a potential therapeutic strategy for preventing the progression of BC.

Zeng Z, Li Y, Pan Y, et al.
Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis.
Nat Commun. 2018; 9(1):5395 [PubMed] Free Access to Full Article Related Publications
Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.

Dong Z, Huang K, Liao B, et al.
Prediction of sorafenib treatment-related gene expression for hepatocellular carcinoma: preoperative MRI and histopathological correlation.
Eur Radiol. 2019; 29(5):2272-2282 [PubMed] Related Publications
PURPOSE: To investigate the feasibility of prediction for targeted therapy-related gene expression in hepatocellular carcinoma (HCC) using preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI).
MATERIALS AND METHODS: Ninety-one patients (81 men, mean age 53.9 ± 12 years) with solitary HCC who underwent preoperative enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, intratumoral vessels, peritumor enhancement, peritumor hypointensity, signal intensity ratio on DWI, T1 relaxation times, and the reduction rate between pre- and post-contrast enhancement images were assessed. The operation and histopathological evaluation were performed within 2 weeks after MRI examination (mean time 7 days). The expression levels of BRAF, RAF1, VEGFR2, and VEGFR3 were evaluated. The associations between these imaging features and gene expression levels were investigated.
RESULTS: Tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.002) were significantly associated with BRAF expression, and tumor incomplete capsules or non-capsules (p = 0.001) and intratumoral vessels (p = 0.013) with RAF1 expression. There was no significant association between the expression of VEGFR2, VEGFR3, and all examined MRI features. Multivariate logistic regression showed that incomplete tumor capsule (p = 0.002) and non-capsule (p = 0.004) were independent risk factors of HCC with high BRAF expression; incomplete tumor capsule (p < 0.001) and non-capsule (p = 0.040) were independent risk factors of HCC with high RAF1 expression.
CONCLUSION: The presence of incomplete capsule or intratumoral vessels and the absence of capsule are potential indicators of high BRAF and RAF1 expression. Gadoxetic acid-enhanced MRI may facilitate the choice of gene therapy for patients with HCC.
KEY POINTS: • Incomplete tumor capsule and non-capsule were independent risk factors of HCC with high BRAF and RAF1 expression. • The presence of intratumoral vessels was a potential indicator of high BRAF and RAF1 expression. • Gadoxetic acid-enhanced MRI may be a predictor of efficacy of treatment with sorafenib.

Surov A, Meyer HJ, Höhn AK, et al.
Metabolo-volumetric parameters of 18F-FDG-PET can predict expression of EGFR and HIF 1alpha in uterine cervical cancer.
Cancer Biomark. 2019; 24(1):135-140 [PubMed] Related Publications
BACKGROUND: The aim of our study was to investigate possible relationships between 18F-FDG-PET parameters and clinically relevant histopathological findings in patients with cervical cancer (CC).
METHODS: Eighteen female patients (mean age 55.4 years) with histologically confirmed squamous cell CC were involved into the study. In all cases, 18F-FDG-PET CT was performed. Mean and maximum standardized uptake values (SUVmean and SUVmax), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) were determined on PET-images. For every tumor the following specimen stainings were performed: epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, hypoxia-inducible factor (HIF)-1α, and histone 3. All stained specimens were digitalized and analyzed by using the ImageJ software 1.48v. Spearman's correlation coefficient (p) was used to analyze associations between investigated parameters. p-values < 0.05 were taken to indicate statistical significance.
RESULTS: TLG and MTV correlated well with expression of EGFR (p= 0.601, P= 0.008 and p= 0.586, P= 0.011, respectively). SUVmedian correlated inversely with expression of HIF 1alpha (p=-0.509, P= 0.031). SUVmean tended to correlate with expression of EGFR and HIF 1alpha. None of the PET parameters correlated with expression of Histone 3, p53 and VEGF.
CONCLUSION: TLG and MTV can reflect expression of EGFR and SUVmedian correlated significantly with expression of HIF-1α. None of the PET parameters can predict expression of Histone 3, p53 and VEGF.

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