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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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    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).

Liang W, Guo B, Ye J, et al.
Vasorin stimulates malignant progression and angiogenesis in glioma.
Cancer Sci. 2019; 110(8):2558-2572 [PubMed] Free Access to Full Article Related Publications
Glioma, the most common human primary brain tumor, is characterized by invasive capabilities and angiogenesis. Vasorin (VASN), a transmembrane protein, is reported to be associated with vascular injury repair and is overexpressed in some human tumors. However, its role in tumor progression and angiogenesis in glioma is unknown. In this study, VASN was shown to be overexpressed in high-grade gliomas, and the expression level correlated with tumor grade and microvessel density in glioma specimens. Glioma patients with high VASN expression had a shorter overall survival time. Knockdown of VASN in glioma cells by shRNA significantly inhibited the malignancy of glioma, including cell proliferation, colony formation, invasion, and sphere formation. Ectopic expression of VASN increased glioma progression in vitro. The expression of VASN correlated with the mesenchymal type of glioblastoma multiforme (GBM) subtyped by gene set enrichment analysis (GSEA). Our results showed that the concentration of VASN was increased in the conditioned medium (CM) from glioma cells with VASN overexpression, and the CM from glioma cells with knockdown or overexpressed VASN inhibited or promoted HUVEC migration and tubulogenesis in vitro, respectively. Glioma growth and angiogenesis were stimulated upon ectopic expression of VASN in vivo. The STAT3 and NOTCH pathways were found to be activated and inhibited by VASN overexpression. Our findings suggest that VASN stimulates tumor progression and angiogenesis in glioma, and, as such, represents a novel therapeutic target for glioma.

Matsuoka A, Mizumoto Y, Ono M, et al.
Novel strategy of ovarian cancer implantation: Pre-invasive growth of fibrin-anchored cells with neovascularization.
Cancer Sci. 2019; 110(8):2658-2666 [PubMed] Free Access to Full Article Related Publications
Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34-positive and vascular endothelial growth factor A (VEGF-A)-positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin-positive and α smooth muscle actin (αSMA)-positive cancer-associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net-anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF-targeted intraperitoneal anti-cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin-anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.

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

Nakamura Y, Miyata Y, Takehara K, et al.
The Pathological Significance and Prognostic Roles of Thrombospondin-1, and -2, and 4N1K-peptide in Bladder Cancer.
Anticancer Res. 2019; 39(5):2317-2324 [PubMed] Related Publications
BACKGROUND/AIM: Thrombospondins (TSPs) play a role as inhibitors of angiogenesis under various pathological conditions. The aim of the study was to evaluate the pathological significance and prognostic role of the 4N1K-peptide (KRFYVVMWKK), which is derived from TSP-1 and -2, in bladder cancer.
MATERIALS AND METHODS: Two-hundred and six bladder cancer tissues were examined for expression of TSP-1, TSP-2, and 4N1K-peptide by immunohistochemistry. Cancer cell proliferation, apoptosis, angiogenesis and matrix metalloproteinase (MMP)-9 immunoreactivity were also examined.
RESULTS: Expression of TSP-2 and 4N1K-peptide was negatively associated with T stage, metastasis, and grade. TSP-2 expression was negatively associated with cancer cell proliferation and MMP-9 expression, whereas 4N1K-peptide was significantly associated with apoptosis, angiogenesis, and MMP-9 expression. Multivariate analysis showed that 4N1K-peptide expression was a significant predictor of metastasis (hazard ratio=3.90, p=0.002).
CONCLUSION: TSP-2 and 4N1K peptide played important roles in malignant aggressiveness and progression of bladder cancer via complex mechanisms involving cell proliferation, apoptosis, angiogenesis, and MMP-9.

Atiya HI, Dvorkin-Gheva A, Hassell J, et al.
Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis.
Anticancer Res. 2019; 39(5):2277-2287 [PubMed] Related Publications
BACKGROUND: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application.
MATERIALS AND METHODS: Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified.
RESULTS: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells.
CONCLUSION: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development.

