VEGFC

Gene Summary

Gene:VEGFC; vascular endothelial growth factor C
Aliases: VRP, Flt4-L, LMPH1D
Location:4q34.3
Summary:The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. The encoded protein promotes angiogenesis and endothelial cell growth, and can also affect the permeability of blood vessels. The proprotein is further cleaved into a fully processed form that can bind and activate VEGFR-2 and VEGFR-3 receptors. [provided by RefSeq, Apr 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:vascular endothelial growth factor C
Source:NCBIAccessed: 16 March, 2017

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 (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: VEGFC (cancer-related)

Camerin GR, Brito AB, Vassallo J, et al.
VEGF gene polymorphisms and outcome of epithelial ovarian cancer patients.
Future Oncol. 2017; 13(5):409-414 [PubMed] Related Publications
AIM: Since VEGF polymorphisms were associated with variable protein production, we analyzed herein their roles in outcome of epithelial ovarian cancer (EOC) patients.
METHODS: Genotypes of 85 patients with primary EOC were identified in DNA by real-time PCR. Progression-free survival and overall survival were analyzed using Kaplan-Meier method, univariate Cox model and bootstrap resampling study.
RESULTS: At 60 months of follow-up, progression-free survival was shorter in patients with VEGF c.-2578 CC genotype compared with others (52.7 vs 82.2%; p = 0.04). Those patients had 2.15 more chance of presenting disease progression than others (p = 0.04); bootstrap study validated the result (p = 0.03).
CONCLUSION: Our data suggest that VEGF c.-2578C>A polymorphism acts as a prognostic factor in EOC.

Al-Shareef H, Hiraoka SI, Tanaka N, et al.
Use of NRP1, a novel biomarker, along with VEGF-C, VEGFR-3, CCR7 and SEMA3E, to predict lymph node metastasis in squamous cell carcinoma of the tongue.
Oncol Rep. 2016; 36(5):2444-2454 [PubMed] Free Access to Full Article Related Publications
Lymph node (LN) metastasis has been suggested as a major prognostic factor for oral cancer. Knockdown of the growth factors and receptors involved in these metastatic mechanisms could significantly reduce LN metastasis and improve the survival of oral cancer patients after treatment. The present study, therefore, aimed to evaluate the expression levels of the following growth factors and receptors in squamous cell carcinoma (SCC) of the tongue: the vascular endothelial growth factor (VEGF)‑C and VEGF‑D, which bind to the cell surface tyrosine kinase receptor VEGF receptor‑3 (VEGFR‑3); C‑C motif chemokine receptor 7 (CCR7); neuropilin (NRP)1 and NRP2; and semaphorin 3E (SEMA3E). Furthermore, we assessed microvessel density (MVD) and lymphatic vessel density (LVD) to demonstrate the correlation between these factors and regional LN metastasis, with respect to the clinicopathological features. Finally, we analyzed the correlation between these proteins and overall or disease‑free survival, in order to demonstrate their prognostic value. Univariate analysis revealed a significant association between LN metastasis and the expression levels of VEGF‑C, VEGFR‑3, CCR7, NRP1, and SEMA3E, as well as LVD, in SCC cells. In contrast, multivariate analysis identified associations between LN metastasis and NRP1 expression, as well as between LN metastasis and LVD; however, no correlation was found between LN metastasis and the expression levels of the other proteins. The expression levels of VEGF‑C, VEGFR‑3, NRP1, and SEMA3E, as well as LVD, were correlated with disease‑free survival time. These results indicate that LN metastasis is associated with poor survival in SCC. This study suggests that NRP1 expression and LVD are independent factors that are likely to predict the risk of LN metastasis in SCC of the tongue, whereas the expression of VEGF‑C, VEGFR‑3, CCR7, and SEMA3E are non‑independent predictive factors.

Maehana S, Nakamura M, Ogawa F, et al.
Suppression of lymphangiogenesis by soluble vascular endothelial growth factor receptor-2 in a mouse lung cancer model.
Biomed Pharmacother. 2016; 84:660-665 [PubMed] Related Publications
The vascular endothelial growth factor (VEGF) family has a key role in the formation of blood vessels and lymphatics. Among the members of this family, VEGF-C is one of the most important factors involved in lymphangiogenesis via binding with two receptors (vascular endothelial growth factor receptor-2 and -3: VEGFR-2 and VEGFR-3). Soluble VEGFR-2 (sVEGFR-2) has a role in maintaining the alymphatic state of the cornea associated with binding to VEGF-C, and selectively inhibits lymphangiogenesis but not angiogenesis. In this study, we introduced sVEGFR-2 into lung cancer cells and evaluated the influence on tumor progression and on genes regulating lymphatic formation and metastasis in vivo. A retroviral vector was used to introduce the sVEGFR-2 gene into Lewis lung carcinoma cells (LLC), which were designated as LLC-sVEGFR-2 cells. Proteins secreted into the culture supernatant by these cells were detected by western blotting using specific antibodies. To examine lymphangiogenesis by primary lung cancer in vivo, LLC-sVEGFR-2 cells were subcutaneously injected into C57BL/6 mice. At 14days after injection, immunohistochemistry was performed using an antibody directed against lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a marker of lymphatics. Expression of mRNA for VEGFR-2, VEGFR-3 and matrix metalloproteinases (MMPs) was also determined by real-time PCR. Furthermore, LLC-sVEGFR-2 cells were directly inoculated into the left lung in C57BL/6 mice and the number of micro-metastases in pulmonary lymph nodes was determined. Introduction of sVEGFR-2 into LLC cells resulted in secretion of sVEGFR-2 protein into the culture supernatant. There were fewer LYVE-1 positive lymphatics after inoculation of LLC-sVEGFR-2 into mice compared with the control group. In addition, VEGFR-2, VEGFR-3, and MMPs gene expression was suppressed in the primary tumors of the LLC-sVEGFR-2 group compared with the control group. Furthermore, there were fewer micro-metastases in the pulmonary lymph nodes of the LLC-sVEGFR-2 group compared with the control group after cells were directly inoculated into the lung. These findings indicate that introduction of sVEGFR-2 suppressed lymphangiogenesis in primary lung cancer and also suppressed lymphogenic metastasis by inhibiting VEGF-C, followed by down-regulation of VEGFR-2, VEGFR-3 and MMPs. Accordingly, sVEGFR-2 might be a promising target for treatment of cancer by regulating lymphangiogenesis and lymphogenic metastasis.

