TNFSF15

Gene Summary

Gene:TNFSF15; TNF superfamily member 15
Aliases: TL1, TL1A, VEGI, TNLG1B, VEGI192A
Location:9q32
Summary:The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is abundantly expressed in endothelial cells, but is not expressed in either B or T cells. The expression of this protein is inducible by TNF and IL-1 alpha. This cytokine is a ligand for receptor TNFRSF25 and decoy receptor TNFRSF21/DR6. It can activate NF-kappaB and MAP kinases, and acts as an autocrine factor to induce apoptosis in endothelial cells. This cytokine is also found to inhibit endothelial cell proliferation, and thus may function as an angiogenesis inhibitor. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor ligand superfamily member 15
Source:NCBIAccessed: 15 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 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: TNFSF15 (cancer-related)

Ma W, Shao Y, Yang W, et al.
Evaluation of (188)Re-labeled NGR-VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts.
Tumour Biol. 2016; 37(7):9121-9 [PubMed] Related Publications
Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine-glycine-arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR-VEGI fusion protein was prepared and labeled with (188)Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that (188)Re-NGR-VEGI exhibits good tumor-to-background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of (188)Re-NGR-VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non-radiolabeled NGR-VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 ± 0.25) of (188)Re-NGR-VEGI at 24 h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5 MBq of (188)Re-NGR-VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that (188)Re-NGR-VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy.

Abe A, Nagatsuma AK, Higuchi Y, et al.
Site-specific fibroblasts regulate site-specific inflammatory niche formation in gastric cancer.
Gastric Cancer. 2017; 20(1):92-103 [PubMed] Related Publications
BACKGROUND: Fibroblasts are the commonest type of cancer stromal cells. Inflammation occurs in cancer tissue, and the inflammatory process has been suggested to be caused by interactions between immune cells and cancer cells. In this study, we clarified that site-specific fibroblasts regulate the formation of a site-specific inflammatory niche according to the depth of gastric cancer cell invasion.
METHODS: Immunohistochemistry was performed with paraffin-embedded tissues. The numbers of immune cells and the fibroblast area were calculated according to the cancer depth. The gene expression patterns of submucosal fibroblasts and subperitoneal fibroblasts stimulated with HSC44PE-conditioned medium were analyzed with a microarray. To examine the effects on the cancer microenvironment of differences in gene expressions between HSC44PE-stimulated submucosal fibroblasts and subperitoneal fibroblasts, assays of HSC44PE proliferation, T cell migration, and M2-like macrophage differentiation were performed.
RESULTS: The distributions of immune cells differed between the submucosal layer and the subserosal layer. The number of M2 macrophages was significantly higher and the fibroblast area was significantly larger in the subserosal layer compared with the submucosal layer. High expression levels of IL1B, TNFSF15, and CCL13 were observed in HSC44PE-stimulated submucosal fibroblasts, and higher expression levels of TGFB2, CSF1, CCL8, and CXCL5 were found in HSC44PE-stimulated subperitoneal fibroblasts. HSC44PE-stimulated subperitoneal fibroblast medium promoted the differentiation of monocytes into M2-like macrophages, whereas HSC44PE-stimulated submucosal fibroblasts significantly induced the migration of Jurkat cells and the growth of HSC44PE cells.
CONCLUSION: The dynamic states of immune cells differ between the submucosal and subserosal layers in cancer tissues. Site-specific fibroblasts regulate site-specific inflammatory niche formation according to the depth of cancer cell invasion.

Cavallini C, Lovato O, Bertolaso A, et al.
Expression and function of the TL1A/DR3 axis in chronic lymphocytic leukemia.
Oncotarget. 2015; 6(31):32061-74 [PubMed] Free Access to Full Article Related Publications
TNF-like ligand 1A (TL1A) and its unique receptor death receptor 3 (DR3) acts as broad T-cell costimulator involved in regulatory mechanisms of adaptive immune response under physiological and pathological settings. Moreover, we have recently shown that TL1A negatively regulates B-cell proliferation. Despite increasing interest on the TL1A/DR3-axis functions, very little is known on its expression and role in leukemia. In this study, we investigated the expression and function of TL1A/DR3 axis in chronic lymphocytic leukemia (CLL). DR3 was differentially expressed in activated CLL cells and predominantly detected in patients with early clinical stage disease. Soluble TL1A has been revealed in the sera of CLL patients where higher TL1A levels were associated with early stage disease. T cells, monocytes and leukemic B cells have been identified as major sources of TL1A in CLL. The relevance of these findings has been sustained by functional data showing that exogenous TL1A reduces CLL proliferation induced by stimulation of the B cell receptor. Overall, these data document the expression of the TL1A/DR3 axis in early-stage CLL. They also identify a novel function for TL1A as a negative regulator of leukemic cell proliferation that may influence the CLL physiopathology and clinical outcome at an early-stage disease.

Daft PG, Yang Y, Napierala D, Zayzafoon M
The growth and aggressive behavior of human osteosarcoma is regulated by a CaMKII-controlled autocrine VEGF signaling mechanism.
PLoS One. 2015; 10(4):e0121568 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma (OS) is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF) plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII) protein is an important regulator of OS growth. Here, we investigate the role of α-CaMKII-induced VEGF in the growth and tumorigenicity of OS. We show that the pharmacologic and genetic inhibition of α-CaMKII results in decreases in VEGF gene expression (50%) and protein secretion (55%), while α- CaMKII overexpression increases VEGF gene expression (250%) and protein secretion (1,200%). We show that aggressive OS cells (143B) express high levels of VEGF receptor 2 (VEGFR-2) and respond to exogenous VEGF (100nm) by increasing intracellular calcium (30%). This response is ameliorated by the VEGFR inhibitor CBO-P11, suggesting that secreted VEGF results in autocrine stimulated α-CaMKII activation. Furthermore, we show that VEGF and α-CaMKII inhibition decreases the transactivation of the HIF-1α and AP-1 reporter constructs. Additionally, chromatin immunoprecipitation assay shows significantly decreased binding of HIF-1α and AP-1 to their responsive elements in the VEGF promoter. These data suggest that α-CaMKII regulates VEGF transcription by controlling HIF-1α and AP-1 transcriptional activities. Finally, CBO-P11, KN-93 (CaMKII inhibitor) and combination therapy significantly reduced tumor burden in vivo. Our results suggest that VEGF-induced OS tumor growth is controlled by CaMKII and dual therapy by CaMKII and VEGF inhibitors could be a promising therapy against this devastating adolescent disease.

