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We consider a simplified chemotaxis model of tumor angiogenesis, described by a Keller-Segel system on the two dimensional infinite cylindrical domain (x , y) ∈ R × S λ , where S λ is the circle of perimeter λ > 0. The domain models a virtual channel where newly generated blood vessels toward the vascular endothelial growth factor will be located. The system is known to allow planar traveling wave solutions of an invading type. In this paper, we establish the nonlinear stability of these traveling invading waves when chemical diffusion is present if λ is sufficiently small. The same result for the corresponding system in one-dimension was obtained by Li-Li-Wang (2014) [17]. Our result solves the problem remained open in Chae-Choi-Kang-Lee (2018) [3] at which only linear stability of the planar traveling waves was obtained under certain artificial assumption. [ABSTRACT FROM AUTHOR]

We consider a hyperbolic–parabolic system arising from a chemotaxis model in tumor angiogenesis, which is described by a Keller–Segel equation with singular sensitivity. It is known to allow viscous shocks (so-called traveling waves). We introduce a relative entropy of the system, which can capture how close a solution at a given time is to a given shock wave in almost L 2 -sense. When the shock strength is small enough, we show the functional is non-increasing in time for any large initial perturbation. The contraction property holds independently of the strength of the diffusion. [ABSTRACT FROM AUTHOR]

Generally, changes in the metabolic status of cells under conditions like hypoxia and accumulation of lactate can be sensed by various sensing mechanisms, leading to modulation of a number of signal transduction pathways and transcription factors. Several of the proangiogenic cytokines like VEGF, FGF, PDGF, TGF-β, Ang-2, ILs, etc. are secreted by cancer cells, under hypoxic microenvironment. These cytokines bind to their receptors on the endothelial cells and activates a number of signaling pathways including Akt/PIP3, Src, p38/MAPK, Smad2/3, etc., which ultimately results in the proliferation and migration of endothelial cells. Transcription factors that are activated in response to the metabolic status of tumors include HIFs, NF-κb, p53, El-2, and FOXO. Many of these transcription factors has been reported to be regulated by a class of histone deacetylase called sirtuins. Sirtuins are NAD+ dependent histone deacetylases that play pivotal role in the regulation of tumor cell metabolism, proliferation, migration and angiogenesis. The major function of sirtuins include, deacetylation of histones as well as some non-histone proteins like NF-κB, FOXOs, PPAR⋎, PGC1-α, enzymes like acetyl coenzymeA and structural proteins like α tubulin. In the cell, sirtuins are generally considered as the redox sensors and their activities are dependent on the metabolic status of the cell. Understanding the intricate regulatory mechanisms adopted by sirtuins, is crucial in devising effective therapeutic strategies against angiogenesis, metastasis and tumor progression. Keeping this in mind, the present review focuses on the role of sirtuins in the process of tumor angiogenesis and the regulatory mechanisms employed by them. [ABSTRACT FROM AUTHOR]

The purpose of this work is to obtain the regular perturbation solutions of a mathematical model for capillary formation in tumor angiogenesis. The model we study here was originally presented in [Levine HA, Sleeman BD and Nilsen-Hamilton M., 2000]. The regular perturbation method is a well-known and highly effective method to obtain the solutions of coupled non-linear differential equations. In fact, a few terms of the perturbation series obtained by this method are good enough to see the structure of the solutions of the model. These solutions govern the movement of the certain cells, namely endothelial, macrophage and pericyte cells, in the capillary which are necessary for the initiation of tumor angiogenesis. Our MATLAB-generated figures show that our numerical simulations are in good agreement with the biological facts about the tumor angiogenesis. Even though computing the terms of the regular perturbation series are kind of tedious, more stable and accurate solutions of the model can be obtained by adding new terms to the series. [ABSTRACT FROM AUTHOR]