Jankowska-Konsur A, Kobierzycki C, Grzegrzolka J, et al.
Expression of CD31 in Mycosis Fungoides.
Anticancer Res. 2016; 36(9):4575-82 [PubMed] Related Publications
BACKGROUND/AIM: Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL) characterized by malignant proliferation of mature T lymphocytes and primary skin involvement. Recent reports suggest that angiogenesis may play a role in the growth and spread of this malignancy. Cluster of differentiation 31 (CD31) is a protein classified into the Ig-superfamily of cell adhesion molecules, expressed on endothelial cells and majority of hematopoietic non-erythroid cells. The aim of our study was to explore the role of angiogenesis in MF.
MATERIALS AND METHODS: We evaluated the expression of CD31 in relation to clinicopathological data and potential impact on patients' outcome in MF utilizing immunohistochemistry (IHC) and western blot (WB) techniques in 73 and 19 MF and 21 and 4 control samples, respectively.
RESULTS: In the IHC study, statistical analysis revealed significantly higher CD31 expression in MF compared to the controls (p<0.0001) with highest expression in advanced stages vs. early ones and controls (p<0.0001 for both). In regard to skin involvement, expression was also elevated in more infiltrative (T3, tumors) and in more extensive (T4, erythroderma) cutaneous lesions compared to less infiltrative and limited skin lesions (T1, T2, patches and/or plaques) (p<0.01 for both). Regarding the extracutaneous spread, higher CD31 expression correlated with nodal involvement (N1-3 vs. N0; p<0.0001). In the WB study, statistical analysis revealed significantly higher CD31 expression only in advanced vs. early stage of MF (p<0.05). In regard to skin involvement, expression was also elevated in T3 and T4 as compared T1+T2 (p=0.08, p<0.05; respectively). Higher CD31 expression correlated with nodal involvement (N1-3 vs. N0; p<0.01). A strong significant correlation between CD31 expression at the protein level analyzed by IHC and WB was noticed (r=0.802, p<0.0001). Moreover, strong positive correlations between IHC expression of CD31 and podoplanin (PDPN; r=0.582, p<0.0001), vascular endothelial growth factor C (VEGFC; r=0.332, p<0.01) and Ki-67 (r=0.330, p<0.01) were disclosed.
CONCLUSION: Expression of CD31 in MF skin biopsies provides new evidence for the role of angiogenesis in the progression of MF. Additionally, the new data revealed prompts for further research on potential use of CD31 as a new marker of the disease advancement, as well as the target of new therapeutic strategies.

Micocci KC, Moritz MN, Lino RL, et al.
ADAM9 silencing inhibits breast tumor cells transmigration through blood and lymphatic endothelial cells.
Biochimie. 2016 Sep-Oct; 128-129:174-82 [PubMed] Related Publications
ADAMs are transmembrane multifunctional proteins that contain disintegrin and metalloprotease domains. ADAMs act in a diverse set of biological processes, including fertilization, inflammatory responses, myogenesis, cell migration, cell proliferation and ectodomain cleavage of membrane proteins. These proteins also have additional functions in pathological processes as cancer and metastasis development. ADAM9 is a member of ADAM protein family that is overexpressed in several types of human carcinomas. The aim of this study was to investigate the role of ADAM9 in hematogenous and lymphatic tumor cell dissemination assisting the development of new therapeutic tools. The role of ADAM9 in the interaction of breast tumor cells (MDA-MB-231) and endothelial cells was studied through RNA silencing. ADAM9 silencing in MDA-MB-231 cells had no influence in expression of several genes related to the metastatic process such as ADAM10, ADAM12, ADAM17, cMYC, MMP9, VEGF-A, VEGF-C, osteopontin and collagen XVII. However, there was a minor decrease in ADAM15 expression but an increase in that of MMP2. Moreover, ADAM9 silencing had no effect in the adhesion of MDA-MB-231 cells to vascular (HMEC-1 and HUVEC) and lymphatic cells (HMVEC-dLyNeo) under flow condition. Nevertheless, siADAM9 in MDA-MB-231 decreased transendothelial cell migration in vitro through HUVEC, HMEC-1 and HMVEC-dLyNeo (50%, 40% and 32% respectively). These results suggest a role for ADAM9 on the extravasation step of the metastatic cascade through both blood and lymph vessels.

Xia H, Shen J, Chen S, et al.
Overexpression of VEGF-C correlates with a poor prognosis in esophageal cancer patients.
Cancer Biomark. 2016; 17(2):165-70 [PubMed] Related Publications
BACKGROUND: The prognostic value of vascular endothelial growth factor C (VEGF-C) in patients with esophageal cancer (EC) remains controversial. The aim of this meta-analysis was to clarify the association of VEGF-C with survival in EC patients.
METHODS: We performed a meta-analysis that included eligible studies to expound the effect of VEGF-C in EC survival. Eligible studies published until November 2015 was identified using available databases. STATA 12.0 was performed in this meta-analysis.
RESULTS: We identified 13 studies, including 1203 patients, in this meta-analysis. The combined hazard ratio of 1.70 (95% CI, 1.43-2.03, P < 0.001) shows that VEGF-C overexpression was significantly correlated with poor overall survival in EC patients. Furthermore, the results suggested a significant relationship between VEGF-C expression and overall survival was also showed in studies with patient source, patient number ≥ 70, methods detecting VEGF-C by reverse transcription PCR (RT-PCR) or ELISA and histology type. Moreover, combined odds ratio of VEGF-C displayed that VEGF-C overexpression was significantly association with stage, depth of tumor invasion, lymph node status and metastasis of EC (P < 0.05). However, it has no correlation with differentiation degree of EC (P > 0.05).
CONCLUSION: VEGF-C overexpression shows an unfavorable prognosis for EC patients.