Yamanegi K, Kawabe M, Futani H, et al.
Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.
Int J Oncol. 2015; 46(5):1994-2002 [PubMed] Related Publications
The level of vascular endothelial growth inhibitor (VEGI) has been reported to be negatively associated with neovascularization in malignant tumors. The soluble form of VEGI is a potent anti-angiogenic factor due to its effects in inhibiting endothelial cell proliferation. This inhibition is mediated by death receptor 3 (DR3), which contains a death domain in its cytoplasmic tail capable of inducing apoptosis that can be subsequently blocked by decoy receptor 3 (DcR3). We investigated the effects of sodium valproate (VPA) and trichostatin A (TSA), histone deacetylase inhibitors, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Consequently, treatment with VPA and TSA increased the VEGI and DR3 expression levels without inducing DcR3 production in the OS cell lines. In contrast, the effect on the HMVE cells was limited, with no evidence of growth inhibition or an increase in the DR3 and DcR3 expression. However, VPA-induced soluble VEGI in the OS cell culture medium markedly inhibited the vascular tube formation of HMVE cells, while VEGI overexpression resulted in enhanced OS cell death. Taken together, the HDAC inhibitor has anti-angiogenesis and antitumor activities that mediate soluble VEGI/DR3-induced apoptosis via both autocrine and paracrine pathways. This study indicates that the HDAC inhibitor may be exploited as a therapeutic strategy modulating the soluble VEGI/DR3 pathway in osteosarcoma patients.

Zhang Z, Yu D, Lu J, et al.
Functional genetic variants of TNFSF15 and their association with gastric adenocarcinoma: a case-control study.
PLoS One. 2014; 9(9):e108321 [PubMed] Free Access to Full Article Related Publications
The purpose of this study was to identify functional genetic variants in the promoter of tumor necrosis factor superfamily member 15 (TNFSF15) and evaluate their effects on the risk of developing gastric adenocarcinoma. Forty DNA samples from healthy volunteers were sequenced to identify single nucleotide polymorphisms (SNPs) in the TNFSF15 promoter. Two TNFSF15 SNPs (-358 T > C and -638 A > G) were identified by direct sequencing. Next, genotypes and haplotypes of 470 gastric adenocarcinoma patients and 470 cancer-free controls were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. Serologic tests for Helicobacter pylori infection were measured by enzyme-linked immuno-sorbent assay (ELISA). Subjects carrying the TNFSF15 -358 CC genotype were at an elevated risk for developing gastric adenocarcinoma, compared with those with the -358 TT genotype (OR 1.42, 95% CI, 1.10 to 2.03). H. pylori infection was a risk factor for developing gastric adenocarcinoma (OR 2.31, 95% CI, 1.76 to 3.04). In the H. pylori infected group, subjects with TNFSF15 -358 CC genotype were at higher risks for gastric adenocarcinoma compared with those carrying -358 TT genotype (OR: 2.01, 95%CI: 1.65 to 4.25), indicating that H. pylori infection further influenced gastric adenocarcinoma susceptibility. The -358 T>C polymorphism eliminates a nuclear factor Y (NF-Y) binding site and the -358 C containing haplotypes showed significantly decreased luciferase expression compared with -358 T containing haplotypes. Collectively these findings indicate that functional genetic variants in TNFSF15 may play a role in increasing susceptibility to gastric adenocarcinoma.

Ma W, Li G, Wang J, et al.
In vivo NIRF imaging-guided delivery of a novel NGR-VEGI fusion protein for targeting tumor vasculature.
Amino Acids. 2014; 46(12):2721-32 [PubMed] Related Publications
Pathological angiogenesis is crucial in tumor growth, invasion and metastasis. Previous studies demonstrated that the vascular endothelial growth inhibitor (VEGI), a member of the tumor necrosis factor superfamily, can be used as a potent endogenous inhibitor of tumor angiogenesis. Molecular probes containing the asparagine-glycine-arginine (NGR) sequence can specifically bind to CD13 receptor which is overexpressed on neovasculature and several tumor cells. Near-infrared fluorescence (NIRF) optical imaging for targeting tumor vasculature offers a noninvasive method for early detection of tumor angiogenesis and efficient monitoring of response to anti-tumor vasculature therapy. The aim of this study was to develop a new NIRF imaging probe on the basis of an NGR-VEGI protein for the visualization of tumor vasculature. The NGR-VEGI fusion protein was prepared from prokaryotic expression, and its function was characterized in vitro. The NGR-VEGI protein was then labeled with a Cy5.5 fluorophore to afford Cy5.5-NGR-VEGI probe. Using the NIRF imaging technique, we visualized and quantified the specific delivery of Cy5.5-NGR-VEGI protein to subcutaneous HT-1080 fibrosarcoma tumors in mouse xenografts. The Cy5.5-NGR-VEGI probe exhibited rapid HT-1080 tumor targeting, and highest tumor-to-background contrast at 8 h post-injection (pi). Tumor specificity of Cy5.5-NGR-VEGI was confirmed by effective blocking of tumor uptake in the presence of unlabeled NGR-VEGI (20 mg/kg). Ex vivo NIRF imaging further confirmed in vivo imaging findings, demonstrating that Cy5.5-NGR-VEGI displayed an excellent tumor-to-muscle ratio (18.93 ± 2.88) at 8 h pi for the non-blocking group and significantly reduced ratio (4.92 ± 0.75) for the blocking group. In conclusion, Cy5.5-NGR-VEGI provided highly sensitive, target-specific, and longitudinal imaging of HT-1080 tumors. As a novel theranostic protein, Cy5.5-NGR-VEGI has the potential to improve cancer treatment by targeting tumor vasculature.