Wang R, Lou X, Feng G, et al.
IL-17A-stimulated endothelial fatty acid β-oxidation promotes tumor angiogenesis.
Life Sci. 2019; 229:46-56 [PubMed] Related Publications
AIMS: Tumor growth is an angiogenesis-dependent process that requires sustained new vessel growth. Interleukin-17 (IL-17A) is a key cytokine that modulates tumor progression. However, whether IL-17A affects the metabolism of endothelial cells is unknown.
MAIN METHODS: A xenograft model was established by implanting H460 (human lung cancer cell line) cells transfected with IL-17A-expressing or control vector. The effects of IL-17A on sprouting and tube formation of human umbilical vein endothelial cells (HUVECs) were measured. After treatment with IL-17A, the proliferation and migration of HUVECs were examined. Liquid chromatography-mass spectrometry (LC-MS) and Seahorse were used to detect the effects of IL-17A on mitochondrial respiration and fatty acid β-oxidation (FAO) in HUVECs. Western blotting was used to examine signaling pathways.
KEY FINDINGS: Herein, we found that IL-17A promoted H460 tumor growth and angiogenesis in vivo and in vitro. Moreover, IL-17A stimulated angiogenesis by enhancing FAO, increasing mitochondrial respiration of endothelial cells. The AMP-activated protein kinase (AMPK) signaling pathway was activated to promote FAO. Finally, IL-17A-induced angiogenesis was blocked when FAO was inhibited using etomoxir.
SIGNIFICANCE: In summary, these results indicate that IL-17A stimulates angiogenesis by promoting FAO. Thus, our study might provide a new therapeutic target for angiogenic vascular disorders.

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

Ma H, Qiu P, Xu H, et al.
The Inhibitory Effect of Propylene Glycol Alginate Sodium Sulfate on Fibroblast Growth Factor 2-Mediated Angiogenesis and Invasion in Murine Melanoma B16-F10 Cells In Vitro.
Mar Drugs. 2019; 17(5) [PubMed] Free Access to Full Article Related Publications
Melanoma is one of the most malignant and aggressive types of cancer worldwide. Fibroblast growth factor 2 (FGF2) is one of the critical regulators of melanoma angiogenesis and metastasis; thus, it might be an effective anti-cancer strategy to explore FGF2-targeting drug candidates from existing drugs. In this study, we evaluate the effect of the marine drug propylene glycol alginate sodium sulfate (PSS) on FGF2-mediated angiogenesis and invasion. The data shows that FGF2 selectively bound to PSS with high affinity. PSS inhibited FGF2-mediated angiogenesis in a rat aortic ring model and suppressed FGF2-mediated invasion, but not the migration of murine melanoma B16-F10 cells. The further mechanism study indicates that PSS decreased the expression of activated matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and also suppressed their activity. In addition, PSS was found to decrease the level of Vimentin in B16-F10 cells, which is known to participate in the epithelial-mesenchymal transition. Notably, PSS did not elicit any changes in cancer cell viability. Based on the results above, we conclude that PSS might be a potential drug to regulate the tumor microenvironment in order to facilitate the recovery of melanoma patients.

Sammarco G, Varricchi G, Ferraro V, et al.
Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.