Sun Q, Peng C, Cong B, et al.
Involvement of syk and VEGF-C in invasion of lung adenocarcinoma A549 cells.
J Cancer Res Ther. 2016 Apr-Jun; 12(2):640-4 [PubMed] Related Publications
BACKGROUND AND AIMS: Lung cancer has become one of the most dangerous malignant tumors in the world nowadays, whose pathogenesis is complex involving multi-genes and multi-elements. This study aims to investigate the values of spleen tyrosine kinase (Syk) and vascular endothelial growth factor-C (VEGF-C) in lymphangiogenesis and metastasis of lung adenocarcinoma A549 cells.
MATERIALS AND METHODS: The pcDNA3.1-VEGF-C and pLNCX-syk were constructed and transfected into A549 cells. After cells with stable expression were sorted, the level of VEGF-C was tested by RT-PCR and immunohistochemistry and the mRNA of syk was tested by RT-PCR. The cell invasion assay was investigated by transwell chamber in vitro. Restriction enzyme digestion and gel electrophoresis demonstrated successful construction of the pcDNA3.1-VEGF-C.
RESULTS: RT-PCR and immunohistochemistry revealed higher expression of VEGF-C in VEGFC-construct-transfected A549 cells than that in controls (P < 0.05). Successful construction of the pLNCX-syk was demonstrated by restriction enzyme electrophoresis and sequencing. RT-PCR revealed Syk expression higher in syk-construct-transfected cells than in controls (P < 0.05).
CONCLUSIONS: The results indicate a potential link between the upregulation of Syk and VEGF-C expression and lung adenocarcinoma.

Fu MR, Conley YP, Axelrod D, et al.
Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction.
Breast. 2016; 29:231-40 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Lymphedema following breast cancer surgery is considered to be mainly due to the mechanical injury from surgery. Recent research identified that inflammation-infection and obesity may be the important predictors for lymphedema. The purpose of this exploratory research was to prospectively examine phenotype of arm lymphedema defined by limb volume and lymphedema symptoms in relation to inflammatory genes in women treated for breast cancer. A prospective, descriptive and repeated-measure design using candidate gene association method was used to enroll 140 women at pre-surgery and followed at 4-8 weeks and 12 months post-surgery. Arm lymphedema was determined by a perometer measurement of ≥5% limb volume increase from baseline of pre-surgery. Lymphedema symptom phenotype was evaluated using a reliable and valid instrument. Saliva samples were collected for DNA extraction. Genes known for inflammation were evaluated, including lymphatic specific growth factors (VEGF-C & VEGF-D), cytokines (IL1-a, IL-4, IL6, IL8, IL10, & IL13), and tumor necrosis factor-a (TNF-a). No significant associations were found between arm lymphedema phenotype and any inflammatory genetic variations. IL1-a rs17561 was marginally associated with symptom count phenotype of ≥8 symptoms. IL-4 rs2070874 was significantly associated with phenotype of impaired limb mobility and fluid accumulation. Phenotype of fluid accumulation was significantly associated with IL6 rs1800795, IL4 rs2243250 and IL4 rs2070874. Phenotype of discomfort was significantly associated with VEGF-C rs3775203 and IL13 rs1800925. Precision assessment of heterogeneity of lymphedema phenotype and understanding the biological mechanism of each phenotype through the exploration of inherited genetic susceptibility is essential for finding a cure. Further exploration of investigative intervention in the context of genotype and gene expressions would advance our understanding of heterogeneity of lymphedema phenotype.

Assawasuparerk K, Rawangchue T, Phonarknguen R
Scabraside D Derived from Sea Cucumber Induces Apoptosis and Inhibits Metastasis via iNOS and STAT-3 Expression in Human Cholangiocarcinoma Xenografts.
Asian Pac J Cancer Prev. 2016; 17(4):2151-7 [PubMed] Related Publications
Scabraside D, a sulfated triterpene glycoside, was extracted from the sea cucumber Holothuria scabra. It shows anti-proliferation in many of cancer cell lines, but the function and mechanisms of action of scabraside D in human cholangiocarcinoma (HuCCA) have not previously determined. In this study, we investigated the activity of scabraside D on HuCCA cell apoptosis, lymphangiogenesis and metastasis in a nude mouse model. Scabraside D induced signs of apoptosis, such as cell shrinkage, nuclear condensation, nuclear fragmentation and DNA fragmentation on TUNEL assays, while effectively decreasing expression of BCl-2 but increasing caspase-3 gene level expression. Immunohistochemistry revealed that scabraside D significantly reduced lymphatic vessel density (LVD). Moreover, scabraside D treatment significantly decreased VEGF-C, MMP-9 and uPA gene expression, which play important roles in the lymphangiogenesis and invasion of cancer cells in metastasis processes. Quantitative real-time PCR showed that scabraside D significantly decreased iNOS and STAT-3 gene expression. This study demonstrated that scabraside D plays a role in activation of HuCCA tumor apoptosis and inhibition of lymphangiogenesis, invasion and metastasis through decreasing BCl-2, MMP-9, uPA and VEGF-C and increasing caspase-3 expression by suppression of iNOS and STAT-3 expression. Therefore, scabraside D could be a promising candidate for cholangiocarcinoma treatment.