San Huang Decoction (SHD), a Chinese herb formula, has been popularly prescribed in the clinical treatment of patients suffering from breast cancer. The aim of this study was to explore the anti-angiogenic effects of SHD in breast cancer and explain the underlying mechanism. Transwell and Matrigel assays showed that SHD reduced human umbilical vein endothelial cell migration and tubule formation and ELISA and qRT-PCR assays demonstrated its mediation of vascular endothelial growth factor (VEGF) expression. siRNA silencing of aurora kinase A (AURKA) produced results similar to those obtained by inhibition of AURKA with SHD. In addition, a chorioallantoic membrane assay was carried out to directly examine the effect of SHD on breast cancer anti-angiogenesis and immunofluorescence and immunohistochemical staining analysis showed that SHD reduced the expression of CD31, AURKA, and VEGF in a xenograft model. Furthermore, SHD regulated extracellular signal-regulated kinase expression in breast cancer cells, which was examined by western blotting. In conclusion, our findings indicated that SHD treatment mimicked the decrease in tumor neovascularization in breast cancer cells after the siRNA-mediated knockdown of AURKA. Thus, SHD may inhibit tumor angiogenesis in breast cancer by targeting AURKA and downregulating the ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Angiogenesis plays a crucial role in tumor growth and metastasis, and is heavily influenced by the tumor microenvironment (TME). Endothelial cell dysfunction is a key factor in tumor angiogenesis and is characterized by the aberrant expression of pro-angiogenic factors. Endothelial cell specific molecule-1 (ESM1), also known as endocan, is a marker of endothelial cell dysfunction. Although ESM1 is primarily expressed in normal endothelial cells, dysregulated ESM1 expression has been observed in human tumors and animal tumor models, and implicated in tumor growth, metastasis and angiogenesis. The precise role of ESM1 in tumor angiogenesis and its potential regulatory mechanisms are not yet conclusively defined. However, the aim of the present review was to explore the involvement of ESM1 in the process of tumor angiogenesis in the TME and the characteristics of neovascularization. In addition, the present review discusses the interaction between ESM1 and angiogenic factors, as well as the mechanisms through which ESM1 contributes to tumor angiogenesis. Furthermore, the reciprocal regulation between ESM1 and the TME is explored. Finally, the potential of targeting ESM1 as a therapeutic strategy for tumor angiogenesis is presented. [ABSTRACT FROM AUTHOR]

The focal adhesion protein, Hic-5 plays a key role in promoting extracellular matrix deposition and remodeling by cancer associated fibroblasts within the tumor stroma to promote breast tumor cell invasion. However, whether stromal matrix gene expression is regulated by Hic-5 is still unknown. Utilizing a constitutive Hic-5 knockout, Mouse Mammary Tumor Virus-Polyoma Middle T-Antigen spontaneous breast tumor mouse model, bulk RNAseq analysis was performed on cancer associated fibroblasts isolated from Hic-5 knockout mammary tumors. Functional network analysis highlighted a key role for Hic-5 in extracellular matrix organization, with both structural matrix genes, as well as matrix remodeling genes being differentially expressed in relation to Hic-5 expression. The subcellular distribution of the MRTF-A transcription factor and expression of a subset of MRTF-A responsive genes was also impacted by Hic-5 expression. Additionally, cytokine array analysis of conditioned media from the Hic-5 and Hic-5 knockout cancer associated fibroblasts revealed that Hic-5 is important for the secretion of several key factors that are associated with matrix remodeling, angiogenesis and immune evasion. Together, these data provide further evidence of a central role for Hic-5 expression in cancer associated fibroblasts in regulating the composition and organization of the tumor stroma microenvironment to promote breast tumor progression. [ABSTRACT FROM AUTHOR]

The tumor immune microenvironment (TIME) has largely been reported to cooperate on tumor onset and progression, as a consequence of the phenotype/functional plasticity and adaptation capabilities of tumor-infiltrating and tumor-associated immune cells. Immune cells within the tumor micro (tissue-local) and macro (peripheral blood) environment closely interact by cell-to-cell contact and/or via soluble factors, also generating a tumor-permissive soil. These dangerous liaisons have been investigated for pillars of tumor immunology, such as tumor associated macrophages and T cell subsets. Here, we reviewed and discussed the contribution of selected innate immunity effector cells, namely neutrophils and natural killer cells, as “soloists” or by their “dangerous liaisons”, in favoring tumor progression by dissecting the cellular and molecular mechanisms involved.

Tumor angiogenesis is enhanced in all types of tumors to supply oxygen and nutrients for their growth and metastasis. With the development of anti-angiogenic drugs, the importance of technology that closely monitors tumor angiogenesis has also been emerging. However, to date, the technology for observing blood vessels requires specialized skills with expensive equipment, thereby limiting its applicability only to the laboratory setting. Here, we used a preclinical optical imaging system for small animals and, for the first time, observed, in real time, the entire process of blood vessel development in tumor-bearing mice injected with indocyanine green. Time-lapse sequential imaging revealed blood vessel volume and blood flow dynamics on a microscopic scale. Upon analyzing fluorescence dynamics at each stage of tumor progression, vessel volume and blood flow were found to increase as the tumor developed. Conversely, these vascular parameters decreased when the mice were treated with angiogenesis inhibitors, which suggests that the effects of drugs targeting angiogenesis can be rapidly and easily screened. The results of this study may help evaluate the efficacy of angiogenesis-targeting drugs by facilitating the observation of tumor blood vessels easily in a laboratory unit without large and complex equipment.