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

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

Hu Q, Liu F, Yan T, et al.
MicroRNA‑576‑3p inhibits the migration and proangiogenic abilities of hypoxia‑treated glioma cells through hypoxia‑inducible factor‑1α.
Int J Mol Med. 2019; 43(6):2387-2397 [PubMed] Free Access to Full Article Related Publications
The most common and aggressive type of brain cancer in adults is glioblastoma multiforme (GBM), and hypoxia is a common feature of glioblastoma. As the histological features of glioma include capillary endothelial cell proliferation, they are highly prone to invading the surrounding normal brain tissue, which is often one of the reasons for the failure of treatment. However, the mechanisms involved in this process are not fully understood. MicroRNAs (miRs) are a class of non‑coding RNA that are able to inhibit the malignant progression of tumor cells through the regulation of downstream genes. In the present study, the low expression of miR‑576‑3p was detected in glioma samples and hypoxia‑treated glioma cells using a reverse transcription‑quantitative polymerase chain reaction. The present study focused on the effects of miR‑576‑3p on hypoxia‑induced glioma. The results of the functional experiments revealed that the overexpression of miR‑576‑3p significantly inhibited the migration and pro‑angiogenic abilities of the glioma cells under hypoxic conditions (P<0.05) compared with in the lentivirus‑miR‑negative control group. Furthermore, luciferase reporter gene assays were used to validate the hypothesis that miR‑576‑3p interacts with the 3'‑untranslated region of hypoxia‑inducible factor‑1α (HIF‑1α) and induces a reduction in the protein levels of matrix metalloproteinase‑2 and vascular endothelial growth factor. Rescue experiments demonstrated that the restoration of HIF‑1α expression attenuated the effect of miR‑576‑3p on the migration and proangiogenic abilities of glioma cells. In conclusion, the present study confirms that miR‑576‑3p is a novel GBM inhibitor and its inhibition of the migration and proangiogenic capacity of hypoxia‑induced glioma cells is mediated by HIF‑1α.

Adachi Y, Matsuki M, Watanabe H, et al.
Antitumor and Antiangiogenic Activities of Lenvatinib in Mouse Xenograft Models of Vascular Endothelial Growth Factor-Induced Hypervascular Human Hepatocellular Carcinoma.
Cancer Invest. 2019; 37(4-5):185-198 [PubMed] Related Publications
High expression of vascular endothelial growth factor (VEGF) in patients with hepatocellular carcinoma (HCC) is associated with poor prognosis. Here, we investigated the antitumor activity of lenvatinib, a multiple receptor tyrosine kinase inhibitor, in VEGF-overexpressing HCC models. In human umbilical vein endothelial cells, lenvatinib showed potent inhibitory activities against VEGF-induced proliferation and VEGF/basic fibroblast growth factor-induced tube formation. In VEGF-overexpressing HCC xenograft models, characterized by aggressive tumor growth and hypervascularity, lenvatinib had significant antitumor and antiangiogenic activities. These results suggest that potent activity of lenvatinib against VEGF signaling underlies its antitumor and antiangiogenic activities in the hypervascular HCC models.

Yuan SJ, Qiao TK, Qiang JW, Cai SQ
Dynamic contrast enhanced‑magnetic resonance imaging for the early evaluation of the response to docetaxel in rats with epithelial ovarian cancer.
Oncol Rep. 2019; 41(6):3335-3346 [PubMed] Related Publications
Dynamic contrast enhanced‑magnetic resonance imaging (DCE‑MRI) contributes to the early detection and prediction of responses to chemotherapy in cancer. The aim of the present study was to investigate the feasibility of quantitative DCE‑MRI parameters for noninvasively predicting the early response to DTX in epithelial ovarian cancer (EOC). In the present study, using 7,12‑dimethylbenz (A) anthracene, orthotopic EOC was induced in Sprague Dawley rats. Rats with EOC were treated with docetaxel (DTX) on day 0. DCE‑MRI was applied on days 0, 3, 7, 14 and 21. On day 21, the treated tumor types were categorized into sensitive and insensitive groups according to their change in size. Quantitative DCE‑MRI parameters were used to assess the early response to therapy. The experiment was performed again, the treatment group was divided into sensitive and insensitive groups according to their initially obtained cut-off values, and histopathological analyses were performed. Comparing the sensitive group with the insensitive group, there were significant differences in the percentage change in the volume transfer constant (Ktrans), rate constant (kep) and initial area under the curve (IAUC) from day 3 and tumor size from day 14. During the early stages of treatment (on day 3), the percentage change of Ktrans combined with kep produced an AUC of 1, and a sensitivity and specificity of 100 and 100%, respectively, using a cut-off value of a 17.59% reduction in Ktrans and kep. From day 7, there were significant differences in the quantitative index percentage change in angiogenesis in the sensitive group compared with the insensitive group. The percentage change in Ktrans, kep and IAUC were positively correlated with the percentage of change in tumor size and angiogenesis, and negatively correlated with the percentage of change in necrosis. The results of the present study indicated that quantitative DCE‑MRI parameters were superior to imaging tumor size for the early detection and prediction of the response to DTX chemotherapy in EOC.

