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Angiogenesis and Cancer

Angiogenesis is the process which forms new blood vessels. Like normal tissues in the body, tumours need to develop blood vessels to supply oxygen and nutrients in order for them to grow and spread. See the separate page on Angiogenesis inhibitors, which can be used to reduce or slow down the spread and growth of some types of cancer by suppressing the tumours ability to form new blood cells.

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Angiogenesis Inhibitors

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  • PubMed search for publications about Angiogenesis - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Angiogenesis
    MeSH term: Neovascularization, Pathologic
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Ishikura N, Yanagisawa M, Noguchi-Sasaki M, et al.
Importance of Bevacizumab Maintenance Following Combination Chemotherapy in Human Non-small Cell Lung Cancer Xenograft Models.
Anticancer Res. 2017; 37(2):623-629 [PubMed] Related Publications
BACKGROUND: Bevacizumab in combination with chemotherapeutics has shown significant survival benefit in clinical studies in patients with non-small cell lung cancer (NSCLC). Since bevacizumab was administered as standard treatment until disease progression, the importance of bevacizumab during the maintenance phase was not prospectively investigated in these studies.
MATERIALS AND METHODS: Three human NSCLC cell line xenograft models were used to investigate antitumor effect of bevacizumab and tumor microvessel density (MVD) was analyzed.
RESULTS: In A549 and NCI-H292 models, bevacizumab maintenance following combination with paclitaxel exhibited stronger tumor suppression than its absence. In an NCI-H292 model, bevacizumab maintenance continuously inhibited increase of MVD. In an NCI-H2228 model following induction treatment with pemetrexed and bevacizumab, maintenance with pemetrexed plus bevacizumab, had stronger efficacy than pemetrexed alone and led to lower MVD and level of thymidylate synthase.
CONCLUSION: Continuous suppression of angiogenesis by bevacizumab may contribute to the superior efficacy of maintenance treatment containing bevacizumab.

Zhang S, Tang D, Zang W, et al.
Synergistic Inhibitory Effect of Traditional Chinese Medicine Astragaloside IV and Curcumin on Tumor Growth and Angiogenesis in an Orthotopic Nude-Mouse Model of Human Hepatocellular Carcinoma.
Anticancer Res. 2017; 37(2):465-473 [PubMed] Related Publications
AIM: The aim of the present study was to investigate the efficacy of the traditional Chinese medicine (TCM), astragaloside IV (AS-IV) and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma (HCC). We have previously shown the usefulness of orthotopic models of human cancer for evaluation of the efficacy of TCM.
MATERIALS AND METHODS: Nude mice with orthotopic HepG2 HCC were treated with vehicle control (0.01 ml/g normal saline), cisplatinum (2 mg/kg), AS-IV (20 mg/kg), curcumin (100 mg/kg) or AS-IV plus curcumin (20 mg/kg + 100 mg/kg). Tumor inhibition in each group was evaluated by tumor weight at autopsy. The effect of AS-IV and curcumin on tumor angiogenesis was assessed by CD34 staining and expression of fibroblast growth factor-2 (FGF2), matrix metalloproteinase 2 (MMP2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), thrombosis-related factor tissue factor (TF) and coagulation factor VII (FVII), as well as microRNAs miR-122 and miR-221.
RESULTS: AS-IV and curcumin alone and in combination significantly reduced mean tumor weight compared to vehicle control (p<0.05). Tumor microvessel count was reduced by AS-IV and curcumin alone. Expression of FGF2, MMP2, VEGF, HGF, TF and FVII was reduced by AS-IV and curcumin alone. AS-IV and curcumin alone up-regulated expression of miR-122 and down-regulated that of miR-221. The combination of AS-IV and curcumin demonstrated significant synergistic effects on microvessel count as well as on expression of angiogenic and thrombosis-related factors and microRNAs.
CONCLUSION: The present study indicates future clinical potential of combination therapy with AS-IV and curcumin for HCC.

López JI, Erramuzpe A, Guarch R, et al.
CD34 immunostaining enhances a distinct pattern of intratumor angiogenesis with prognostic implications in clear cell renal cell carcinoma.
APMIS. 2017; 125(2):128-133 [PubMed] Related Publications
Clear cell renal cell carcinoma is an aggressive neoplasm related to VHL gene inactivation. The molecular events derived from this initial alteration lead to a permanent intracellular pseudo-hypoxic status that stimulates vascular proliferation. The resulting increased intratumor angiogenesis is the target of most modern therapies. Although intratumor angiogenesis has received full attention in the last years, few studies have focused on its potential importance from a strict morphological approach. Intratumor angiogenesis has been analyzed in a retrospective series of clear cell renal cell carcinomas (n = 208) with long-term follow-up (n = 177). Two different patterns of angiogenesis have been highlighted with CD34 at the front of tumor invasion, termed continuous and discontinuous, respectively. The continuous pattern of angiogenesis showed a complete microvascular network surrounding totally tumor nests. Conversely, the discontinuous pattern displayed an incomplete network around tumor nests. The continuous pattern was associated to shorter 5-year (p = 0.00064, hazard ratio = 2.8) and 15-year (p = 0.014, hazard ratio = 1.7) survivals. Cox regression multivariate analysis also showed that the continuous pattern (p = 0.016373) remains a significant variable when considered together with grade (p = 0.001755) and stage (p = 0.000952). These findings support the notion that a continuous CD34(+) pattern of intratumor angiogenesis may be useful for pathologists in predicting tumor behavior in clear cell renal cell carcinomas.