Gao Y, Ge Z, Zhang Z, et al.
Vascular endothelial growth inhibitor affects the invasion, apoptosis and vascularisation in breast cancer cell line MDA-MB-231.
Chin Med J (Engl). 2014; 127(10):1947-53 [PubMed] Related Publications
BACKGROUND: Breast cancer is one of the most common malignant female diseases worldwide. It is a significant threat to every woman's health. Vascular endothelial growth inhibitor (VEGI) is known to be abundant in endothelial cells. According to previous literature, overexpression of VEGI has been shown to inhibit tumor neovascularisation and progression in cellular and animal models, but there has been limited research on the significance of VEGI in the breast cancer.
METHODS: In our study, cell lines MDA-MB-231 were first constructed in which VEGI mediated by lentivirus over-expressed. The effects of VEGI over-expression on MDA-MB-231 cells were investigated both in vitro and in vivo. The expression of VEGI in the MDA-MB-231 cells after infection of lentivirus was analyzed using real-time PCR and Western blotting. The effect of the biological characteristics of MDA-MB-231 cells was assessed by growth, invasion, adhesion, and migration assay with subcutaneous tumor-bearing nude mice models. Then the growth curves of the subcutaneous tumors were studied. Expressions of VEGI, CD31 and CD34 in the tumors were analyzed by immunohistochemistry and apoptosis was detected by flow cytometry and immunohistochemistry.
RESULTS: Infection of MDA-MB-231 cells within the lentivirus resulted in approximately a 1 000-fold increase in the expression of VEGI. As can be seen in the invasion, adhesion and migration assay, the over-expression of VEGI can inhibit the ability of MDA-MB-231 cells during migration, adhesion and invasion. The volume of the subcutaneous tumor in the over-expression group was distinctly and significantly less than that of the control groups. Immunohistochemistry analysis of the tumor biopsies clearly showed the expression of VEGI in the over-expression group increased while CD31 and CD34 decreased significantly. In vitro and in vivo, the early apoptosis rate and the apoptosis index were increased within the VEGI over-expression group as compared with the control group.
CONCLUSIONS: Taken together, recombinant lentivirus that were successfully constructed, demonstrated up-regulated VEGI gene expression in breast cancer cells. Lentivirus-mediated over-expression of VEGI weakened the ability of the breast cancer cell migration, adhesion and invasion. Over-expression of VEGI diminished the tumorigenic capacity of breast cancer cells in vivo. Up-regulation of VEGI gene expression however inhibited breast cancer MDA-MB-231 cell in the early apoptosis.

Stadler CR, Vegi N, Mulaw MA, et al.
The leukemogenicity of Hoxa9 depends on alternative splicing.
Leukemia. 2014; 28(9):1838-43 [PubMed] Related Publications
Although the transforming potential of Hox genes is known for a long time, it is not precisely understood to which extent splicing is important for the leukemogenicity of this gene family. To test this for Hoxa9, we compared the leukemogenic potential of the wild-type Hoxa9, which undergoes natural splicing, with a full-length Hoxa9 construct, which was engineered to prevent natural splicing (Hoxa9FLim). Inability to undergo splicing significantly reduced in vivo leukemogenicity compared to Hoxa9-wild-typed. Importantly, Hoxa9FLim could compensate for the reduced oncogenicity by collaborating with the natural splice variant Hoxa9T, as co-expression of Hoxa9T and Hoxa9FLim induced acute myeloid leukemia (AML) after a comparable latency time as wild-type Hoxa9. Hoxa9T on its own induced AML after a similar latency as Hoxa9FLim, despite its inability to bind DNA. These data assign splicing a central task in Hox gene mediated leukemogenesis and suggest an important role of homeodomain-less splice variants in hematological neoplasms.

Wu L, Li X, Ye L, et al.
Vascular endothelial growth inhibitor 174 is a negative regulator of aggressiveness and microvascular density in human clear cell renal cell carcinoma.
Anticancer Res. 2014; 34(2):715-22 [PubMed] Related Publications
AIMS: To evaluate the role and expression of vascular endothelial growth inhibitor isoform 174 (VEGI 174) in the microvessels and its correlation with microvessel density (MVD) and prognosis of clear cell renal cell carcinoma (CCRCC).
MATERIALS AND METHODS: Immunohistochemical analysis was performed in 98 cases of renal cell carcinoma and paired normal kidney tissues for VEGI 174 and CD34. The clinical, pathological and follow-up (median follow-up: 54.5 months) information were recorded and analyzed against the VEGI174 and MVD expression.
RESULTS: There was an inverse correlation between VEGI 174 and MVD (r=-0.420, p<0.05) in normal human renal tissues and CCRCC specimens. Compared to normal kidney tissues, the expression of VEGI 174 was significantly lower in CCRCC (0.420±0.151 vs 0.107±0.063, p<0.01, respectively). On the contrary, MVD was higher in CCRCC specimens than in normal renal tissues (72.020±31.709 vs. 53.480±11.071, p<0.01, respectively). The expression of VEGI 174 in G1+G2 tumors was significantly higher than in G3 tumors (0.132±0.055 vs. 0.044±0.025, p<0.05, respectively). There was also a statistical significance in the expression of VEGI 174 in patients of different ages (<60y, 0.102±0.054 vs. ≥60 years, 0.117±0.083, p<0.01, respectively). However, between the staining of VEGI 174 and other pathological parameters (gender, tumour size and stage), there were no significant statistical differences (p>0.05). In addition, MVDs did not differ statistically by pathological grade, stage, gender, age or tumor size (p>0.05). Four patients died of CCRCC-related conditions during follow-up. However, no relationship between the expression of VEGI 174/MVD and overall survival was found in the study (p>0.05).
CONCLUSION: VEGI 174 has a significant role in angiogenesis in CCRCC, and appears to be a negative regulator of aggressiveness during the development and progression of CCRCC.

Hemmerle T, Hess C, Venetz D, Neri D
Tumor targeting properties of antibody fusion proteins based on different members of the murine tumor necrosis superfamily.
J Biotechnol. 2014; 172:73-6 [PubMed] Related Publications
The tumor necrosis factor superfamily (TNFSF) consists of more than 20 members that can modulate cellular and immunological functions, including cell survival and the stimulation of an inflammatory response. Many TNF superfamily members display potent anticancer activity when used as recombinant proteins in vitro and in vivo. While TNF, TRAIL and FasL have already been used as payloads in antibody-based pharmacodelivery strategies, most TNF superfamily members have not yet been investigated as antibody payloads. Here, we report the cloning, production and characterization of eight novel antibody fusion proteins based on CD40L, FasL, TRAIL, LiGHT, VEGI, lymphotoxin alpha, lymphotoxin beta and lymphotoxin alpha1/beta2. The monoclonal antibody F8 was chosen as fusion partner of proven tumor targeting performance, which recognizes the alternatively-spliced EDA domain of fibronectin, a marker of angiogenesis. A quantitative biodistribution analysis performed with radioiodinated protein preparations in tumor-bearing mice revealed that TRAIL and lymphotoxin alpha1/beta2 were able to selectively accumulate at the tumor site, while all other members of the TNF superfamily abrogated the selective tumor targeting performance of the parental antibody or accumulated also in healthy tissues. The study indicates that even cytokines, which are closely related in terms of structure and function, may have a substantially different impact on the biodistribution and functional properties of the corresponding fusions with disease-homing antibodies.