Epstein-Barr virus (EBV) promotes tumor angiogenesis in nasopharyngeal carcinoma (NPC) by activating store-operated Ca2+ entry. Since such entry has been linked to stromal interaction molecule 1 (STIM1), we examined whether the virus acts via STIM1-dependent Ca2+ signaling to promote tumor angiogenesis in NPC. STIM1 expression was detected in NPC cell lines HK1 and CNE2 that were negative or positive for EBV. STIM1 was knocked down in EBV-positive cells using recombinant lentivirus, then cytosolic Ca2+ levels were measured based on fluorescence resonance energy transfer. Cells were also exposed to epidermal growth factor (EGF), and secretion of vascular endothelial growth factor (VEGF) was measured using an enzyme-linked immunosorbent assay. Endothelial tube formation was quantified in an in vitro angiogenesis assay. Growth of CNE2-EBV xenografts was measured in mice, and angiogenesis was assessed based on immunohistochemical staining against CD31. Paraffin-embedded NPC tissues from patients were assayed for CD31 and STIM1. EGFR and ERK signaling pathways were assessed in NPC cell lines. STIM1 expression was higher in EBV-positive than in EBV-negative NPC cell lines. STIM1 knockdown in EBV-positive NPC cells significantly reduced Ca2+ influx and VEGF production after EGF treatment. STIM1 knockdown also inhibited xenograft growth and angiogenesis. Moreover, CD31 expression level was higher in EBV-positive than EBV-negative NPC tissues, and high expression of CD31 co-localized with high expression of STIM1 in EBV-positive tissues from NPC patients. Viral infection of NPC cells led to higher levels of phosphorylated ERK1/2 after EGF treatment, which STIM1 knockdown partially reversed. Our results suggest that EBV promotes EGF-induced ERK1/2 signaling by activating STIM1-dependent Ca2+ signaling, and that blocking such signaling may inhibit EBV-promoted angiogenesis in NPC.

Tumor blood flow (TBF) is related to drug delivery and hypoxia, both of which can impact the efficacy of anti-cancer therapies. Although integrin αvβ3 expression is related to tumor angiogenesis, it remains unclear whether the degree of angiogenesis affects TBF. This study aimed to evaluate the expression of integrin αvβ3 in mouse tumor models using [68Ga]Ga-DOTA-c(RGDfK) peptide positron emission tomography (PET) and immunohistochemical staining. PET studies were conducted using mouse C6 glioma models and MIA PaCa-2 (n = 6 each). The [68Ga]Ga-DOTA-c(RGDfK) peptide was injected via the tail vein (2.17 ± 0.28 MBq), and 10 min static PET scans were performed. Immunohistochemical analysis was conducted using an integrin αVβ3 antibody. [68Ga]Ga-DOTA-c(RGDfK) peptide PET revealed higher uptake of the radiotracer in C6 gliomas than in MIA PaCa-2 tumors. The mean standardized uptake value was significantly higher in C6 gliomas (0.35 ± 0.058) than in MIA PaCa-2 tumors (0.17 ± 0.045). Histological analysis revealed intense integrin αVβ3 expression in the C6 gliomas, whereas the MIA PaCa-2 tumors had low expression levels. This study showed that the expression of integrin αvβ3 can be differentiated by the [68Ga]Ga-DOTA-c(RGDfK) peptide, suggesting the potential applicability of this peptide in the evaluation of the relationship between angiogenesis and TBF.