Chen Y, Wang H, Lin W, Shuai P
ADAR1 overexpression is associated with cervical cancer progression and angiogenesis.
Diagn Pathol. 2017; 12(1):12 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to assess the role of RNA-dependent adenosine deaminase (ADAR1) in cervical squamous cell carcinoma occurrence and progression.
METHODS: ADAR1 expression levels in stage IA and stage IIA cervical squamous cell carcinoma (group A), cervical intraepithelial neoplasia (CIN) specimens (group B), as well as normal and inflamed cervical tissue samples (group C) were assessed by immunohistochemistry. Clinical and pathological data of cervical squamous cell carcinoma patients undergoing surgery were retrospectively evaluated. Chi-square test, comparative analysis of survival curve, disease-free survival and COX risk assessment method were used to understand the association of ADAR1 with the occurrence and progression and prognostic significance of cervical squamous cell carcinoma.
RESULTS: ADAR1 is expressed in the cytoplasm and nuclei. The expression level was high in squamous cell carcinoma tissues (81.18%), while relatively low in the CIN group (21.56%). And there was no expression in non-cancerous tissues. The differences between them were statistically significant using P < 0.05 as criterion. One-factor analysis revealed that ADAR1 was significantly correlated with tumor diameter, horizontal diffusion diameter, vascular invasion, parametrial invasion, vaginal involvement, and pathologically diagnostic criteria for perineural invasion (PNI). Meanwhile, the overall survival rate of ADAR1 positive patients was significantly lower compared with that of patients with no ADAR1 expression (P < 0.05). Analysis also showed that disease-free survival time of ADAR1 positive patients was shorter than that of ADAR1 negative patients, and the difference was significant (P < 0.01). Finally, COX risk assessment showed that parametrical invasion had independent prognostic factors for overall survival of squamous cell carcinoma.
CONCLUSIONS: Results indicated that ADAR1 might play an important role in the occurrence, progression and prognosis of cervical squamous cancer.

Ao Z, Yu S, Qian P, et al.
Tumor angiogenesis of SCLC inhibited by decreased expression of FMOD via downregulating angiogenic factors of endothelial cells.
Biomed Pharmacother. 2017; 87:539-547 [PubMed] Related Publications
Fibromodulin (FMOD), an ECM small leucine-rich proteoglycan (SLRP), was reported to promote angiogenesis not only during wound healing, but also in optical and cutaneous angiogenesis-dependent diseases. However, whether it plays important roles in tumor angiogenesis remains unclear. To explore the role of FMOD in tumor angiogenesis of human small cell lung cancer (SCLC), initially the study analyzed the relationship of FMOD expression in cancer tissues of SCLC with clinical characteristics. The analysis revealed that the positive FMOD expression was significantly associated with extensive stage of SCLC and higher vascular density. In mouse models, xenograft tumors developed with FMOD-silenced H446 cells (H446-shFMOD) exhibited slowed growth rate, decreased microvessel density, and reduced blood perfusion related to that of controls (H446-shCON). Additionally, compared with that of controls, the decreased secretion of FMOD in conditioned medium (CM) from H446-shFMOD inhibited proliferation, migration, and invasion of human umbilical vessel endothelial cells (HUVECs). Moreover, the decreased secretion of FMOD downregulated the expression of VEGF, TGF-β1, FGF-2, and PDGF-B in HUVECs. The findings strongly suggested that the autocrine FMOD of cancer cells may promote tumor angiogenesis of SCLC by upregulating the expression of angiogenic factors that act in concert to facilitate the angiogenic phenotype of endothelial cells as a proangiogenic factor. Therefore, silencing FMOD may be a potentially clinical therapy for repressing tumor angiogenesis.

Dai D, Zhang CF, Williams S, et al.
Ginseng on Cancer: Potential Role in Modulating Inflammation-Mediated Angiogenesis.
Am J Chin Med. 2017; 45(1):13-22 [PubMed] Related Publications
Angiogenesis is a regulated process integral to many physiological and pathological situations, including carcinogenesis and tumor growth. The majority of the angiogenic processes are related to inflammation. The interplay is not only important in the case of pathogen entry but also influential in chronic inflammatory diseases, tumor growth and tissue regeneration. Modulating the interaction between inflammation and angiogenesis could be an important target for cancer treatment and wound healing alike. Ginseng has a wide range of pharmacological effects, including anti-inflammatory and angiogenesis-modulating activities. This paper presents the recent research progresses on the inhibition of angiogenesis by ginseng and its active constituents, with a particular focus on processes mediated by inflammation. The modulatory role of ginseng compounds in inflammation-mediated angiogenesis involving hypoxia and microRNAs are also discussed. With the potential to modulate the angiogenesis at the transcriptional, translational and protein signaling level via various different mechanisms, ginseng could prove to be effective in cancer therapeutics.