Wang A, Zhang W, Jin M, et al.
Differential expression of EBV proteins LMP1 and BHFR1 in EBV‑associated gastric and nasopharyngeal cancer tissues.
Mol Med Rep. 2016; 13(5):4151-8 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Epstein‑Barr virus (EBV) infection is associated with the development of T cell lymphoma, nasopharyngeal cancer (NPC), and EBV‑associated gastric cancer (EBVaGC). This study assessed the expression of the EBV‑associated proteins latent membrane protein 1 (LMP1) and BamHI‑A rightward frame 1 (BARF1) in NPC and EBVaGC tissue specimens and determined their association with clinicopathological data, microvessel density (MVD) and micro‑lymphatic vessel density (MLVD). This study collected 600 gastric cancer and 75 NPC tissue samples. EBV infection was assessed using in situ hybridization, and LMP1 and BARF1 expression was assessed using immunohistochemistry. The levels of MVD and MLVD were assessed using immunostaining of vascular endothelial growth factor (VEGF)‑C, CD34, and lymphatic vessel endothelial receptor 1 (LYVE‑1). Among the 600 gastric cancer cases, 30 were positive for EBV infection, which was shown to be associated with the age of patients (P=0.073), tumor differentiation (P<0.0001), tumor location (P<0.0001) and lymph node metastasis (P<0.0001). In these 30 EBVaGC cases, only one case was weakly positive for LMP1, but 17 cases were BARF1 positive. BARF1 expression was associated with lymph node metastasis of EBVaGC and the level of MLVD. Furthermore, 61 (81%) of 75 NPC patients were EBV positive, among which 38 cases were LMP‑1 positive (62.3%) and LMP1 expression was associated with tumor‑node‑metastasis stage (P=0.011) and lymph node metastasis (P=0.041). MLVD was significantly higher in LMP1‑positive cases than LMP1‑negative cases. There were only 8 (13.3%) cases positive for BARF1 expression. In conclusion, EBV infection exhibits a role in gastric cancer and NPC development; however, expression of EBV‑associated proteins LMP1 and BARF1 have differential functions during tumorigenesis of these two types of cancer.

Kim N, Cho SB, Park YL, et al.
Effect of Recepteur d'Origine Nantais expression on chemosensitivity and tumor cell behavior in colorectal cancer.
Oncol Rep. 2016; 35(6):3331-40 [PubMed] Related Publications
Recepteur d'Origine Nantais (RON) expression is known to induce oncogenic properties including tumor cell growth, survival, motility, angiogenesis and chemoresistance. In the present study, we evaluated whether RON affects chemosensitivity and oncogenic behavior of colorectal cancer cells and investigated its prognostic value in colorectal cancer. To evaluate the impact of RON on chemosensitivity and tumor cell behavior, we treated colorectal cancer cells with small interfering RNAs specific to RON. This was followed by flow cytometric analyses and migration, Matrigel invasion and endothelial tube formation assays. The expression of RON was investigated by immunohistochemistry in colorectal cancer tissues. TUNEL assay and immunohistochemical staining for CD34 and D2-40 were deployed to determine apoptosis, angiogenesis and lymphangiogenesis. RON knockdown enhanced 5-fluorouracil (FU)-induced apoptosis by upregulating the activities of caspases and expression of proapoptotic genes. Moreover, it enhanced 5-FU-induced cell cycle arrest by decreasing the expression of cyclins and cyclin‑dependent kinases and inducing that of p21. Furthermore, RON knockdown augmented the 5-FU-induced inhibition of invasion and migration of colorectal cancer cells. The β-catenin signaling cascade was blocked by RON knockdown upon 5-FU treatment. RON knockdown also decreased endothelial tube formation and expression of VEGF-A and HIF-1α and increased angiostatin expression. Furthermore, it inhibited lymphatic endothelial cell tube formation and the expression of VEGF-C and COX-2. RON expression was observed to be associated with age, tumor size, lymphovascular and perineural invasion, tumor stage, lymph node and distant metastasis, and poor survival rate. The mean microvessel density value of RON-positive tumors was significantly higher than that of RON-negative ones. These results indicate that RON is associated with tumor progression by inhibiting chemosensitivity and enhancing angiogenesis in colorectal cancer.

Regan E, Sibley RC, Cenik BK, et al.
Identification of Gene Expression Differences between Lymphangiogenic and Non-Lymphangiogenic Non-Small Cell Lung Cancer Cell Lines.
PLoS One. 2016; 11(3):e0150963 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
It is well established that lung tumors induce the formation of lymphatic vessels. However, the molecular mechanisms controlling tumor lymphangiogenesis in lung cancer have not been fully delineated. In the present study, we identify a panel of non-small cell lung cancer (NSCLC) cell lines that induce lymphangiogenesis and use genome-wide mRNA expression to characterize the molecular mechanisms regulating tumor lymphangiogenesis. We show that Calu-1, H1993, HCC461, HCC827, and H2122 NSCLC cell lines form tumors that induce lymphangiogenesis whereas Calu-3, H1155, H1975, and H2073 NSCLC cell lines form tumors that do not induce lymphangiogenesis. By analyzing genome-wide mRNA expression data, we identify a 17-gene expression signature that distinguishes lymphangiogenic from non-lymphangiogenic NSCLC cell lines. Importantly, VEGF-C is the only lymphatic growth factor in this expression signature and is approximately 50-fold higher in the lymphangiogenic group than in the non-lymphangiogenic group. We show that forced expression of VEGF-C by H1975 cells induces lymphangiogenesis and that knockdown of VEGF-C in H1993 cells inhibits lymphangiogenesis. Additionally, we demonstrate that the triple angiokinase inhibitor, nintedanib (small molecule that blocks all FGFRs, PDGFRs, and VEGFRs), suppresses tumor lymphangiogenesis in H1993 tumors. Together, these data suggest that VEGF-C is the dominant driver of tumor lymphangiogenesis in NSCLC and reveal a specific therapy that could potentially block tumor lymphangiogenesis in NSCLC patients.