Y-box binding protein-1 (YB-1), involved in cancer progression and chemoradiation resistance, is overexpressed in not only cancer cells but also tumor blood vessels. In this study, we investigated the potential value of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB-1 ASOA) as an antiangiogenic cancer therapy. YB-1 ASOA was superior to natural DNA-based ASO or locked nucleic acid (LNA)-modified YB-1 ASO in both knockdown efficiency and safety, the latter assessed by liver function. YB-1 ASOA administered i.v. significantly inhibited YB-1 expression in CD31-positive angiogenic endothelial cells, but not in cancer cells, in the tumors. With regard to the mechanism of its antiangiogenic effects, YB-1 ASOA downregulated both Bcl-xL/VEGFR2 and Bcl-xL/Tie signal axes, which are key regulators of angiogenesis, and induced apoptosis in vascular endothelial cells. In the xenograft tumor model that had low sensitivity to anti-VEGF antibody, YB-1 ASOA significantly suppressed tumor growth; not only VEGFR2 but also Tie2 expression was decreased in tumor vessels. In conclusion, YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signal axes play pivotal roles in tumor angiogenesis, and YB-1 ASOA may be feasible as an antiangiogenic therapy for solid tumors.

Abstract Background Even though aberrant expression of microRNA (miR)-30d has been reported in prostate cancer (PCa), its associations with cancer progression remain contradictory. The aim of this study was to investigate clinical significance, biological functions and underlying mechanisms of miR-30d deregulation in PCa. Methods Involvement of miR-30d deregulation in malignant phenotypes of PCa was demonstrated by clinical sample evaluation, and in vitro and in vivo experiments. The mechanisms underlying its regulatory effect on tumor angiogenesis were determined. Results miR-30d over-expression was observed in both PCa cells and clinical specimens. High-miR-30d was distinctly associated with high pre-operative PSA and Gleason score, advanced clinical and pathological stages, positive metastasis and biochemical recurrence (BCR), and reduced overall survival of PCa patients. Through gain- and loss-of-function experiments, we found that miR-30d promoted PCa cell proliferation, migration, invasion, and capillary tube formation of endothelial cells, as well as in vivo tumor growth and angiogenesis in a mouse model. Simulation of myosin phosphatase targeting subunit 1 (MYPT1), acting as a direct target of miR-30d, antagonized the effects induced by miR-30d up-regulation in PCa cells. Notably, miR-30d/MYPT1 combination was identified as an independent factor to predict BCR of PCa patients. Furthermore, miR-30d exerted its pro-angiogenesis function, at least in part, by inhibiting MYPT1, which in turn, increased phosphorylation levels of c-JUN and activated VEGFA-induced signaling cascade in endothelial cells. Conclusions miR-30d and/or its target gene MYPT1 may serve as novel prognostic markers of PCa. miR-30d promotes tumor angiogenesis of PCa through MYPT1/c-JUN/VEGFA pathway.

How endothelial cells (ECs) survive in inflammatory environments remains unclear. We recently showed that TAK1 protects ECs against apoptosis induced by TNFα under physiological conditions in the intestine and liver, and under inflammatory conditions in other organs. Our results document that a single gene can affect cell fate decisions in mature ECs.

Malignant proliferation and abundant angiogenesis are major causes of lung adenocarcinoma (LUAD) with high morbidity and mortality. Therefore, the exploration of the key regulatory mechanisms of malignant proliferation and angiogenesis in LUAD provides an opportunity for the development of targeted precision therapy. In this study, we found that the high expression of ATPase family AAA domain-containing protein 3A (ATAD3A) in LUAD was positively associated with the poor survival of patients, while its high expression was positively associated with the angiogenesis of LUAD. Further knockdown of ATAD3A in LUAD significantly inhibited cell proliferation and suppressed expression of vascular endothelial growth factor A, FGF-2, ANG-1, and TGF-β. The opposite effect was observed with ATAD3A overexpression. Furthermore, ATAD3A knockdown significantly inhibited tumor growth and angiogenesis in an in vivo subcutaneous xenograft tumor model. Mechanistic studies suggest that ATAD3A may promote signal transducer and activator of transcription 3 activation, a key signal regulating lung cancer cell proliferation and transcriptional secretion of proangiogenic factors. Therefore, targeted inhibition of ATAD3A may be an effective strategy for LUAD therapy, and ATAD3A may be a potential biomarker for predicting malignant progression., (© 2023 Wiley Periodicals LLC.)