Stubbs C, Bardoli AD, Afshar M, et al.
A Study of Angiogenesis Markers in Patients with Renal Cell Carcinoma Undergoing Therapy with Sunitinib.
Anticancer Res. 2017; 37(1):253-259 [PubMed] Related Publications
BACKGROUND: Sunitinib is a tyrosine kinase inhibitor (TKI) targeting tumour angiogenesis in patients with advanced renal cell carcinoma (RCC). Currently no universally agreed model exists correlating the expression of angiogenesis markers with the success of treatment.
PATIENTS AND METHODS: We retrospectively analysed archival tissue for 59 RCC patients treated with sunitinib. The expression of angiogenesis markers VEGF-A, VEGFR, PDGFββ, PDGFR, CCND1 and CA9 was assessed by immunohistochemistry (IHC) and correlated with overall survival (OS) and progression-free survival (PFS).
RESULTS: The median OS and median PFS of the whole group of patients was 24.6 months (17.3-34.2) and 19.5 months (11-27) respectively. VEGFA was positive in 29% of tumors, whereas VEGFR was expressed in only 12% of tumours. PDGFββ and its receptor were detected in a minority of cases. CCND1 and CA9 were positive in 44% and 60% of cases.
CONCLUSION: The OS and PFS achieved by our patients reflected previous observations seen with sunitinib, but no correlation was found between expression of angiogenesis markers and clinical outcome.

Wang YL, Gong WG, Yuan QL
Effects of miR-27a upregulation on thyroid cancer cells migration, invasion, and angiogenesis.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Thyroid cancer is the most common type of endocrine tumor. MicroRNAs (miRNAs) play a critical role in a variety of diseases, especially cancer occurrence and progression. However, the specific mechanism by which miRNAs trigger disease states has not been fully elucidated. This study aims to investigate the role of miR-27a in thyroid cancer cells. A wound healing assay was adopted to examine cell migration. A transwell assay was applied to assess cell invasion. A thyroid cancer xenograft model was established using BALB/c nude mice. Western blot was performed to quantify iNOS expression. Tumor tissue blood vessel density was evaluated via immunohistochemistry assays. The results indicated that miR-27a downregulation inhibited thyroid cancer cell migration, while upregulation of miR-27a promoted thyroid cancer cell migration (P < 0.05). Furthermore, reduction in miR-27a expression suppressed thyroid cancer cell invasion (P < 0.05). In the nude mouse model of thyroid cancer xenograft, upregulation of miR-27 induced iNOS expression in pathological tumor tissues, whereas miR-27a inhibition resulted in the opposite effect (P < 0.05). CD105 level was also significantly increased during miR-27a upregulation, and was declined when miR-27a was inhibited (P < 0.05). In conclusion, miR-27a upregulation in thyroid cancer cells affects tumor cell migration, invasion, and angiogenesis by targeting downstream genes. Therefore, miR27a may act as a biomarker of thyroid cancer.

Yang T, Yao Q, Cao F, et al.
Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis.
Int J Nanomedicine. 2016; 11:6679-6692 [PubMed] Free Access to Full Article Related Publications
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is activated upon exposure to hypoxic stress. It modulates a number of cellular responses including proliferation, apoptosis, angiogenesis, and metabolism by activating a panel of target genes in response to hypoxia. The HIF-1 level is often upregulated in the hypoxic microenvironment of solid tumors, which contributes to cancer treatment failure. Here we report that silver nanoparticles (AgNPs), which are widely used as an antimicrobial agent, are an effective inhibitor of HIF-1. AgNPs inhibited the activation of a HIF-dependent reporter construct after the cells were exposed to hypoxic conditions or treated with cobalt chloride, a hypoxia mimetic agent. The AgNPs also interfered with the accumulation of HIF-1α protein and the induction of the endogenous HIF target genes, VEGF-A and GLUT1. Since both HIF-1 and vascular endothelial growth factor-A play an important role in angiogenesis, AgNPs also inhibited angiogenesis in vitro. Our data reveal a new mechanism of how AgNPs act on cellular function, that is, they disrupt HIF signaling pathway. This finding provides a novel insight into how AgNPs can inhibit cancer cell growth and angiogenesis.

Pietrzyk Ł
Biomarkers Discovery for Colorectal Cancer: A Review on Tumor Endothelial Markers as Perspective Candidates.
Dis Markers. 2016; 2016:4912405 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is the third most common cancer in the world. The early detection of CRC, during the promotion/progression stages, is an enormous challenge for a successful outcome and remains a fundamental problem in clinical approach. Despite the continuous advancement in diagnostic and therapeutic methods, there is a need for discovery of sensitive and specific, noninvasive biomarkers. Tumor endothelial markers (TEMs) are associated with tumor-specific angiogenesis and are potentially useful to discriminate between tumor and normal endothelium. The most promising TEMs for oncogenic signaling in CRC appeared to be the TEM1, TEM5, TEM7, and TEM8. Overexpression of TEMs especially TEM1, TEM7, and TEM8 in colorectal tumor tissue compared to healthy tissue suggests their role in tumor blood vessels formation. Thus TEMs appear to be perspective candidates for early detection, monitoring, and treatment of CRC patients. This review provides an update on recent data on tumor endothelial markers and their possible use as biomarkers for screening, diagnosis, and therapy of colorectal cancer patients.