Lu Y, Gu X, Chen L, et al.
Interferon-γ produced by tumor-infiltrating NK cells and CD4+ T cells downregulates TNFSF15 expression in vascular endothelial cells.
Angiogenesis. 2014; 17(3):529-40 [PubMed] Related Publications
Endothelial cells in an established vasculature secrete tumor necrosis factor superfamily-15 (TNFSF15; VEGI; TL1A) that functions as a negative modulator of neovascularization to maintain blood vessel stability. TNFSF15 gene expression diminishes at angiogenesis and inflammation sites such as in cancers and wounds. We reported previously that vascular endothelial growth factor and monocyte chemotactic protein-1 contribute to TNFSF15 downmodulation in ovarian cancer. Here we show that interferon-γ (IFNγ) suppresses TNFSF15 expression in human umbilical vein endothelial cells. This activity is mediated by IFNγ receptor and the transcription factor STAT1. Immunohistochemical analysis of ovarian cancer clinical specimens indicates that TNFSF15 expression diminishes while tumor vascularity increases in specimens with high-grades of IFNγ expression. Since tumor-infiltrating NK and CD4(+) T cells are the main sources of IFNγ in tumor lesions, we isolated these cells from peripheral blood of healthy individuals, treated the cells with ovarian cancer OVCAR3 cell-conditioned media, and found a onefold and tenfold increase of IFNγ production in NK and CD4(+) T cells, respectively, compared with that in vehicle-treated cells. These findings support the view that tumor-infiltrating NK and CD4(+) T cells under the influence of cancer cells significantly increase the production of IFNγ, which in turn inhibits TNFSF15 expression in vascular endothelial cells, shifting the balance of pro- and anti-angiogenic factors toward escalated angiogenesis potential in the tumor.

Jia W, Sander AJ, Jia G, et al.
Vascular endothelial growth inhibitor (VEGI) is an independent indicator for invasion in human pituitary adenomas.
Anticancer Res. 2013; 33(9):3815-22 [PubMed] Related Publications
Pituitary ademonas are benign tumours from the pituitary gland but may have an invasive and destructive growth pattern. There is little understanding of the growth and progression control of pituitary tumours. In the present study, we investigated the expression of vascular endothelial growth inhibitor (VEGI), a vascular endothelial growth and apoptosis regulator and VEGI receptor Death Receptor-3 (DR3), in clinical pituitary tumours. Pituitary tumours from 95 patients were included in the study. Fresh pituitary tumours were obtained immediately after surgery and processed for histological and molecular-based analyses. Histopathological and clinical information including tumour size, tumour invasion and endocrine status were analyzed against the gene transcript expression of VEGI, DR3 and VEGF. VEGI and VEGF family and VEGF receptors were quantitatively determined for their gene transcript expression. The expression levels of VEGI were significantly lower in pituitary tumours which invaded the sella floor, and with suprasellar extension than in non-invasive tumours (p=0.0073). VEGI levels were also negatively correlated with cavernous sinus invasion stage (p<0.0001), in that a high level of VEGI was associated with low tumour grade. Multivariate analysis indicated that VEGI is an independent factor predictive of invasion (p=0.05). It was further demonstrated that the relationship between VEGI and pituitary tumour invasion were independent of the expression of VEGF and its receptors. Low levels of VEGI transcripts were associated with the intratumoural haemorrhage (p=0.05). Out of all the pituitary tumours, 59 were non-functional. Out of the functional tumours, it was found that follicle stimulating hormone (FSH)-expressing and gonadotrophic tumours tended to have markedly low levels of VEGI transcripts, compared with non-functional tumours (p=0.0026 and p=0.003, respectively). The opposite was seen with thyroid-stimulating hormone (TSH)-secreting tumours. Levels of DR3 in tumours with sella destruction were also lower than in those without destruction. VEGI, possibly via DR3, suppresses the aggressive nature of pituitary tumours and its expression level is closely linked to the invasion and destruction of the suprasellar and sella regions. It also has implications for the endocrine nature of these tumours. VEGI thus has an important predictive and prognostic value in patients with pituitary tumours.

Morral-Ruíz G, Melgar-Lesmes P, Solans C, García-Celma MJ
Multifunctional polyurethane-urea nanoparticles to target and arrest inflamed vascular environment: a potential tool for cancer therapy and diagnosis.
J Control Release. 2013; 171(2):163-71 [PubMed] Related Publications
Activation of inflammatory pathways in endothelial cells contributes to tumour growth and progression in multiple human cancers. Cellular adhesion molecules are involved in leukocyte recruitment to the vascular inflammatory environment where it plays a critical role in angiogenesis, suppression of apoptosis, proliferation, invasion and metastasis. We describe here the development of streptavidin-coated polyurethane-urea nanoparticles as multifunctional nanocarriers for fluorescence imaging or targeting of the tumour environment to identify and arrest the vascular network irrigating the tumour tissue. The design of these multifunctional nanoparticles involves incorporating streptavidin to the nanoparticle polymeric matrix. The obtained nanoparticles are spherical and exhibit an average diameter of 70-74 nm. Streptavidin-coated nanoparticles spontaneously bind biotinylated antibodies against VCAM-1 and ICAM-1 which in vitro and in vivo specifically attached to inflamed endothelial cells. Indeed the incorporation of CBO-P11 (a specific inhibitor of the vascular endothelial growth factor proangiogenic and proinflammatory pathway) to these nanoparticles allows a targeted pharmacological effect thereby decreasing the proliferation only in inflamed endothelial cells. The multiple functionalisation strategy described here could be exploited for tumour diagnostics or targeted drug delivery to tumour vasculature with a good safety profile and an attractive array of possibilities for biomedical applications.