Imafuji H, Matsuo Y, Ueda G, et al.
Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL‑8 production in pancreatic cancer.
Oncol Rep. 2019; 41(6):3508-3516 [PubMed] Related Publications
Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem‑R). To elucidate the mechanism of Gem‑R, two Gem‑R PaCa cell lines were established from AsPC‑1 and MIA PaCa‑2 cells. It was demonstrated that expression of interleukin‑8 (IL‑8) mRNA was significantly upregulated in Gem‑R PaCa cells by cDNA microarray and RT‑qPCR analyses. Increased IL‑8 secretion by Gem‑R cells was confirmed by cytokine array and enzyme‑linked immunosorbent assay. Moreover, we found that co‑culture with Gem‑R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti‑CXCR2 (main receptor for IL‑8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL‑8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem‑R increased IL‑8 production and consequently increased tumor angiogenesis, the IL‑8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem‑R.

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

Bonanno L, Zulato E, Pavan A, et al.
LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Liver kinase B1 (

Tang E, Wang Y, Liu T, Yan B
Gastrin promotes angiogenesis by activating HIF-1α/β-catenin/VEGF signaling in gastric cancer.
Gene. 2019; 704:42-48 [PubMed] Related Publications
Angiogenesis is recognized as a sign of cancer and facilitates cancer progression and metastasis. Suppression of angiogenesis is a desirable strategy for gastric cancer (GC) management. In this study, we showed a novel role of gastrin in angiogenesis of GC. We observed that treatment with gastrin 17 (G17) increased the proliferation of AGS cells and enhanced tube formation during normoxia and hypoxia. The expression level of VEGF were increased by G17 treatment as well. Experiments on the mechanism showed that G17 promoted HIF-1α expression, which subsequently enhanced β-catenin nuclear localization and activation of TCF3 and LEF1 and finally resulted in angiogenesis by upregulating VEGF. An in vivo experiment confirmed that G17 enhanced GC cell proliferation and angiogenesis in the resultant tumor. In conclusion, our findings indicate that gastrin promotes angiogenesis via activating HIF-1α/β-catenin/VEGF axis in GC.

Cioca A, Muntean D, Bungardean C
CD105 as a tool for assessing microvessel density in renal cell carcinoma.
Indian J Pathol Microbiol. 2019 Apr-Jun; 62(2):239-243 [PubMed] Related Publications
Background: Angiogenesis plays an essential role in both tumor growth and metastasis. CD105 expression was correlated with prognosis in many tumors, but its value in renal cell carcinoma (RCC) is still questionable.
Materials and Methods: The aim of this study was to evaluate microvessel density (MVD) by using CD105 marker, in 95 cases of renal cell carcinoma.
Results: CD105 showed positivity in 93 cases. The mean MVD value was significantly higher in clear cell carcinoma compared to papillary and chromophobe subtypes (P = 0.000). We noticed a significant correlation between MVD and ISUP grade (P = 0.007). The highest MVD value was observed in tumors with ISUP grade 1 and 2, while the lowest MVD value was noted in ISUP grade 3 tumors. A high vessel density was identified in tumors with a low Fuhrman grade, compared to those with a high grade (P = 0.010). MVD value was lower in tumors with a larger diameter, compared to small ones (P = 0.026).
Conclusion: In conclusion, CD105 expression (MVD) is inversely related to tumor aggressiveness in clear cell RCC and can be used as a favorable prognosis marker. The vascularity differences between histological subtypes of RCCs could be useful for a better selection of patients that may benefit from anti-angiogenic therapies.