Zhu L, Xue H, Sun H, et al.
Insulinoma Detection With MDCT: Is There a Role for Whole-Pancreas Perfusion?
AJR Am J Roentgenol. 2017; 208(2):306-314 [PubMed] Related Publications
OBJECTIVE: The purpose of this study is to investigate the role of whole-pancreas perfusion in detecting insulinomas with the use of MDCT.
MATERIALS AND METHODS: From January 2011 to December 2011, a total of 70 consecutive patients (33 men and 37 women; mean age, 46 years; range, 17-73 years) who underwent biphasic contrast-enhanced CT and whole-pancreas CT perfusion for suspected insulinomas were identified retrospectively. Patients were monitored for at least 3 years. Two radiologists who were blinded to the clinical and surgical data independently evaluated the images, first assessing only the biphasic contrast-enhanced CT images to detect tumor and assess diagnostic confidence on a 5-point scale. Next, perfusion parametric maps were evaluated and pancreatic perfusion parameters measured, and the presence of tumor was reidentified using a combination of the biphasic CT and perfusion image sets. A ROC curve was generated to compare the diagnostic accuracy of the two image sets.
RESULTS: The mean blood flow (BF) values of both the insulinomas and the insulinoma-harboring regions were statistically significantly higher (p < 0.01, for both) than the BF value of tumor-free pancreatic parenchyma. For the detection of insulinoma, biphasic CT had a sensitivity of 88.1%, a specificity of 85.7%, a positive predictive value of 91.1%, and a negative predictive value of 81.4%, whereas combined biphasic CT and perfusion had a sensitivity of 94.6%, a specificity of 94.7%, a positive predictive value of 96.7%, and a negative predictive value of 91.5%. The mean area under the ROC curve increased from 0.939 with biphasic CT to 0.999 with the addition of perfusion. Nine of 46 tumors (19.6%) for which findings were negative (n = 2) or indeterminate (n = 7) on biphasic CT were correctly diagnosed with the addition of perfusion.
CONCLUSION: The addition of pancreatic perfusion to biphasic contrast-enhanced CT may improve the detection of insulinomas.

Cui Y, Zhang C, Luo R, et al.
Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles.
Int J Nanomedicine. 2016; 11:5671-5682 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Arginine-glycine-aspartic acid (RGD)-based nanoprobes allow specific imaging of integrin αvβ3, a protein overexpressed during angiogenesis. Therefore, this study applied a novel RGD-coupled, polyacrylic acid (PAA)-coated ultrasmall superparamagnetic iron oxide (USPIO) (referred to as RGD-PAA-USPIO) in order to detect tumor angiogenesis and assess the early response to antiangiogenic treatment in human nasopharyngeal carcinoma (NPC) xenograft model by magnetic resonance imaging (MRI).
MATERIALS AND METHODS: The binding specificity of RGD-PAA-USPIO with human umbilical vein endothelial cells (HUVECs) was confirmed by Prussian blue staining and transmission electron microscopy in vitro. The tumor targeting of RGD-PAA-USPIO was evaluated in the NPC xenograft model. Later, mice bearing NPC underwent MRI at baseline and after 4 and 14 days of consecutive treatment with Endostar or phosphate-buffered saline (n=10 per group).
RESULTS: The specific uptake of the RGD-PAA-USPIO nanoparticles was mainly dependent on the interaction between RGD and integrin αvβ3 of HUVECs. The tumor targeting of RGD-PAA-USPIO was observed in the NPC xenograft model. Moreover, the T2 relaxation time of mice in the Endostar-treated group decreased significantly compared with those in the control group both on days 4 and 14, consistent with the immunofluorescence results of CD31 and CD61 (P<0.05).
CONCLUSION: This study demonstrated that the magnetic resonance molecular nanoprobes, RGD-PAA-USPIOs, allow noninvasive in vivo imaging of tumor angiogenesis and assessment of the early response to antiangiogenic treatment in NPC xenograft model, favoring its potential clinical translation.

Li G, Zheng J, Xu B, et al.
Simvastatin inhibits tumor angiogenesis in HER2-overexpressing human colorectal cancer.
Biomed Pharmacother. 2017; 85:418-424 [PubMed] Related Publications
Overexpression of the HER2 oncogene contributes to tumor angiogenesis, which is an essential hallmark of cancer. Simvastatin has been reported to exhibit antitumor activities in several cancers; however, its roles and molecular mechanismsin the regulation of colorectal angiogenesis remain to be clarified. Here, we show that colon cancer cells express high levels of VEGF, total HER2 and phosphorylated HER2, and simvastatin apparently decreased their expression in HER2-overexpressing colon cancer cells. Simvastatin pretreatment reduced endothelial tube formation in vitro and microvessel density in vivo. Furthermore, simvastatin markedly inhibited tumor angiogenesis even in the presence of heregulin (HRG)-β1 (a HER2 co-activator) pretreatment in HER2+ tumor cells. Mechanistic investigation showed that simvastatin significantly abrogated HER2-induced tumor angiogenesis by inhibiting VEGF secretion. Together, these results provide a novel mechanism underlying the simvastatin-induced inhibition of tumor angiogenesis through regulating HER2/VEGF axis.

Zhu D, Shen Z, Liu J, et al.
The ROS-mediated activation of STAT-3/VEGF signaling is involved in the 27-hydroxycholesterol-induced angiogenesis in human breast cancer cells.
Toxicol Lett. 2016; 264:79-86 [PubMed] Related Publications
Breast cancer (BC) is the leading cause of cancer-related mortality among females worldwide, and angiogenesis plays a crucial role in BC progression. 27-Hydroxycholesterol (27HC) is an endogenous selective estrogen receptor modulator, which promotes the growth and metastasis of BC. Here, we further found that, 27HC improved the angiogenic ability of BC in a VEGF-dependent manner. For the molecular mechanisms, on one hand, as an estrogen-like factor, 27HC enhanced the expression of VEGF by the classical ERα/VEGF signaling in ER-positive BC cells; on the other hand, in both ER-positive and ER-negative BC cells, 27HC enhanced the generation of ROS, which in turn activated the STAT-3/VEGF signaling in an ER independent manner. Either blocking the generation of ROS or knockdown of STAT-3 attenuated the 27HC-induced autocrine of VEGF and angiogenesis. These findings not only suggested a mechanism whereby 27HC enhanced the angiogenesis, but also helped to recognize the 27HC as a novel potential harmful factor in BC, especially in the menopause patients.