Wu LY, Cheng H, Deng XH, et al.
[Expression and role of vascular endothelial growth inhibitor in sporadic clear cell renal cell carcinoma].
Zhonghua Yi Xue Za Zhi. 2013; 93(10):741-5 [PubMed] Related Publications
OBJECTIVE: To evaluate the expression of vascular endothelial growth inhibitor (VEGI) in sporadic clear cell renal cell carcinoma (CCRCC) and explore its relationships between VEGI expression, pathologic grade and tumor staging.
METHODS: Western blot and immunohistochemical staining were used to detect the expression of VEGI in CCRCC cell line (786-O cells), CCRCC and paired normal kidney tissues. A total of 50 CCRCC cases were recruited. There were 37 males and 13 females with an average age of 53 ± 12 years. The tumor sizes were < 7 cm (n = 33) and ≥ 7 cm (n = 17). Their pathologic grades were G1 (n = 14), G2 (n = 22) and G3 (n = 14) and pathologic stages pT1 (n = 32), 10 pT2 (n = 10) and pT3 (n = 8).
RESULTS: VEGI protein was predominantly located in cytoplasm. Compared with normal kidney tissues(mean optic density (MOD) of VEGI staining: 0.40 ± 0.16), it was lower in CCRCC tissues (MOD: 0.11 ± 0.06, P < 0.01). In addition, the positive rate of VEGI expression, the expression intensity and the MOD of VEGI protein were negatively correlated with the pathologic grade of CCRCC (r = -0.640, P < 0.01; r = -0.831, P < 0.01; r = -0.781, P < 0.01 respectively). The MOD of VEGI expression in ≥ 7 cm tumors (MOD, 0.08 ± 0.04) was significantly lower than that in < 7 cm tumors (MOD: 0.12 ± 0.06, P < 0.05). However, there was no correlations between the VEGI protein level and age, gender and pathologic stage of patients (P > 0.05).
CONCLUSION: VEGI protein is predominantly located in cytoplasm. Compared with CCRCC tissues, VEGI protein level is higher in normal ones. In consideration of negative correlations between VEGI expression, pathologic grade and tumor size, it is implied that VEGI may play a negative regulatory role in the occurrence and development of CCRCC.

Zhang N, Wu P, Shayiremu D, et al.
Suppression of renal cell carcinoma growth in vivo by forced expression of vascular endothelial growth inhibitor.
Int J Oncol. 2013; 42(5):1664-73 [PubMed] Related Publications
Vascular endothelial growth inhibitor (VEGI) has been associated with tumor-related vasculature in certain malignancies. However, its implication in renal cell carcinoma (RCC), an angiogenesis-dependent tumor, remains unknown. In the present study, we investigated the role played by VEGI in RCC. The expression of VEGI was examined in human renal tissue and RCC cell lines using immunohistochemical staining and RT-PCR, respectively. The biological impact of modifying the expression of VEGI in RCC cells was evaluated using in vitro and in vivo models. We show that VEGI mRNA is expressed in a wide variety of human RCC cell lines, all of normal renal and most of RCC tissue specimens. VEGI protein expression was observed in normal renal tubular epithelial cells, but was decreased or absent in RCC specimens, particularly in tumors with high grade. Moreover, forced expression of VEGI led to an inhibition of vascular endothelial tube formation, decrease in the motility and adhesion of RCC cells in vitro. Interestingly, forced expression of VEGI had no bearing on growth, apoptosis and invasive capacity of RCC cells. However, tumor growth was reduced in xenograft models. Immunohistochemical staining showed that microvessel density decreased in VEGI forced expression xenograft tumor samples. Taken together, our findings showed that the expression of VEGI is decreased in RCC, particularly in tumors with higher grade. Together with its inhibitory effect on cellular motility, adhesion, vascular endothelial tube formation and tumor growth in vivo, this suggests that VEGI functions mainly through inhibition of angiogenesis and is a negative regulator of aggressiveness during the development and progression of RCC.

Mares J, Szakacsova M, Soukup V, et al.
Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results.
Neoplasma. 2013; 60(3):295-301 [PubMed] Related Publications
The aim of the study was to define specific genetic profile in Ta and T1 urinary bladder carcinoma patients with and without recurrence by gene expression microarrays. Eleven patients with the time to recurrence shorter than one year (patients with recurrence) and 11 patients with time to recurrence longer than 4 years (patients without recurrence) were enrolled. Data from microarrays were subjected to a panel of statistical analyses to identify bladder cancer recurrence-associated gene signatures. Initial screening using the GeneSpring and Bioconductor software tools revealed a putative set 47 genes differing in gene expression in both groups. After the validation, 33 genes manifested significant differences between both groups. The significant expression was observed in the group of patients without recurrence by 30 genes of which the highest differences were detected by ANXA1, ARHGEF4, FLJ32252, GNE, NINJ1, PRICKLE1, PSAT1, RNASE1, SPTAN1, SYNGR1, TNFSF15, TSPAN1, and WDR34. These genes code for signal transduction, vascular remodeling and vascular endothelial growth inhibition mainly. In the group with recurrence, 3 genes had significant differences, the highest differences were identified by two genes (PLOD2 and WDR72). Loci of genes with significant changes of gene expression were located on characteristic chromosomes for bladder cancer: 7 loci on chromosome 9, 8 loci on chromosomes 1, 2, 3, 12,14,15,16, and 22. We have selected and validated 15 genes that are differentially expressed in superficial bladder cancer. We hope that this cohort of genes will serve as a promising pool of candidate biomarkers for early stage bladder cancer. Our results indicate that it may be possible to identify patients with a low and high risk of disease recurrence at an early stage using a molecular profile.

Ge Z, Sanders AJ, Ye L, et al.
Expression of death receptor-3 in human breast cancer and its functional effects on breast cancer cells in vitro.
Oncol Rep. 2013; 29(4):1356-64 [PubMed] Related Publications
Death receptor-3 (DR3) plays controversial roles in cancer. Currently, DR3 is known to be a functional receptor of vascular endothelial growth inhibitor (VEGI). The role of DR3 in breast cancer remains unclear. The present study investigated DR3 expression in a clinical cohort of breast cancer patients and its role in breast cancer cells in vitro. The expression of DR3 was examined in a breast cancer cohort using quantitative PCR (Q-PCR) and immunohistochemistry (IHC) in comparison to the patients' data. In vitro function of DR3 was examined through the targeting of this molecule in MCF7 and MDA-MB-231 breast cancer cells using ribozyme transgene technology. Decreased DR3 expression was noted in breast cancer tissues compared to normal tissues and decreased expression of DR3 was generally associated with a poorer prognosis as well as a significantly shorter long-term survival (p=0.038). Targeting of DR3 in vitro in breast cancer cell lines resulted in impaired migratory rates compared to respective control cells. Collectively, these data suggest a complex role for DR3 in breast cancer development and progression.