Ouh YT, Cho HW, Lee JK, et al.
CXC chemokine ligand 1 mediates adiponectin-induced angiogenesis in ovarian cancer.
Tumour Biol. 2019; 42(4):1010428319842699 [PubMed] Related Publications
OBJECTIVES: Adiponectin is a cytokine secreted from adipose tissue that regulates energy homeostasis, inflammation, and cell proliferation. Obesity is associated with increased risk of various cancers, including ovarian cancer. Adipokines, including adiponectin, have been implicated as a factor linking obesity and carcinogenesis. The oncogenic role of adiponectin is not known with regard to various cancer types. We sought to determine the role of adiponectin in angiogenesis in ovarian cancer in vitro.
METHODS: We transfected SKOV3 cells with vascular endothelial growth factor small interfering RNA in order to identify the independent angiogenic role of adiponectin in ovarian cancer. The vascular endothelial growth factor knockdown SKOV3 cell lines were treated with adiponectin for 48 h. The cytokines involved in adiponectin-mediated angiogenesis were explored using the human angiogenesis cytokine array and were verified with the enzyme-linked immunosorbent assay. The angiogenic effect of adiponectin was evaluated using the human umbilical vein endothelial cell tube formation assay. We also investigated the effects of adiponectin treatment on the migration and invasion of SKOV3 cells.
RESULTS: The number of tubes formed by human umbilical vein endothelial cell decreased significantly after knockdown of vascular endothelial growth factor (via transfection of vascular endothelial growth factor small interfering RNA into SKOV3 cells). When these vascular endothelial growth factor knockdown SKOV3 cells were treated with adiponectin, there was an increase in the number of tubes in a tube formation assay. Following adiponectin treatment, the CXC chemokine ligand 1 secretion increased in a cytokine array. This was confirmed by both enzyme-linked immunosorbent assay and Western blot. The increased secretion of CXC chemokine ligand 1 by adiponectin occurred regardless of vascular endothelial growth factor knockdown. In addition, the induction of migration and invasion of SKOV3 cells were significantly stronger with adiponectin treatment than they were without.
CONCLUSION: Adiponectin treatment of ovarian cancer cells induces angiogenesis via CXC chemokine ligand 1 independently of vascular endothelial growth factor. These findings suggest that adiponectin may serve as a novel therapeutic target for ovarian cancer.

Redondo M, Abitei C, Téllez T, et al.
Clinical-pathological characteristics and short-term follow-up associated with proliferation, apoptosis and angiogenesis in a prospective cohort of patients with colorectal tumours.
Tumour Biol. 2019; 42(4):1010428319835684 [PubMed] Related Publications
We investigate the clinical and pathological features related to variations in colorectal tumour apoptosis, proliferation and angiogenesis and the influence of the latter in short-term mortality (2 years); 551 tumour samples from a prospective cohort of patients with colorectal cancer were examined and tumour biology markers were determined as follows: percentage of apoptotic cells, by the terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling technique; Ki-67 antigen, as a cell proliferation marker and density of microvessels (as a marker of angiogenesis). An increase in the percentage of cellular apoptosis is significantly related to the presence of poorly differentiated tumours, with vascular invasion (p < 0.001). The CD105 angiogenesis marker is not related to any clinical-pathological parameter except that of higher frequency in older patients (p = 0.03). Ki-67 is more frequently expressed in tumours with less nervous invasion (p = 0.05). Neither apoptosis nor angiogenesis present any significant association with short-term survival. The only marker clearly related to 2-year survival is Ki-67, which is shown to be a good prognostic factor in the multivariate analysis (hazard ratio = 0.49; 95% confidence interval = 0.27-0.90). Therefore, in a prospective cohort of colorectal cancer patients, only Ki-67 is a marker of good prognosis in short-term follow-up.