Le CP, Nowell CJ, Kim-Fuchs C, et al.
Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.
Nat Commun. 2016; 7:10634 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

Zhang J, Zhang G, Yang S, et al.
Macrophage migration inhibitory factor regulating the expression of VEGF-C through MAPK signal pathways in breast cancer MCF-7 cell.
World J Surg Oncol. 2016; 14:51 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
BACKGROUND: As a kind of versatility of cytokines, overexpression of macrophage migration inhibitory factor (MIF) and vascular endothelial growth factor-C (VEGF-C) have been reported in a wide variety of tumors. However, the correlation and mechanism between MIF and VEGF-C are still not clear. As an important signal transduction system, MAPK signaling pathways participate in a variety of biological behavior of cells. The purposes of this study are to study the relationship between MIF and VEGF-C and discuss the role of MAPK signal pathway in the relationship.
METHODS: In this study, we first knocked down the MIF using small interfering RNA (siRNA) and built the stable low expression MIF breast cancer cells (siRNA-MIF-MCF-7) and the negative control cells (siRNA-NC-MCF-7). And then, we evaluated the expression of MIF using Western blot to confirm the effect of transfection. Using real-time fluorescent quantitative polymerase chain reaction and enzyme-linked immunosorbent experiment, we respectively examined the different expression of VEGF-C between siRNA-MIF-MCF-7 and siRNA-NC-MCF-7 and breast cancer cells MCF-7. Moreover, we investigated the expression of p38 MAPK, P-p38 MAPK, p44/42 MAPK, and P-p44/42 MAPK in the three kinds of cells by Western blot to analyze the regulatory mechanism to VEGF-C.
RESULTS: We found that MIF siRNA markedly reduced the expression of MIF. And the expression level of VEGF-C, p38 MAPK, P-p38-MAPK, p44/42-MAPK, and P-p44/42 MAPK in siRNA-MIF-MCF-7 cells had different degree of decrease compared with siRNA-NC-MCF-7 cells and MCF-7 cells.
CONCLUSIONS: These results suggest that MIF can regulate the expression of VEGF-C in breast cancer cells. And its regulatory mechanism may work by activating the MAPK signaling pathway.

Woliński K, Stangierski A, Szczepanek-Parulska E, et al.
VEGF-C Is a Thyroid Marker of Malignancy Superior to VEGF-A in the Differential Diagnostics of Thyroid Lesions.
PLoS One. 2016; 11(2):e0150124 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
INTRODUCTION: Thyroid nodular goiter is one of the most common medical conditions affecting even over a half of adult population. The risk of malignancy is rather small but noticeable-estimated by numerous studies to be about 3-10%. The definite differentiation between benign and malignant ones is a vital issue in endocrine practice. The aim of the current study was to assess the expression of vascular endothelial growth factor A (VEGF-A) and VEGF-C on the mRNA level in FNAB washouts in case of benign and malignant thyroid nodules and to evaluate the diagnostic value of these markers of malignancy.
MATERIALS AND METHODS: Patients undergoing fine-needle aspiration biopsy (FNAB) in our department between January 2013 and May 2014 were included. In case of all patients who gave the written consent, after ultrasonography (US) and fine-needle aspiration biopsy (FNAB) performed as routine medical procedure the needle was flushed with RNA Later solution, the washouts were frozen in -80 Celsius degrees. Expression of VEGF-A and VEGF-C and GADPH (reference gene) was assessed in washouts on the mRNA level using the real-time PCR technique. Probes of patients who underwent subsequent thyroidectomy and were diagnosed with differentiated thyroid cancer (DTC; proved by post-surgical histopathology) were analyzed. Similar number of patients with benign cytology were randomly selected to be a control group.
RESULTS: Thirty one DTCs and 28 benign thyroid lesions were analyzed. Expression of VEGF-A was insignificantly higher in patients with DTCs (p = 0.13). Expression of VEGF-C was significantly higher in patients with DTC. The relative expression of VEGF-C (in comparison with GAPDH) was 0.0049 for DTCs and 0.00070 for benign lesions, medians - 0.0036 and 0.000024 respectively (p<0.0001).
CONCLUSIONS: Measurement of expression VEGF-C on the mRNA level in washouts from FNAB is more useful than more commonly investigated VEGF-A. Measurement of VEGF-C in FNAB washouts do not allow for fully reliable differentiation of benign and malignant thyroid nodules and should be interpreted carefully. Further studies on larger groups are indicated. However, measurement of VEGF-C on mRNA level can bring important information without exposing patient for additional risk and invasive procedures.

Lin CC, Chen PC, Lein MY, et al.
WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells.
Oncotarget. 2016; 7(9):9993-10005 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by a poor prognosis and a low survival rate. Vascular endothelial growth factor-C (VEGF-C) has been implicated in lymphangiogenesis and is correlated with cancer metastasis. WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4 is an extracellular matrix-related protein that belongs to the CCN family and stimulates many biological functions. Our previous studies showed that WISP-1 plays an important role in OSCC migration and angiogenesis. However, the effect of WISP-1 on VEGF-C regulation and lymphangiogenesis in OSCC is poorly understood. Here, we showed a correlation between WISP-1 and VEGF-C in tissue specimens from patients with OSCC. To examine the lymphangiogenic effect of WISP-1, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. The results showed that conditioned media from WISP-1-treated OSCC cells promoted tube formation and cell migration in LECs. We also found that WISP-1-induced VEGF-C is mediated via the integrin αvβ3/integrin-linked kinase (ILK)/Akt signaling pathway. In addition, the expression of microRNA-300 (miR-300) was inhibited by WISP-1 via the integrin αvβ3/ILK/Akt cascade. Collectively, these results reveal the detailed mechanism by which WISP-1 promotes lymphangiogenesis via upregulation of VEGF-C expression in OSCC. Therefore, WISP-1 could serve as therapeutic target to prevent metastasis and lymphangiogenesis in OSCC.