Li Z, Yin PH, Yang SS, et al.
Recombinant attenuated Salmonella typhimurium carrying a plasmid co-expressing ENDO-VEGI151 and survivin siRNA inhibits the growth of breast cancer in vivo.
Mol Med Rep. 2013; 7(4):1215-22 [PubMed] Related Publications
The aim of this study was to investigate the antitumor effect of a plasmid co-expressing ENDO-VEGI151 and survivin siRNA on breast cancer in nude mice, and to explore the feasibility of attenuated Salmonella typhimurium (S. typhimurium) as a delivery vector for cancer gene therapy in vivo. Three recombinant expression plasmids pENDO‑VEGI151 (pEV), pSurvivin-siRNA (psi-survivin) and co-expressing plasmid pENDO-VEGI151/survivin‑siRNA (pEV/si-survivin), were transferred into the attenuated S. typhimurium strain SL7207, respectively. MDA-MB-231 cells were infected with these recombinants in vitro, and the expression of ENDO-VEGI151 and survivin was detected. In order to detect S. typhimurium distribution and gene delivery efficiency in vivo, the plasmid pEGFP-N1 which encodes green fluorescent protein was transferred into SL7207, and the recombinant known as SL-pEGFP was orally administered to tumor-bearing nude mice. The gene transfer efficiency, distribution and survival time of the SL-pEGFP in vivo were evaluated by detection of GFP fluorescence. SL-pEGFP not only infected the cancer cells effectively, but also allowed the survival and expression of specific genes mainly in the xenografts of nude mice. To further identify the anticancer effects of these recombinants in vivo, mice burdened with xenografts were randomly divided into 6 groups, which were subjected to intragastric administration of vehicle, SL7207, SL-pcDNA3.1, SL-pEV, SL-psi-survivin and SL-pEV/si-survivin, respectively. Eight weeks after implantation, tumor size, weight, inhibition rate, intratumoral microvessel density (MVD), apoptotic index (AI), ENDO‑VEGI151 and survivin expression were evaluated. Compared with the SL-pEV or SL-psi-survivin-treated groups, the growth of tumors was significantly reduced in the SL-pEV/si-survivin group with an inhibition rate of 90.28 vs. 69.12 and 65.61%, respectively. MVD and the expression of survivin were decreased significantly in the SL-pEV/si-survivin-treated group, while AI increased significantly in the SL-pEV/si-survivin-treated group. These results indicated that attenuated S. typhimurium carrying the dual function plasmid pEV/si-survivin cannot only be specifically enriched in the tumor tissue, but also showed a synergistic antitumor effect in vivo.

Zhang N, Wu P, Wu L, et al.
The differential expression of vascular endothelial growth inhibitor isoforms, VEGI251, VEGI174 and VEGI192 in human clear-cell renal cell carcinoma.
Cancer Genomics Proteomics. 2013 Jan-Feb; 10(1):47-53 [PubMed] Related Publications
UNLABELLED: Vascular endothelial growth inhibitor (VEGI) is a recently identified antiangiogenic cytokine that belongs to the tumour necrosis factor (TNF) superfamily, and may be essential for many physiological and pathological processes. However, the expression of VEGI and in particular its isoforms, VEGI251, VEGI192 and VEGI174, in clear-cell renal cell carcinoma (CCRCC) remain unknown. In the current study, we investigated the expression of the three isoforms of VEGI in CCRCC. The expression of VEGI was examined in paired human normal renal and CCRCC specimens (n=73). The transcripts of the three isoforms of VEGI were all detected in human renal normal and tumour tissues. Levels of VEGI174 and VEGI192 transcripts in normal renal specimens were higher than those in CCRCC (p=0.021 and p=0.038, respectively). Levels of VEGI251 were similar in normal and tumour specimens (p=0.67). The numbers of VEGI174 and VEGI192 transcripts in T1a+T1b tumours were higher than those in T2+T3 tumours (p=0.006 and p=0.018, respectively). Moreover, VEGI192 transcript levels were negatively correlated with pathological nuclear grade (r=-0.216, p=0.022). In immunohistochemical staining, VEGI192 staining in normal and CCRCC tissues differed significantly (100% vs. 39.7%, p<0.0001). VEGI192 staining intensity was also negatively correlated with pathological nuclear grade (r=-0.781, p=0.002).
CONCLUSION: Transcripts of VEGI isoforms were detectable in normal and tumour renal tissues. VEGI192 and VEGI174 expressions markedly decreased in CCRCC and are linked to pathological grade and stage. VEGI192 and VEGI174 are more likely to be putative tumour suppressive factors and a potential therapeutic target in CCRCC.

Yu L, Deng L, Li J, et al.
The prognostic value of vascular endothelial growth factor in ovarian cancer: a systematic review and meta-analysis.
Gynecol Oncol. 2013; 128(2):391-6 [PubMed] Related Publications
OBJECTIVE: The prognostic role of vascular endothelial growth factor (VEGF) in ovarian cancer remains inconclusive. This meta-analysis aimed to explore the association between VEGF overexpression and survival outcomes in ovarian cancer patients.
METHODS: Studies were identified from PubMed and EMBASE searches performed on January 2nd, 2011. After careful review, survival data were extracted from eligible studies. A meta-analysis was performed to generate combined hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) in serum and tumor tissue studies.
RESULTS: Sixteen studies with 1111 patients were analyzed. Elevated serum VEGF was significantly associated with poor PFS [HR 2.46, 95% CI (1.84, 3.29)] and OS [HR 2.21, 95% CI (1.57, 3.13)]. No significant heterogeneity existed in serum studies. Similarly, tissue VEGF overexpression was associated with poor PFS [HR 1.63, 95% CI (1.09, 2.42)] and OS [HR 1.70, 95% CI (1.01, 2.87)]. However, significant heterogeneity was found in tissue studies, with I(2) of 44% for PFS and 64% for OS. Studies were stratified into subgroups by International Federation of Gynecology and Obstetrics (FIGO) stages. Subgroup analyses showed that high tissue VEGF was significantly associated with shorter PFS [HR 5.34, 95% CI (1.95, 14.59)] and OS [HR 6.13, 95% CI (2.47, 15.26)] in studies where predominantly early-stage patients were included, but not in studies with a majority of advanced-stage patients. Subgroup analysis was not performed in serum studies because all those studies enrolled more patients in advanced stages than early stages.
CONCLUSIONS: Overexpression of VEGF in primary tumor and serum associates with poor PFS and OS for patients with ovarian cancer. The association between high tissue VEGF level and poor prognosis exists in early stage patients, but not in advanced stage patients.