Alsultan AA, Barentsz MW, Smits MLJ, et al.
Angiogenesis in
Semin Nucl Med. 2019; 49(3):204-210 [PubMed] Related Publications
In order to evaluate the role of angiogenesis in

Xie C, Ji N, Tang Z, et al.
The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers.
Mol Cancer. 2019; 18(1):83 [PubMed] Free Access to Full Article Related Publications
The proliferation and metastasis ability of tumors are mediate by the "mutual dialogue" between cells in the tumor microenvironment (TME). Extracellular vesicles (EVs), mainly exosomes and microvesicles, play an important role in achieving intercellular substance transport and information transfer in the TME. Initially considered "garbage dumpsters" and later referred to as "signal boxes", EVs carry "cargo" (proteins, lipids, or nucleic acids) that can redirect the function of a recipient cell. Currently, the molecular mechanisms and clinical applications of EVs in head and neck cancers (HNCs) are still at an early stage and need to be further investigate. In this review, we provide insight into the TME of HNCs, classifying and summarizing EVs derived from different cell types and illuminating their complex signaling networks involved in mediating tumor proliferation, invasion and metastasis, vascular angiogenesis and cancer drug resistance. In addition, we highlight the application of EVs in HNCs, underlining the special pathological and physiological environment of HNCs. The application of tumor heterogeneous EVs in saliva and circulating blood diagnostics will provide a new perspective for the early screening, real-time monitoring and prognostic risk assessment of HNCs. Given the concept of precise and individual therapy, nanostructured EVs are equipped with superior characteristics of biocompatibility, low immunogenicity, loadability and modification ability, making these molecules one of the new strategies for HNCs treatment.

Shi Y, Song Y, Liu P, Li P
YKL-40 can promote angiogenesis in sporadic cerebral cavernous malformation (CCM).
J Clin Neurosci. 2019; 64:220-226 [PubMed] Related Publications
The factors affecting the formation of sporadic CCMs remain unclear. A cDNA microarray was used to identify characteristic gene expression patterns in sporadic CCMs. Transcription level of YKL-40 was confirmed by reverse transcription-polymerase chain reaction (RT-PCR). The location and expression were revealed by immunochemistry, immunofluorescence staining and level of YKL-40 was quantified by Western blotting. Alterations to endothelial function following the up or down regulation of gene expression was assessed by Transwell assays, cell counting kit-8 assays and capillary-like tube formation assays in human brain microvascular endothelial cells (HBMECs) in vitro. We generated a murine model by stereotaxically injecting HBMECs with expressing amounts of YKL-40 into the brain. cDNA microarray and RT-PCR results revealed that the transcription level of YKL-40 was ≥140-fold higher in sporadic CCMs in healthy controls. Histological staining revealed excessive YKL-40 expression in the CCM endothelium. Western blotting results analysis showed that YKL-40 protein expression was significantly higher in CCM endothelium (P < 0.05). YKL-40 over-expressing HBMECs showed increased cell proliferation, migration and tube formation ability compared with the control group, whereas downregulating of YKL-40 inhibited the proliferation, migration of HBMECs and capillary-like tube formation (P < 0.05). In animals, increased of YKL-40 was associated with abnormal vascular lesions that were similar to CCMs. YKL-40 is over-expressed in the CCM endothelium and acts as an angiogenic factor that promotes the pathogenesis of sporadic CCMs. YKL-40 may therefore represent a potential therapeutic target in the treatment of sporadic CCM.