Yin Y, Jiang J
JOG Technique Versus Nonspiral Axial Scan in Pancreatic Perfusion Computed Tomography Imaging and Their Preliminary Application.
J Comput Assist Tomogr. 2016 Nov/Dec; 40(6):880-885 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to investigate the advantages and disadvantages of JOG technique in pancreatic perfusion computed tomography (CT) imaging.
METHODS: First, 40 male patients with nonpancreatic diseases, aged 40 to 60 years, were averagely assigned into 2 groups (A and B). Patients in group A and B underwent nonspiral axial perfusion and JOG technique CT scans of the pancreas, respectively. Second, 23 patients with pancreatic masses were randomly assigned into nonspiral axial scan and JOG groups.
RESULTS: There were no significant differences in all perfusion parameters among the pancreatic head, body, and tail within groups (P > 0.05). Perfusion and time to peak of the pancreatic head, body, and tail differed significantly between groups A and B (P < 0.05). There were significant differences in perfusion parameter values between pancreatic carcinoma tissue and normal pericarcinoma tissue in the nonspiral axial scan group. In the JOG group, perfusion and time to peak differed significantly (P < 0.05).
CONCLUSIONS: The JOG technique should be cautiously selected on pancreatic perfusion CT scans.

Okubo Y, Motohashi O, Nakayama N, et al.
The clinicopathological significance of angiogenesis in hindgut neuroendocrine tumors obtained via an endoscopic procedure.
Diagn Pathol. 2016; 11(1):128 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As the World Health Organization grading system for gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) may not always correlate with tumor progression, it is imperative that other independent predictors of tumor progression be established. To identify such predictors, we conducted a retrospective histopathological study of hindgut NETs, obtained from endoscopic procedures, and used statistical analyses to evaluate predictive factors.
METHODS: We first obtained clinicopathological data of cases of hindgut NETs. Tissue sections from tumor samples were prepared and subjected to pathological examination. In particular, we calculated the microvessel density (MVD) and lymphatic microvessel density (LMVD) values, and performed appropriate statistical analyses.
RESULTS: A total of 42 cases of hindgut NETs were selected for the study, 41 from the rectum and 1 from the sigmoid colon. Based on the Ki-67 labeling index, 34 cases were classified as NET G1 tumors and 8 as NET G2 tumors. MVD values ranged from 1.4/mm(2) to 73.9/mm(2) and LMVD values from 0/mm(2) to 22.9/mm(2). MVD and LMVD were identified as risk factors for venous and lymphatic invasion of hindgut NETs. Moreover, MVD positively correlated with the maximum diameter of the tumor.
CONCLUSIONS: Tumor progression of NETs may cause angiogenesis and lymphangiogenesis, via an unknown mechanism, as well as lymphovascular invasion. Angiogenesis likely plays an important role in occurrence and progression in the initial phase of hindgut NETs.

Guo Q, Yuan Y, Jin Z, et al.
Association between Tumor Vasculogenic Mimicry and the Poor Prognosis of Gastric Cancer in China: An Updated Systematic Review and Meta-Analysis.
Biomed Res Int. 2016; 2016:2408645 [PubMed] Free Access to Full Article Related Publications
Background. Vasculogenic mimicry can promote tumor growth and metastasis. This article is aimed at conducting a systematic meta-analysis to explore the clinicopathological and prognostic significance of vasculogenic mimicry and gastric cancer. Methods. We searched Pubmed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and the VIP and Wanfang Database for eligible studies. We manually searched for printed journals and relevant textbooks. Subgroups analyses were performed based on the region, manuscript quality, methods of vasculogenic mimicry identification, pathology, and number of patients. Results. Nine studies with 997 patients were included in this meta-analysis. A significant association was observed between vasculogenic mimicry-positive patients and those with gastric cancer with poor overall survival (hazard ratio = 2.24, 95% confidence interval: 1.45-3.47), poor pathological grading, high tumor node metastasis clinical stage, lymph node metastasis, deep tumor invasion, and distant metastasis. Conclusions. Vasculogenic mimicry is associated with a poor prognosis in patients with gastric cancer in China. Clinical studies with large samples are needed worldwide and standardized protocols should be adopted in the future to achieve a better understanding of the relationship between gastric cancer and vasculogenic mimicry.

Zhou Y, Jin G, Mi R, et al.
Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma.
J Cancer Res Clin Oncol. 2016; 142(12):2447-2459 [PubMed] Related Publications
PURPOSE: Fatty acids (FAs) are essential for membrane lipids biosynthesis and energy consumption in cancer cells. De novo FAs synthesis is catalyzed by fatty acid synthase (FASN), which is overexpressed and correlates with histological grade in glioma. Herein, we focused on the role of FASN in glioma neovascularization.
METHODS: The expression levels of FASN, Ki67 and CD34 were determined using immunohistochemistry (IHC). FASN specific-targeted shRNA and C75 were applied to evaluate the influence of FASN on glioma stem cell proliferation, migration and tube formation ability in vitro. An intracranial glioma model was established to study the effects of FASN on tumor growth and neovascularization in vivo.
RESULTS: IHC staining showed that the expression level of FASN correlated with tumor grade, Ki67 levels and microvessels density (MVD) in human gliomas. Inhibition of FASN using shRNAs or C75 decreased tumor growth, prolonged the overall survival of xenograft mice and decreased MVD in brain tumor sections. Moreover, inhibition of FASN blocked hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGF-A) signaling and upregulated the anti-angiogenic isoform-VEGF165b.
CONCLUSION: Our results suggest that FASN plays a pivotal role in glioma neovascularization, and inhibition of FASN may be a potential target for anti-angiogenic therapy for glioma.