Kalitin NN, Karamysheva AF
RARα mediates all-trans-retinoic acid-induced VEGF-C, VEGF-D, and VEGFR3 expression in lung cancer cells.
Cell Biol Int. 2016; 40(4):456-64 [PubMed] Related Publications
The regulation of vascular endothelial growth factors C (VEGF-C) and D (VEGF-D), and their receptor VEGFR3 gene and protein expression by all-trans-retinoic acid (atRA) in A549 lung cancer cells, was investigated. We showed that atRA treatment increased VEGF-C, VEGF-D, and VEGFR3 protein and mRNA contents in dose-dependent manner. atRA-mediated increase of both ligands and receptor expression correlated with the elevated level of retinoic acid receptor α (RARα) expression, while the level of another atRA receptor, peroxisome proliferator-activated receptor β/δ (PPARβ/δ), was decreased. We demonstrated that the classical counterpart of RARα, retinoid X receptor α (RXRα), was down-regulated in both cytoplasm and nucleus of A549 cells upon atRA addition. On the contrary, the nuclear quantity of another possible RARα counterpart, transcription factor Sp1, was increased after atRA treatment.

Park KJ, Cho SB, Park YL, et al.
Prospero homeobox 1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis.
Gastric Cancer. 2017; 20(1):104-115 [PubMed] Related Publications
BACKGROUND: Prospero homeobox 1 (PROX1) functions as a tumor suppressor gene or an oncogene in various cancer types. However, the distinct function of PROX1 in gastric cancer is unclear. We determined whether PROX1 affected the oncogenic behavior of gastric cancer cells and investigated its prognostic value in patients with gastric cancer.
METHODS: A small interfering RNA against PROX1 was used to silence PROX1 expression in gastric cancer cell lines AGS and SNU638. Expression of PROX1 in gastric cancer tissues was investigated by performing immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined by performing the TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40.
RESULTS: PROX1 knockdown induced apoptosis by activating cleaved caspase-3, caspase-7, caspase-9, and poly(ADP-ribose) polymerase, and by decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL. PROX1 knockdown also suppressed tumor cell proliferation. In addition, PROX1 knockdown decreased lymphatic endothelial cell invasion and tube formation and the expression of vascular endothelial growth factor (VEGF)-C and -D and cyclooxygenase (COX)-2. However, PROX1 knockdown only decreased umbilical vein endothelial cell invasion, not tube formation. The mean Ki-67 labeling index and lymphatic vessel density value of PROX1-positive tumors were significantly higher than those of PROX1-negative tumors. However, no significant difference was observed between PROX1 expression and apoptotic index or microvessel density. PROX1 expression was significantly associated with age, cell differentiation, lymph node metastasis, cancer stage, and poor survival.
CONCLUSIONS: These results indicate that PROX1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis.

Zhao G, Zhu G, Huang Y, et al.
IL-6 mediates the signal pathway of JAK-STAT3-VEGF-C promoting growth, invasion and lymphangiogenesis in gastric cancer.
Oncol Rep. 2016; 35(3):1787-95 [PubMed] Related Publications
Gastric cancer shows the highest invasive and metastasis features, especially lymph metastasis, which is closely associated with poor prognosis of gastric cancer. Although there is evidence that interleukin-6 (IL-6) can promote gastric cancer progression, the underlying specific mechanisms and the mechanisms of gastric cancer lymphangiogenesis are largely unknown. In the present study, we explore whether IL-6 could promote the proliferation and invasion activity of gastric cancer cells, and whether IL-6 mediating VEGF-C production affected the lymphangiogenesis in gastric cancer cells. Our results revealed that IL-6 and its receptors (IL-6 and gp130) are broadly expressed in various gastric cancer cell lines including SGC-7901, MGC, MKN-28 and AGS. Exogenous IL-6 increased the ability of gastric cancer cell proliferation and invasion, which could be weakened by AG490. in addition, exogenous IL-6 promoted the VEGF-C production of gastric cancer cells and the lymphangiogenesis of HDLECs. As we expected, AG490 was able to reduce these effects. Western blot analysis showed that IL-6 increased JKA, STAT3, p-STAT3 and VEGF-C protein levels in the gastric cancer cells. However, the JKA, STAT3, p-STAT3 and VEGF-C protein expression levels were inhibited by AG490. Our data suggested that IL-6 mediates the singnal pathway of JAK-STAT3-VEGF-C promoting the growth, invasion and lymphangiogenesis in gastric cancer. Thus, IL-6 and its related signal pathways may be a promising target for treatment of gastric cancer growth and lymphangiogenesis.

Chi BJ, Du CL, Fu YF, et al.
Silencing of CCR7 inhibits the growth, invasion and migration of prostate cancer cells induced by VEGFC.
Int J Clin Exp Pathol. 2015; 8(10):12533-40 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Early in prostate cancer development, tumor cells express vascular endothelial growth factor C (VEGF-C), a secreted molecule that is important in angiogenesis progression. CC-chemokine receptor 7 (CCR7), another protein involved in angiogenesis, is strongly expressed in most human cancers, where it activated promotes tumor growth as well as favoring tumor cell invasion and migration. The present study aimed to investigate the effect of down-regulating CCR7 expression on the growth of human prostate cancer cells stimulated by VEGFC. The CCR7-specific small interfering RNA (siRNA) plasmid vector was constructed and then transfected into prostate cancer cells. The expression of CCR7 mRNA and protein was detected by quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation, apoptosis, cell cycle distribution and cell migration were assessed following knockdown of CCR7 by RNA interference (RNAi). Western blot analysis was used to identify differentially expressed angiogenesis- and cell cycle-associated proteins in cells with silenced CCR7. The expression levels of CCR7 in prostate cancer cells transfected with siRNA were decreased, leading to a significant inhibition of prostate cancer cell proliferation, migration and invasion induced by VEGFC. Western blot analysis revealed that silencing of CCR7 may inhibit vascular endothelial growth factor, matrix metalloproteinase (MMP)-2 and MMP-9 protein expression. In conclusion, the present study demonstrated that RNAi can effectively silence CCR7 gene expression and inhibit the growth of prostate cancer cells, which indicates that there is a potential of targeting CCR7 as a novel gene therapy approach for the treatment of prostate cancer.