Chi J, Jiang Z, Qiao J, et al.
Synthesis and anti-metastasis activities of norcantharidin-conjugated carboxymethyl chitosan as a novel drug delivery system.
Carbohydr Polym. 2019; 214:80-89 [PubMed] Related Publications
Carboxymethyl chitosan (CMCS), a water-soluble derivative of chitosan possessing numerous enhanced physicochemical and biological properties, has emerged as a promising biopolymer carrier for new drug delivery. Norcantharidin (NCTD) is an effective anti-tumor compound with severe nephrotoxicity. In this study, norcantharidin-conjugated carboxymethyl chitosan (CMCS-NCTD) was synthesized to reduce systemic toxicity and improve anti-tumor efficiency of NCTD. Our results demonstrated that CMCS-NCTD could significantly inhibit migration of tumor cells both in vitro and in vivo in a dose-dependent manner (P < 0.05). The enhanced anti-tumor effects of CMCS-NCTD were confirmed by inhibiting the growth of solid tumors and extending survival time of tumor-bearing mice. Further investigation for the underlying mechanisms indicated that CMCS-NCTD could inhibit tumor angiogenesis and reduce degradation of extracellular matrix by regulating the expressions of VEGF, MMP-9 and TIMP-1. Overall, our findings suggested that CMCS-NCTD was an excellent polymer derivative for cancer treatment, and CMCS was a promising platform for efficient delivery of anti-cancer drugs.

Wang C, Xu S, Tian Y, et al.
Lysyl Oxidase-Like Protein 2 Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer.
Neoplasia. 2019; 21(4):413-427 [PubMed] Free Access to Full Article Related Publications
Tumor lymphangiogenesis has been previously documented to predict regional lymph node metastasis and promote the spread to distant organs. However, the underlying mechanism initiating tumor lymphangiogenesis remains unclear. Here we described a novel role of tumor cell-derived Lysyl Oxidase-like protein 2 (LOXL2) in promoting lymphangiogenesis and lymph node metastasis in breast cancer. Immunohistochemistry (IHC) analysis of samples from breast cancer patients showed that the expression of LOXL2 was positively correlated with lymphatic vessel density and breast cancer malignancy. In animal studies, LOXL2-overexpressing breast cancer cells significantly increased lymphangiogenesis and lymph node metastasis, whereas knockdown of LOXL2 suppressed both processes. In order to study the mechanisms of lymphangiogenesis progression, we performed further in vitro investigations and the data revealed that LOXL2 significantly enhanced lymphatic endothelial cells (LECs) invasion and tube formation through directly activation of the Akt-Snail and Erk pathways. Moreover, LOXL2 also stimulated fibroblasts to secrete high level of pro- lymphangiogenic factors VEGF-C and SDF-1α. Taken together, our study elucidates a novel function of tumor cell secreted LOXL2 in lymphangiogenesis and lymph node metastasis, demonstrating that LOXL2 serves as a promising target for anti-lymphangiogenesis and anti-metastasis therapies for breast cancer.

Hassanien OA, Abouelkheir RT, Abou El-Ghar MI, et al.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Diagnostic Tool in the Assessment of Tumour Angiogenesis in Urinary Bladder Cancer.
Can Assoc Radiol J. 2019; 70(3):254-263 [PubMed] Related Publications
PURPOSE: The aim of study is to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and correlation with tumour angiogenesis in evaluation of urinary bladder cancer.
MATERIAL AND METHODS: The study included 81 patients with recent presumed diagnosis of bladder tumour or who came for follow up after management of histopathologically proven bladder cancer. All had DCE-MRI with time-signal intensity curve. The radiologic results then correlated with the histopathologic results using both haematoxylin and eosin stain and immuno-histochemical staining for localization and evaluation of CD34 immunoreactivity as a detector for the microvessel density (MVD) and tumour angiogenesis.
RESULTS: Seventy-one cases were pathologically proven to be malignant: 41 cases (58%) showed type III time-signal intensity curve (descending); 22 cases (31%) showed type II (plateau); and 8 cases (11%) showed type I (ascending) curve. The sensitivity of DCE-MRI in stage T1 bladder tumour was 80%; in stage T2, it was (90.9%); and in stage T3, it was (96.9%). Overall accuracy of DCE-MRI in tumour staging was 89.5% and P = .001 (significant). Values more than the cutoff value = 76.13 MVD are cystitis with sensitivity (90%), specificity (91%), and P value is .001, which is statistically highly significant.
CONCLUSION: There is a strong positive association between DCE-MRI (staging and washout slope of the time-signal intensity curve) with histopathologic grade, tumour stage, and MVD in bladder cancer. So, DCE-MRI can be used as reliable technique in preoperative predictions of tumour behavior and affect the planning of antiangiogenetic therapy.