Li SC, Martijn C, Cui T, et al.
The somatostatin analogue octreotide inhibits growth of small intestine neuroendocrine tumour cells.
PLoS One. 2012; 7(10):e48411 [PubMed] Free Access to Full Article Related Publications
Octreotide is a widely used synthetic somatostatin analogue that significantly improves the management of neuroendocrine tumours (NETs). Octreotide acts through somatostatin receptors (SSTRs). However, the molecular mechanisms leading to successful disease control or symptom management, especially when SSTRs levels are low, are largely unknown. We provide novel insights into how octreotide controls NET cells. CNDT2.5 cells were treated from 1 day up to 16 months with octreotide and then were profiled using Affymetrix microarray analysis. Quantitative real-time PCR and western blot analyses were used to validate microarray profiling in silico data. WST-1 cell proliferation assay was applied to evaluate cell growth of CNDT2.5 cells in the presence or absence of 1 µM octreotide at different time points. Moreover, laser capture microdissected tumour cells and paraffin embedded tissue slides from SI-NETs at different stages of disease were used to identify transcriptional and translational expression. Microarrays analyses did not reveal relevant changes in SSTR expression levels. Unexpectedly, six novel genes were found to be upregulated by octreotide: annexin A1 (ANXA1), rho GTPase-activating protein 18 (ARHGAP18), epithelial membrane protein 1 (EMP1), growth/differentiation factor 15 (GDF15), TGF-beta type II receptor (TGFBR2) and tumour necrosis factor (ligand) superfamily member 15 (TNFSF15). Furthermore, these novel genes were expressed in tumour tissues at transcript and protein levels. We suggest that octreotide may use a potential novel framework to exert its beneficial effect as a drug and to convey its action on neuroendocrine cells. Thus, six novel genes may regulate cell growth and differentiation in normal and tumour neuroendocrine cells and have a role in a novel octreotide mechanism system.

Wu J, Jiang Y, Yang W, et al.
Dual function of RGD-modified VEGI-192 for breast cancer treatment.
Bioconjug Chem. 2012; 23(4):796-804 [PubMed] Related Publications
Identification of endogenous angiogenesis inhibitors has led to development of an increasingly attractive strategy for cancer therapy and other angiogenesis-driven diseases. Vascular endothelial growth inhibitor (VEGI), a potent and relatively nontoxic endogenous angiogenesis inhibitor, has been intensively studied, and this work shed new light on developing promising anti-angiogenic strategies. It is well-documented that the RGD (Arg-Gly-Asp) motif exhibits high binding affinity to integrin α(v)β(3), which is abundantly expressed in cancer cells and specifically associated with angiogenesis on tumors. Here, we designed a fusion protein containing the special RGD-4C motif sequence and VEGI-192, aimed at offering more effective multiple targeting to tumor cells and tumor vasculature, and higher anti-angiogenic and antitumor efficacy. Functional tests demonstrated that the purified recombinant human RGD-VEGI-192 protein (rhRGD-VEGI-192) potently inhibited endothelial growth in vitro and suppressed neovascularization in chicken chorioallantoic membrane in vivo, to a higher degree as compared with rhVEGI-192 protein. More importantly, rhRGD-VEGI-192, but not rhVEGI-192 protein, could potentially target MDA-MB-435 breast tumor cells, significantly inhibiting growth of MDA-MB-435 cells in vitro, triggered apoptosis in MDA-MB-435 cells by activation of caspase-8 as well as caspase-3, which was mediated by activating the JNK signaling associated with upregulation of pro-apoptotic protein Puma, and consequently led to the observed significant antitumor effect in vivo against a human breast cancer xenograft. Our study indicated that the RGD-VEGI-192 fusion protein might represent a novel anti-angiogenic and antitumor strategy.

Duan L, Yang G, Zhang R, et al.
Advancement in the research on vascular endothelial growth inhibitor (VEGI).
Target Oncol. 2012; 7(1):87-90 [PubMed] Related Publications
Vascular endothelial growth inhibitor (VEGI), also known as tumor necrosis factor superfamily member 15 or TNF ligand-related molecule 1, is identified as one kind of antiangiogenic cytokine that belongs to the tumor necrosis factor superfamily. VEGI includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. VEGI can activate multiple signaling pathways including nuclear factor-kappaB, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Moreover, it suppresses endothelial cell proliferation, angiopoiesis, and tumor growth. Genetic engineering techniques have been used to produce recombinant human vascular endothelial growth inhibitor, and great progress has been made in its application for curing cancer. VEGI could serve as a potential target in the development of angiogenesis-based cancer therapy, and this paper briefly summarizes the progress of the research on VEGI.

Deng W, Gu X, Lu Y, et al.
Down-modulation of TNFSF15 in ovarian cancer by VEGF and MCP-1 is a pre-requisite for tumor neovascularization.
Angiogenesis. 2012; 15(1):71-85 [PubMed] Related Publications
Persistent inflammation and neovascularization are critical to cancer development. In addition to upregulation of positive control mechanisms such as overexpression of angiogenic and inflammatory factors in the cancer microenvironment, loss of otherwise normally functioning negative control mechanisms is likely to be an important attribute. Insights into the down-modulation of such negative control mechanisms remain largely unclear, however. We show here that tumor necrosis factor superfamily-15 (TNFSF15), an endogenous inhibitor of neovascularization, is a critical component of the negative control mechanism that operates in normal ovary but is missing in ovarian cancer. We show in clinical settings that TNFSF15 is present prominently in the vasculature of normal ovary but diminishes in ovarian cancer as the disease progresses. Vascular endothelial growth factor (VEGF) produced by cancer cells and monocyte chemotactic protein-1 (MCP-1) produced mainly by tumor-infiltrating macrophages and regulatory T cells effectively inhibits TNFSF15 production by endothelial cells in vitro. Using a mouse syngeneic tumor model, we demonstrate that silencing TNFSF15 by topical shRNA treatments prior to and following mouse ovarian cancer ID8 cell inoculation greatly facilitates angiogenesis and tumor growth, whereas systemic application of recombinant TNFSF15 inhibits angiogenesis and tumor growth. Our findings indicate that downregulation of TNFSF15 by cancer cells and tumor infiltrating macrophages and lymphocytes is a pre-requisite for tumor neovascularization.