Capozzi M, VON Arx C, DE Divitiis C, et al.
Antiangiogenic Therapy in Pancreatic Neuroendocrine Tumors.
Anticancer Res. 2016; 36(10):5025-5030 [PubMed] Related Publications
In recent years, many progresses have been pursued in the management of advanced pancreatic neuroendocrine tumor (pNET); most of them were prompted by increasing knowledge of biology of these neoplasms, including the identification of promising biological targets for therapy. PNETs belong to a group of rare neoplastic diseases. They originate from neuroendocrine system cells and are very heterogeneous regarding anatomic localization and aggressiveness. Recently, many efforts have been particularly focused on the identification of pathologic pathways and innovative drugs in order to treat patients with unresectable, metastatic disease, in progressive well-differentiated pNETs. Chemotherapy remains the mainstay of treatment of poorly-differentiated pNETs. The positive results obtained by sunitinib, a multi-targeted tyrosine kinase receptor inhibitor of vascular endothelial growth factor receptor (VEGFR) 1-3, platelet-derived growth factor receptor (PDGFR), c-kit, RET, colony stimulating factor-1 receptor (CSF-1R) and Fms-like tyrosine kinase 3 (FLT3), with direct antitumor and antiangiogenic effects, have highlighted the importance of tumor angiogenesis inhibition in controlling these tumors. Angiogenesis is a crucial process during tumor progression and plays a key role in development of metastasis. The role of angiogenesis in the malignant spread of pNET cells is finally supported by in vivo studies conducted on the RIP1-Tag2 mouse model. In this mini-review, we focus on the two pharmaceuticals that have given the most interesting results in clinical trials: bevacizumab and sunitinib. These drugs are changing the management of advanced pNETs.

El-Maadawy EA, Talaat RM, Sadek RF, et al.
Hepatitis C Virus Associations with Non Hodgkin's Lymphoma: Insights on In ammation/Angiogenesis and CD Markers.
Asian Pac J Cancer Prev. 2016; 17(9):4415-4420 [PubMed] Related Publications
We aimed to investigate any association between hepatitis C virus (HCV) infection and non-Hodgkin's lymphoma (NHL) in the view of cytokines that control in ammation/angiogenesis and their correlation with certain CD markers. NHL patients with or without HCV infection were studied. CD5, CD30, CD3, CD20 and CD45 were immunohistochemically evaluated. Plasma levels of vascular endothelial and platelet derived growth factors (VEGF, and PDGF), tumor necrosis factor (TNF-α), transforming growth factor (TGF-β), interleukin-6 (IL-6), IL-8, IL-4, IL-12 and interferon gamma (IFN-γ) were detected by enzyme-linked immunosorbent assay (ELISA). HCV+ve NHL patients showed a signi cant reduction in VEGF, PDGF, IFN-γ, CD5 and CD45 and a signi cant increase in IL-12 and IL-8. In conclusion, there was a signi cant change in cytokine secretion and expression of CD markers in HCV+ve NHL patients. Based on our results, HCV infection in NHL patients requires more in-depth investigations to explore any role in lymphoma progression.

Wirbisky SE, Weber GJ, Schlotman KE, et al.
Embryonic atrazine exposure alters zebrafish and human miRNAs associated with angiogenesis, cancer, and neurodevelopment.
Food Chem Toxicol. 2016; 98(Pt A):25-33 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
MicroRNAs (miRNAs) are short, single-stranded RNA that regulate post-transcriptional control of mRNA translation. Knowledge on the role of these critical regulators in toxicological responses in increasing, but is still limited. Atrazine is a herbicide used throughout the Midwestern US that is reported to frequently contaminate potable water supplies above the maximum contaminant level of 3 parts per billion. Atrazine is a suspected endocrine disrupting chemical and studies have begun to investigate the genetic mechanisms of toxicity; however, studies investigating epigenetic mechanisms are limited. In this study both zebrafish and human miRNAs were significantly altered in response to an embryonic atrazine exposure of 0.3, 3, or 30 ppb in zebrafish. Altered miRNAs are known to play a role in angiogenesis, cancer, or neuronal development, differentiation, and maturation. Targeted analysis of altered human miRNAs with genes previously identified to be altered by atrazine exposure revealed several targets linked to cell cycle and cell signaling. Further analysis of hsa-miRNA-126-3p, which had altered expression in all three atrazine treatments at 72 hpf, revealed alterations also occurred at 60 hpf in the 30 ppb treatment group. Results from this study indicate miRNA deregulation in zebrafish and human miRNAs following an embryonic atrazine exposure in zebrafish.