Zhao W, Wang J, Zhu B, et al.
IGFBP7 functions as a potential lymphangiogenesis inducer in non-small cell lung carcinoma.
Oncol Rep. 2016; 35(3):1483-92 [PubMed] Related Publications
Lymphangiogenesis is not only involved in the processes of embryonic development, tissue repair and chronic inflammation, but also in tumor lymphatic metastasis. Metastatic tumor cells spreading through lymphatic vessels occur in non-small cell lung carcinoma (NSCLC), with regional lymph node metastasis often being the most important prognostic factor for carcinoma patients. Recent research has identified a range of lymphangiogenic growth factors that could conceivably play a great role in promoting tumor lymphangiogenesis and lymphatic metastasis. The most extensively accepted signaling pathways promoting lymphangiogenesis in tumors include the secreted lymphangiogenic proteins: vascular endothelial growth factor-C (VEGF-C) and VEGF-D, and their cognate receptor on lymphatic endothelium VEGF receptor-3 (VEGFR-3). Targeting VEGF pathway strategy sometimes failed to decrease tumor metastasis in vivo experiments and clinical trials. It is unclear whether the tumor cells induced the lymphangiogenesis process, while VEGF pathway could not completely illustrate the mechanism of tumor cell lymphatic metastasis. To explore the novel tumor lymphangiogenesis targets, we screened 181 candidate genes between high lymphatic vascular density (LVD) and low LVD in lung adenocarcinomas using Human Genome U133 Plus 2.0 Microarray. Insulin-like growth factor binding protein 7 (IGFBP7) was proven to be associated with metastatic clinicopathological features and high LVD. Furthermore, by assessing the capability of lymphatic endothelial cell forming lymphatic vessel-like structures in vitro, it appears to enhance lymphangiogenesis.

Denicolaï E, Tabouret E, Colin C, et al.
Molecular heterogeneity of glioblastomas: does location matter?
Oncotarget. 2016; 7(1):902-13 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
Glioblastomas in adults are highly heterogeneous tumors that can develop throughout the brain. To date no predictive-location marker has been identified. We previously derived two glioblastoma cell lines from cortical and periventricular locations and demonstrated distinct transcriptomic profiles. Based on these preliminary results, the aim of this study was to correlate glioblastoma locations with the expression of ten selected genes (VEGFC, FLT4, MET, HGF, CHI3L1, PROM1, NOTCH1, DLL3, PDGFRA, BCAN). Fifty nine patients with newly diagnosed glioblastomas were retrospectively included. Tumors were classified into cortical and periventricular locations, which were subsequently segregated according to cerebral lobes involved: cortical fronto-parietal (C-FP), cortical temporal (C-T), periventricular fronto-parietal (PV-FP), periventricular temporal (PV-T), and periventricular occipital (PV-O). Gene expression levels were determined using RT-qPCR. Compared to cortical glioblastomas, periventricular glioblastomas were characterized by a higher expression of two mesenchymal genes, VEGFC (p = 0.001) and HGF (p = 0.001). Among cortical locations, gene expressions were homogeneous. In contrast, periventricular locations exhibited distinct expression profiles. PV-T tumors were associated with higher expression of two proneural and cancer stem cell genes, NOTCH1 (p = 0.028) and PROM1 (p = 0.033) while PV-FP tumors were characterized by high expression of a mesenchymal gene, CHI3L1 (p = 0.006). Protein expression of NOTCH1 was correlated with RNA expression levels. PV-O glioblastomas were associated with lower expression of VEGFC (p = 0.032) than other periventricular locations, whereas MET overexpression remained exceptional. These data suggest a differential gene expression profile according to initial glioblastoma location.

Yamaguchi T, Fushida S, Yamamoto Y, et al.
Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination.
Gastric Cancer. 2016; 19(4):1052-65 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
BACKGROUND: Tumor-associated macrophages (TAMs) of the M2 phenotype are known to promote tumor proliferation and to be associated with a poor prognosis in numerous cancers. Here, we investigated whether M2 macrophages participate in the development of peritoneal dissemination in gastric cancer.
METHODS: The characteristics of peritoneal macrophages in gastric cancer patients with or without peritoneal dissemination were examined by flow cytometry and the real-time quantitative polymerase chain reaction. The effects of M2 macrophages on phenotypic changes of the gastric cancer cell line MKN45 were assessed with a direct or indirect co-culture system in vitro and an in vivo mouse xenograft model.
RESULTS: The number of peritoneal macrophages with the M2 phenotype (CD68(+)CD163(+) or CD68(+)CD204(+)) was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination. Higher expression of the M2-related messenger RNAs (IL-10, vascular endothelial growth factor A, vascular endothelial growth factor C, matrix metalloproteinase 1, and amphiregulin) and lower expression of M1-related messenger RNAs (TNF-α, CD80, CD86, and IL-12p40) were also confirmed in the TAMs. Macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype. Moreover, the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model.
CONCLUSIONS: Intraperitoneal TAMs in gastric cancer patients with peritoneal dissemination were polarized to the M2 phenotype, and could contribute to tumor proliferation and progression. Therefore, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer.

Huang YW, Zhou Y, Lan CY, et al.
Tumor-induced VEGF-C overexpression in retroperitoneal lymph nodes in VX2 carcinoma-bearing rabbits.
Drug Des Devel Ther. 2015; 9:5949-56 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
OBJECTIVE: To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status.
METHODS: Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining.
RESULTS: Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P<0.05). The enlargement of RLNs was found on day 21. Expression of VEGF-C was significantly upregulated in peripheral white blood cells, tumor mass, and RLNs in an association with cancer progression. DDP resulted in a suppression of VEGF-C expression, whereas the influences on tumor mass and lymphatic metastasis were insignificant.
CONCLUSION: Elevated VEGF-C expressions in peripheral white blood cells and RLNs are associated with tumor progression and lymphatic metastasis. DDP treatment inhibits VEGF-C expression and fails to protect against metastatic cervical cancer.