Li YJ, Qing X, Tao QX, et al.
Vasculogenic Mimicry Formation Is Associated with Erythropoietin Expression but Not with Erythropoietin Receptor Expression in Cervical Squamous Cell Carcinoma.
Biomed Res Int. 2019; 2019:1934195 [PubMed] Free Access to Full Article Related Publications
Background: Vasculogenic mimicry (VM), as an endothelium-independent cancer microcirculation, has been observed in many malignancies including cervical cancer. Erythropoietin (EPO) and erythropoietin receptor (EPO-R) could produce an angiogenic effect to promote cervical squamous cell carcinoma (CSCC) progression. However, the association between VM formation and EPO/EPO-R expression in CSCC is poorly explored.
Methods: Seventy-six paraffin-embedded CSCC samples, 25 high-grade squamous intraepithelial lesion (HSIL) samples, 20 low-grade squamous intraepithelial lesion (LSIL) samples, and 20 normal cervix samples were collected. Immunohistochemistry SP method was performed to detect EPO/EPO-R expression and CD31/periodic acid-Schiff (PAS) double staining was performed to detect VM formation. The associations of EPO/EPO-R and VM with clinicopathological parameters of CSCC were analyzed. The associations between VM formation and EPO/EPO-R expression were also analyzed.
Results: The positive expression rates of EPO and EPO-R were gradually increasing along the progression of normal cervix-LSIL-HSIL-CSCC sequence (
Conclusion: These data suggest that increased EPO/EPO-R expression may play an important role in cervical carcinogenesis. EPO overexpression may promote VM formation in CSCC.

Keskin S, Kutluk AC, Tas F
Prognostic and Predictive Role of Angiogenic Markers in Non- Small Cell Lung Cancer
Asian Pac J Cancer Prev. 2019; 20(3):733-736 [PubMed] Related Publications
Objective: Despite the existence of detailed consensus guidelines, challenges remain regarding the role angiogenetic factors on non-small cell lung cancer (NSCLC). This study was conducted to determine the role of the vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and angiopoietin2 (Ang2) in patients with NSCLC. Methods: This study included 64 consecutive patients with non-small cell lung cancer, who admitted to clinic. Pre-treatment serum VEGF, IL-8 and Ang2 levels were evaluated. Patients were treated according to internationally accepted guidelines. Results: VEGF and IL-8 serum levels of patients with both squamous cell carcinoma and adenocarcinoma were significantly higher than controls (p<0.05). In addition, IL-8 levels were lower among treatment-responders than non-responders (p:0.031). Impact of elevated or decreased levels of VEGF, Ang2 and IL-8 on survival was evaluated, accepting median level as reference. There was no correlation between the serum levels of VEGF, Ang2, IL-8 and survival. Conclusion: We found that the levels of angiogenic markers were significantly different between non-small cell lung cancer patients and controls. These markers could elicit more information related to stage and prognosis.

Gervasio KA, Dalvin LA, Shields CL
Spontaneous Regression of Florid Retinal Neovascularization Following Resolution of Traction Retinal Detachment in an Eye With Treated Retinoblastoma.
J Pediatr Ophthalmol Strabismus. 2019; 56:e24-e27 [PubMed] Related Publications
A 19-month-old boy with unilateral retinoblastoma with iris and retinal neovascularization at initial presentation displayed traction retinal detachment, retinal non-perfusion, and persistent retinal neovascularization after completion of intra-arterial chemotherapy. Two months following resolution of traction retinal detachment, restoration of retinal perfusion and regression of neovascularization occurred without additional intervention. Spontaneous regression of retinal neovascularization is possible following resolution of traction retinal detachment. [J Pediatr Ophthalmol Strabismus. 2019;56:e24-e27.].

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