Shi L, Yang F, Luo F, et al.
Evodiamine exerts anti-tumor effects against hepatocellular carcinoma through inhibiting β-catenin-mediated angiogenesis.
Tumour Biol. 2016; 37(9):12791-12803 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly vascular tumor with high microvessel density and high levels of circulating vascular endothelial growth factor (VEGF). Thus, the angiogenesis pathway is an attractive therapeutic target for HCC. The anti-tumor effects of evodiamine, a quinolone alkaloid isolated from Euodia rutaecarpa (Juss.) Benth. (Rutaceae), were investigated in a mouse xenograft model using BALB/c nude mice, various HCC cell lines (HepG2, SMMC-7721, H22), and human umbilical vein endothelial cells (HUVECs). The effects of evodiamine on tumor volumes and weights, levels of tumor markers, angiogenesis in vivo and in vitro, cell viability, and cell migration and invasion were measured, and the mechanism through which its effects are achieved was investigated. Transcriptional regulation of VEGFa via interaction with β-catenin was established by luciferase activity assays and electrophoretic mobility shift assays. In a subcutaneous H22 xenograft model, evodiamine inhibited tumor growth and reduced serum tumor markers and the levels of β-catenin and VEGFa. It also blocked VEGF-induced angiogenesis in a Matrigel plug assay. Evodiamine suppressed cellular proliferation, invasion, and migration and inhibited tube formation of HUVECs. Moreover, in a concentration-dependent manner, evodiamine reduced the number of capillary sprouts from Matrigel-embedded rat thoracic aortic rings. Also, evodiamine suppressed various biomarkers of angiogenesis and the expression of β-catenin. Evodiamine decreased β-catenin levels activated by LiCl, which led to reduced expression of VEGFa. In addition, β-catenin interacted with VEGFa and transcriptionally regulated VEGFa, an effect inhibited by evodiamine in HCCs. Moreover, in an SMMC-7721 xenograft model, evodiamine suppressed tumor growth, various biomarkers of angiogenesis, and the levels of β-catenin and VEGFa. Evodiamine has anti-tumor effects on HCCs through inhibiting β-catenin, which interacts with and reduces VEGFa expression, thus inhibiting angiogenesis. These results indicate that evodiamine, which inhibits cellular invasion and migration and blocks angiogenesis, is a potential therapeutic agent for HCCs.

Fan F, Tian C, Tao L, et al.
Candesartan attenuates angiogenesis in hepatocellular carcinoma via downregulating AT1R/VEGF pathway.
Biomed Pharmacother. 2016; 83:704-711 [PubMed] Related Publications
Angiotensin II type 1 receptor (AT1R) was reported to express in many types of tumors, promoting tumor growth and angiogenesis. We herein examined AT1R expression in liver cancer and the potential antitumor effects of AT1R antagonist Candesartan in liver cancer. We found that AT1R expression was positively correlated with VEGF-A expression and microvascular density (MVD) in 40 HCC patients. Angiotensin II and Candesartan neither had effects on the proliferation of liver cancer cells in vitro. However, Angiotensin II upregulated AT1R protein expression and promoted production of VEGF-A in liver cancer cells in a dose-dependent manner. Candesartan was able to reverse this process in a dose-dependent manner. Moreover, Candesartan downregulated the expression of VEGF-A in SMMC-7721 bearing xenografts in mice and inhibited tumor growth and angiogenesis in vivo. Our data suggested that AT1R antagonist Candesartan might be useful to suppress liver cancer by inhibiting angiogenesis.

Li W, Miao S, Miao M, et al.
Hedgehog Signaling Activation in Hepatic Stellate Cells Promotes Angiogenesis and Vascular Mimicry in Hepatocellular Carcinoma.
Cancer Invest. 2016; 34(9):424-430 [PubMed] Related Publications
Previous studies have established that hedgehog (Hh) signaling mediates tumor-stroma interaction and promotes hepatocellular carcinoma progression. Here, we demonstrated that activation of Hh signaling in hepatic stellate cell (HSC) line LX-2 by Huh-7-derived sonic Hh led to increased secretion of angiogenic factors and promoted angiogenesis in vitro. The activated LX-2 also enhanced vascular mimicry of hepatoma cells. Furthermore, co-injection of Huh-7 and LX-2 significantly accelerated tumor growth with enhanced angiogenesis compared with Huh-7 alone, which could be partly abrogated by Hh signaling inhibitor. Collectively, our data showed that paracrine Hh signaling mediated pro-angiogenic function of HSC and enhanced hepatoma growth.

Yin H, Shao Y, Chen X
The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma.
Neurol Sci. 2017; 38(1):129-136 [PubMed] Related Publications
To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P < 0.05). Downregulated the expression of CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies.

Urbanowicz M, Kutzner H, Riveiro-Falkenbach E, Rodriguez-Peralto JL
Infectious Angiogenesis-Different Pathways, the Same Goal.
Am J Dermatopathol. 2016; 38(11):793-801 [PubMed] Related Publications
Infectious angiogenesis is the biological response of neoangiogenesis induced by infectious organisms. The authors present 3 exemplary entities which show paradigmatic clinico-pathological settings of infectious angiogenesis: Bacillary angiomatosis, Orf (ecthyma contagiosum), and Kaposi sarcoma. The authors review the literature and elucidate etiopathogenetic pathways leading to the phenomenon of neovascularization stimulated by infectious organisms. The authors describe the clinical and histological pictures, interactions between microorganisms and host cells, and changes that occur within cellular structures, as well as angiogenic factors that underpin infectious angiogenesis. The importance of chronic inflammation and tumor angiogenesis is emphasized.