Li Z, Yang S, Chang T, et al.
Anti-angiogenesis and anticancer effects of a plasmid expressing both ENDO-VEGI151 and small interfering RNA against survivin.
Int J Mol Med. 2012; 29(3):485-90 [PubMed] Related Publications
We have previously reported that the overexpression of the endostatin-vascular endothelial cell growth inhibitor (VEGI) fusion protein inhibits angiogenesis and achieves a strong anticancer effect. In this study, we constructed the dual-function expression plasmid pCDNA3.1-ENDO-VEGI151/survivin-small interfering RNA (siRNA) (pEV/si-survivin), and evaluated the anti-angiogenesis and anticancer effects of this plasmid. Efficient siRNA sequences against survivin were identified; and the pEV/si-survivin expression vector was constructed and transfected into MDA-MB-231 cells and human umbilical vein endothelial cells (HUVECs). The expression levels of ENDO-VEGI151 and survivin were detected by RT-PCR and Western blotting analysis. MTT assay was used to detect the proliferation of cancer cell lines. Flow cytometry was used to detect cell cycle states and apoptosis. The expression of both ENDO-VEGI151 and survivin-siRNA were detected in MDA-MB-231 and HUEVC cells transfected with pEV/si-survivin. The expression of survivin was reduced in cells transfected with pEV/si-survivin. Furthermore, pEV/si-survivin inhibited proliferation and promoted apoptosis in MDA-MB-231 and HUEVC cells. It also caused cell cycle arrest in both cell lines. In conclusion, the dual-function expression plasmid pEV/si-survivin is involved in inhibition of angiogenesis and promoting tumor cell apoptosis in vitro. Therefore, it is also expected to improve the treatment of tumors by exerting synergistic effects in vivo.

Slebioda TJ, Rowley TF, Ferdinand JR, et al.
Triggering of TNFRSF25 promotes CD8⁺ T-cell responses and anti-tumor immunity.
Eur J Immunol. 2011; 41(9):2606-11 [PubMed] Related Publications
TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNF-like protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD4(+) T-cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8(+) T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8(+) T-cell-dependent manner and renders mice immune to a subsequent challenge with tumor cells. To gain further insight into the role of TNFRSF25 in CD8(+) T-cell responses, we analyzed the effect of TNFRSF25 triggering on OT-I TCR transgenic T cells. We demonstrate that TNFRSF25 triggering in vivo with soluble TL1A promotes the proliferation and accumulation of antigen-specific CD8(+) T cells as well as their differentiation into CTLs. Furthermore, we show that TNFRSF25 also functions as a costimulatory receptor for memory CD8(+) T cells. Thus, TNFRSF25 triggering enhances the secondary expansion of endogenous antigen-specific memory CD8(+) T cells. Our data suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be used to enhance the immunogenicity of vaccines that aim to elicit human anti-tumor CD8(+) T cells.

Ammerpohl O, Pratschke J, Schafmayer C, et al.
Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma.
Int J Cancer. 2012; 130(6):1319-28 [PubMed] Related Publications
Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a "cirrhotic" methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands.

Recchia F, Candeloro G, Necozione S, et al.
Premenopausal hormone-responsive breast cancer with extensive axillary nodes involvement: total estrogen blockade and chemotherapy.
Anticancer Res. 2011; 31(2):671-6 [PubMed] Related Publications
BACKGROUND: Poor prognosis is associated with estrogen- and/or progesterone receptor-positive (ER(+), PGR(+)) premenopausal breast cancer (PM-BC) with high Ki-67 labeling index and extensive axillary lymph node involvement. The role of adjuvant chemotherapy (CT) and hormonal therapy have not yet been established in these patients.
PATIENTS AND METHODS: Twenty-five PM-BC patients received, in sequence, leuprorelin, taxane-anthracycline induction chemotherapy, radiation therapy, a platinum-based intensification high-dose CT, followed by leuprorelin and anastrazole for five years. Vascular endothelial growth factor (VEGF) levels were measured as the primary end-point; secondary end-points were 10-year relapse-free survival (RFS) and overall survival (OS) rates.
RESULTS: The median patient age was 44 years, and the mean number of positive axillary nodes was 14. All patients were ER(+) and/or PGR(+), with a median Ki-67 index of 33%. Five patients were Cerb-B2 positive. Grade 4 hematologic toxicity was observed in all patients, no patient showed a decrease of cardiac ejection fraction and hot flashes and arthralgias were of moderate intensity. After a median follow-up of 70 months, VEGF levels significantly decreased (p<0.001); 10-year RFS and OS were 76% and 78%, respectively.
CONCLUSION: Total estrogen blockade and high-dose CT in PM-BC patients is feasible, has moderate toxicity, significantly reduces VEGF levels, and seems to improve the expected RFS and OS.

Raymond E, Hobday T, Castellano D, et al.
Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors.
Cancer Metastasis Rev. 2011; 30 Suppl 1:19-26 [PubMed] Related Publications
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show limited sensitivity to cytotoxic agents, requiring the search for novel therapies. Recently, data from a phase III trial demonstrated that sunitinib produces a clinically significant improvement in progression-free survival in patients with unresectable, advanced, or metastatic GEP-NETs. Based on this finding, sunitinib became the first targeted drug approved for the treatment of GEP-NETs, paving the way for the approval of other anticancer agents in this drug-orphan disease. To date, results of trials involving other multitargeted tyrosine kinase inhibitors, such as sorafenib, the monoclonal antibody bevacizumab, and insulin-like growth factor 1 receptor inhibitors, have also shown promising results, and some are already being studied in phase III trials. This review updates the results of ongoing trials using inhibitors of growth factors and tyrosine kinase receptors involved in the carcinogenesis of GEP-NETs.

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