Li G, Yang F, Gu S, et al.
MicroRNA-101 induces apoptosis in cisplatin-resistant gastric cancer cells by targeting VEGF-C.
Mol Med Rep. 2016; 13(1):572-8 [PubMed] Related Publications
Deregulation of microRNAs (miRNAs) is known to be associated with drug resistance in human cancers. However, the precise role of miR‑101 in the cisplatin (DPP) resistance of human gastric cancer cells has not been elucidated, yet. The present study revealed that miR‑101 was markedly downregulated in gastric cancer cell lines compared to that in the normal gastric mucosa epithelial cell line GES1. Furthermore, a significant decrease in miR‑101 levels, accompanied with an increased expression of vascular endothelial growth factor (VEGF)‑C in DDP‑resistant SGC7901 gastric cancer cells (SGC7901/DDP) compared with those in native SGC7901 cells was observed. In addition, forced overexpression of miR‑101 significantly inhibited cell proliferation, while enhancing cisplatin‑induced apoptosis of SGC7901/DDP cells. A luciferase reporter assay confirmed that VEGF‑C was a direct target of miR‑101 in SGC7901/DDP cells. Forced overexpression of miR‑101 in SGC7901/DDP cells reduced the expression of VEGF‑C, while knockdown of miR‑101 expression significantly enhanced VEGF‑C expression in SGC7901/DDP cells. Finally, overexpression of VEGF‑C inhibited DDP‑induced apoptosis in SGC7901 cells. In conclusion, the results of the present study suggested that miR‑101 inhibited the proliferation and promoted DDP‑induced apoptosis of DDP‑resistant gastric cancer cells, at least in part via targeting VEGF-C.

Li J, Ye L, Sun PH, et al.
MTA1 Is Up-regulated in Colorectal Cancer and Is Inversely Correlated with Lymphatic Metastasis.
Cancer Genomics Proteomics. 2015 Nov-Dec; 12(6):339-45 [PubMed] Related Publications
BACKGROUND: Metastasis-associated protein 1 (MTA1) plays an important role in tumourigenesis and progression of certain cancer types. In the current study, we analyzed the relationship between MTA1 expression and disease progression of colorectal cancer (CRC).
MATERIALS AND METHODS: CRC tissues (n=93) and adjacent normal colorectal tissues (n=70) were analyzed by quantitative real-time polymerase chain reaction. MTA1 knockdown was established in RKO and HT115 cells using MTA1 siRNA.
RESULTS: The expression of MTA1 was significantly increased in CRC tissues compared to paired normal colorectal tissues, but decreased expression of MTA1 was correlated with poor prognosis (higher lymph node involvement stage, TNM stage, local invasion and recurrence) that was associated with increased expression of VEGFC and -D and the receptor VEGFR3.
CONCLUSION: MTA1 is up-regulated in CRC. MTA1 expression is inversely associated with lymphatic metastases and the expression of VEGFC, VEGFD and VEGFR3.

Pinheiro C, Garcia EA, Morais-Santos F, et al.
Reprogramming energy metabolism and inducing angiogenesis: co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas.
BMC Cancer. 2015; 15:835 [PubMed] Article available free on PMC after 01/10/2017 Related Publications
BACKGROUND: Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior.
METHODS: The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients' clinicopathological parameters.
RESULTS: Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis.
CONCLUSIONS: The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.

Staiano RI, Loffredo S, Borriello F, et al.
Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.
J Leukoc Biol. 2016; 99(4):531-40 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation.

Liu HT, Xing AY, Chen X, et al.
MicroRNA-27b, microRNA-101 and microRNA-128 inhibit angiogenesis by down-regulating vascular endothelial growth factor C expression in gastric cancers.
Oncotarget. 2015; 6(35):37458-70 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Vascular Endothelial Growth Factor C (VEGF-C) has critical roles in angiogenesis in human cancers; however, the underlying mechanisms regulating VEGF-C expression remain largely unknown. In the present study, VEGF-C protein expression and the density of blood vessels or lymphatic vessels were determined by immunohistochemistry in 103 cases of gastric cancer tissues. Suppression of VEGF-C by miR-27b, miR-101 and miR-128 was investigated by luciferase assays, Western blot and ELISA. The miRNAs expression levels were detected in human gastric cancers by real-time quantitative PCR. Cell proliferation, migration and invasion assays were performed to assess the effect of miRNAs on gastric cancer cells and human umbilical vascular endothelial cells (HUVECs). Our data showed that high VEGF-C expression was significantly associated with increased tumor size, advanced TNM classification and clinical stage, higher microvessel density (MVD) and lymphatic density (LVD), as well as poor survival in patients with gastric cancer. Furthermore, VEGF-C was found to be a direct target gene of miR-27b, miR-101, and miR-128. The expression levels of the three miRNAs were inversely correlated with MVD. Overexpression of miR-27b, miR-101, or miR-128 suppressed migration, proliferation activity, and tube formation in HUVECs by repressing VEGF-C secretion in gastric cancer cells. We conclude that miR-27b, miR-101 and miR-128 inhibit angiogenesis by down-regulating VEGF-C expression in gastric cancers.

Zhang L, Wang JH, Liang RX, et al.
RASSF8 downregulation promotes lymphangiogenesis and metastasis in esophageal squamous cell carcinoma.
Oncotarget. 2015; 6(33):34510-24 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Lymphatic vessels are the major routes of human esophageal squamous cell carcinoma (ESCC) metastasis. Tumor cells secrete pro-lymphangiogenic factors to induce new lymphatic vessels, promoting lymph node metastasis. In this study, we show that RAS association domain family 8 (RASSF8) expression in ESCC clinical samples was inversely correlated with lymph node metastasis and patients survival. Tumor cells with low RASSF8 expression had higher apparent migratory ability, and promoted and lymphangiogenesis both in vitro and in vivo. RASSF8 downregulation enhanced VEGF-C expression and caused subcellular redistribution of p65 in ESCC. Our results show that RASSF8 acts as a tumor suppressor in ESCC and is a potential therapeutic target for preventing lymph node metastasis.

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