Beppu T, Terasaki K, Sasaki T, et al.
MRI and 11C-methyl-L-methionine PET Differentiate Bevacizumab True Responders After Initiating Therapy for Recurrent Glioblastoma.
Clin Nucl Med. 2016; 41(11):852-857 [PubMed] Related Publications
PURPOSE: Normalization of tumor vasculature after administering bevacizumab (BEV) makes assessment of therapeutic response using MRI difficult. The aim of this study was to clarify whether PET with C-methyl-L-methionine (MET-PET) would supplement MRI assessing of response after initiating BEV in glioblastoma.
METHODS: Twenty patients with recurrent glioblastoma were treated with biweekly BEV plus temozolomide. Both MRI and MET-PET were performed before treatment (baseline) and at 4 and 8 weeks after starting treatment. Results on MRI (response or nonresponse) were compared with those on MET-PET, with response defined as a tumor-to-normal brain ratio of SUV (SUVT/N) of less than 1.6. Progression-free survival (PFS) was compared between responders and nonresponders on MRI alone and MET-PET alone. Progression-free survival was also compared between patients showing response on both MRI and MET-PET and patients showing response on MRI but nonresponse on MET-PET at each time point.
RESULTS: PFS was significantly longer in responders than nonresponders on both MRI at 4 and 8 weeks and MET-PET at 8 weeks, whereas MET-PET at 4 weeks provided no information regarding outcomes. Combined assessment with MRI and MET-PET at 4 weeks was not provide predictive of PFS, whereas patients showing response on both modalities (true responders) at 8 weeks exhibited significantly longer PFS than did patients showing response on MRI but nonresponse on MET-PET (pseudoresponders).
CONCLUSIONS: Combined assessment with MRI and MET-PET at 8 weeks can differentiate true responders who are predicted to show more favorable prognosis from pseudoresponders.

Van Der Gucht A, Pomoni A, Jreige M, et al.
68Ga-NODAGA-RGDyK PET/CT Imaging in Esophageal Cancer: First-in-Human Imaging.
Clin Nucl Med. 2016; 41(11):e491-e492 [PubMed] Related Publications
Ga-NODAGA-RGDyK(cyclic) and FDG PET/CT were performed in a 39-year-old man for the work-up of a moderately differentiated carcinoma of the gastro-esophageal junction within a clinical study protocol. Although FDG PET images showed intense, diffuse hypermetabolic lesion activity, NODAGA-RGDyK illustrated the neo-angiogenesis process with tracer uptake clearly localized in non-FDG-avid perilesional structures. Neo-angiogenesis is characterized by ανβ3 integrin expression at the lesion surface of newly formed vessels. This case supports evidence that angiogenesis imaging might therefore be a crucial step in early disease identification and localization, metastatization potential, and in monitoring the efficacy of antiangiogenic therapies.

Hercbergs A, Davis PJ, Lin HY, Mousa SA
Possible contributions of thyroid hormone replacement to specific behaviors of cancer.
Biomed Pharmacother. 2016; 84:655-659 [PubMed] Related Publications
l-Thyroxine (T4) is the principal replacement hormone for patients who have hypothyroidism. Some preclinical and clinical evidence supports the possibility that T4 can at least permissively affect certain features of established cancers and cancer-relevant angiogenesis. Thus, in the occasional patient with hypothyroidism and concomitant cancer, it appears reasonable to consider thyroid hormone replacement exclusively with 3,3',5-triiodo-l-thyronine (T3). This use of T3 has been shown to be effective and safe in early experience with medical induction of euthyroid hypothyroxinemia in patients with advanced solid tumors.

Choi SH, Lee JY, Suh JS, et al.
Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis.
Int J Nanomedicine. 2016; 11:4643-4656 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Angiogenesis plays a critical role in the growth and metastasis of cancer, and growth factors released from cancer promote blood-vessel formation in the tumor microenvironment. The angiogenesis is accelerated via interactions of growth factors with the high-affinity receptors on cancer cells. In particular, heparan sulfate proteoglycans (HSPGs) on the surface of cancer cells have been shown to be important in many aspects of determining a tumor's phenotype and development. Specifically, the regulation of the interactions between HSPGs and growth factors results in changes in tumor progression. A peptide with heparin-binding (HBP) activity has been developed and synthesized to inhibit tumor growth via the prevention of angiogenesis. We hypothesized that HBP could inhibit the interaction of growth factors and HSPGs on the surface of cancer cells, decrease paracrine signaling in endothelial cells (ECs), and finally decrease angiogenesis in the tumor microenvironment. In this study, we found that HBP had antiangiogenic effects in vitro and in vivo. The conditioned media obtained from a breast cancer cell line treated with HBP were used to culture human umbilical vein ECs (HUVECs) to evaluate the antiangiogenic effect of HBP on ECs. HBP effectively inhibited the migration, invasion, and tube formation of HUVECs in vitro. In addition, the expressions of angiogenesis-mediating factors, including ERK, FAK, and Akt, were considerably decreased. HBP also decreased the levels of invasive factors, including MMP2 and MMP9, secreted by the HUVECs. We demonstrated significant suppression of tumor growth in a breast cancer xenograft model and enhanced distribution of HBP at the site of tumors. Taken together, our results show that HBP has antiangiogenic effects on ECs, and suggest that it may serve as a potential antitumor agent through control of the tumor microenvironment.

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