Background: Endostar, an anti-angiogenic drug, has been approved for treating non-small cell lung cancer (NSCLC). At present, endostar combined with radiotherapy or chemotherapy has achieved ideal results in the treatment of some tumors, but there is a lack of application and study in NSCLC. This study investigated the therapeutic effect and potential mechanism of endostar combined with cisplatin (EC) in NSCLC., Methods: HE staining, TUNEL staining, immunofluorescence, colony formation ability, and cell migration ability were used to evaluate the anti-tumor activity of EC. The expressions of FMOD, VEGF, FGF-2, and PDGF-B were detected by western blotting and qPCR. The target of combination therapy was analyzed by m6A sequencing and RNA sequencing. METTL3 knockdown and overexpressed A549 cells were constructed and co-cultured with HUVECs to further evaluate the effect of METLL3 on combination therapy., Results: Combination therapy significantly reduced the colony formation and migration ability of NSCLC cells, induced cell apoptosis, and inhibited the tube formation ability of HUVECs. The results of m6A sequencing and RNA sequencing showed that the EC could down-regulate the expression level of FMOD in tumor tissues, which might be related to the reduction of its m6A methylation modification regulatory enzyme METTL3. Restricting FMOD expression could reduce the expression of FGF2, TGF-β1, VEGF and PDGF-B. Moreover, overexpression of METTLE almost abolished the anti-tumor effect of EC and promoted angiogenesis., Conclusions: Endostar combined with cisplatin might exert anti-tumor effects by down-regulating the expression of METTL3 and FMOD., (© 2024. The Author(s).)

Background/aim: Individuals with Down syndrome (DS), attributed to triplication of human chromosome 21 (Hsa21), exhibit a reduced incidence of solid tumors. However, the prevalence of glioblastoma among individuals with DS remains a contentious issue in epidemiological studies. Therefore, this study examined the gliomagenicity in Ts1Cje mice, a murine model of DS., Materials and Methods: We employed the Sleeping Beauty transposon system for the integration of human oncogenes into cells of the subventricular zone of neonatal mice., Results: Notably, Sleeping Beauty-mediated de novo murine gliomagenesis was significantly suppressed in Ts1Cje mice compared to wild-type mice. In glioblastomas of Ts1je mice, we observed an augmented presence of M1-polarized tumor-associated macrophages and microglia, known for their anti-tumor efficacy in the early stage of tumor development., Conclusion: Our findings in a mouse model of DS offer novel perspectives on the diminished gliomagenicity observed in individuals with DS., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti-cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo-vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR-dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon-encapsulated PEGylated liposomes to tumor-bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objective: To evaluate the inhibitory effect of ginsenoside Rg3 combined with 5-fluorouracil (5-FU) on tumor angiogenesis and tumor growth in colon cancer in mice., Methods: CT26 mouse model of colon cancer was established and the mice were randomly assigned to the control group, the ginsenoside Rg3 group, the 5-FU group, and the Rg3 combined with 5-FU group. The 5-FU group was injected intraperitoneally at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 10 days. Treatment for the Rg3 group was given at the dose of 20 mg/kg, 0.2 mL/animal, and once a day for 21 days via gastric gavage. The dose and the mode of treatment for the Rg3+5-FU combination group were the same as those for the 5-FU and the Rg3 group. The control group was intraperitoneally injected with 0.2 mL/d of normal saline for 10 days. The expression of vascular endothelial growth factor (VEGF) and CD31 and the microvascular density (MVD) of the tumor tissues were examined by immunohistochemistry. The blood flow signals and tumor necrosis were examined by color Doppler flow imaging (CDFI). The quality of life, survival rate, tumor volume, tumor mass, and tumor inhibition rate of the mice were monitored., Results: After 21 days of treatment, the tumor volume and the tumor mass of all treatment groups were significantly decreased compared with those the control group, with the combination treatment group exhibiting the most significant decrease. The tumor inhibition rates of the Rg3 group, the 5-FU group, and the combination group were 29.96%, 68.78%, and 73.42%, respectively. Rg3 treatment alone had inhibitory effect on tumor growth to a certain degree, while 5-FU treatment alone or 5-FU combined with Rg3 had a stronger inhibitory effect on tumor growth. The tumor inhibition rate of the combination group was higher than that of the 5-FU group, but the difference was not statistically significant ( P >0.05). Color Doppler ultrasound showed that there were multiple localized and large tumor necrotic areas that were obvious and observable in the Rg3 group and the combination group, and that there were only small tumor necrotic areas in the 5-FU group and the control group. The tumor necrosis rate of the combination group was (55.63±3.12)%, which was significantly higher than those of the other groups ( P <0.05). CDFI examination of the blood flow inside of the tumor of the mice showed that the blood flow signals in the combination group were mostly grade 0-Ⅰ, and that the blood flow signals in the control group were the most abundant, being mostly grade Ⅱ-Ⅲ. The abundance of the blood flow signals in the Rg3 and 5-FU groups were between those of the control group and the combination group. Compared with those of the control group, the expression levels of MVD and VEGF in the tumor tissues of the Rg3 group, the 5-FU group, and the combination group were significantly decreased, with the combination group showing the most significant decrease ( P <0.05). HE staining results indicated that there was significant tumor necrosis in mice in the control group and that there were more blood vessels. In contrast, in the tumor of the Rg3 group and the 5-FU group, there were fewer blood vessels and necrotic gaps appeared within the tumors. In the combination group, the tumor tissues had the fewest blood vessels and rope-like necrosis was observed. The mice started dying on the 18th day after treatment started, and all the mice in the control group died on the 42nd day. By this time, there were 3, 5, and 7 mice still alive in the Rg3 group, the 5-FU group, and the combination group, respectively, presenting a survival rate of 30%, 50%, and 70%, respectively. All mice in all the groups died on day 60 after treatment started., Conclusion: Ginsenoside Rg3 combined with 5-FU can significantly inhibit tumor angiogenesis and tumor growth of colon cancer in mice and improve the survival and quality of life of tumor-bearing mice., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Board of Journal of Sichuan University (Medical Sciences).)

Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been identified as crucial regulators of various biological processes through epigenetic regulation, transcriptional regulation, and post-transcriptional regulation. Growing evidence suggests that dysregulation and activation of non-coding RNAs are closely associated with tumor angiogenesis, a process essential for tumor growth and metastasis and a major contributor to cancer-related mortality. Therefore, understanding the molecular mechanisms underlying tumor angiogenesis is of utmost importance. Numerous studies have documented the involvement of different types of non-coding RNAs in the regulation of angiogenesis. This review provides an overview of how non-coding RNAs regulate tumor angiogenesis. Additionally, we discuss emerging strategies that exploit non-coding RNAs for anti-angiogenic therapy in cancer treatment. Ultimately, this review underscores the crucial role played by non-coding RNAs in tumor angiogenesis and highlights their potential as therapeutic targets for anti-angiogenic interventions against cancer.

Intravital microscopy allows a direct visualization of cells' behavior in their environment in a living organism with all its complexity. With appropriated models, longitudinal studies of structural and functional changes can be followed in the same animal on long period. In the field of cancer, the dorsal window chamber model is the model of choice for tumor events such as cells migration, vessels growth, and their permeability or interactions between cells and vessels. Coupled with wide-field, confocal, or multiphoton fluorescence microscopes, high spatial and temporal resolutions of the cellular events can be analyzed in vivo., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Ovarian cancer is one of the most common gynecologic malignancies. Recurrence and metastasis often occur after treatment, and it has the highest mortality rate of all gynecological tumors. Cancer stem cells (CSCs) are a small population of cells with the ability of self-renewal, multidirectional differentiation, and infinite proliferation. They have been shown to play an important role in tumor growth, metastasis, drug resistance, and angiogenesis. Ovarian cancer side population (SP) cells, a type of CSC, have been shown to play roles in tumor formation, colony formation, xenograft tumor formation, ascites formation, and tumor metastasis. The rapid progression of tumor angiogenesis is necessary for tumor growth; however, many of the mechanisms driving this process are unclear as is the contribution of CSCs. The aim of this review was to document the current state of knowledge of the molecular mechanism of ovarian cancer stem cells (OCSCs) in regulating tumor angiogenesis., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Lcn2 overexpression in metastatic breast cancer (MBC) can lead to cancer progression by inducing the epithelial-to-mesenchymal transition and enhancing tumor angiogenesis. In this study, we engineered a PEGylated liposomal system encapsulating lipocalin 2 (Lcn2) small interfering RNA (Lcn2 siRNA) for selective targeting MBC cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. The PEGylated liposomes were decorated with octreotide (OCT) peptide. OCT is an octapeptide analog of somatostatin growth hormone, having affinity for somatostatin receptors, overexpressed on breast cancer cells. Optimized OCT-targeted Lcn2 siRNA encapsulated PEGylated liposomes (OCT-Lcn2-Lipo) had a mean size of 152.00 nm, PDI, 0.13, zeta potential 4.10 mV and entrapment and loading efficiencies of 69.5% and 7.8%, respectively. In vitro uptake and intracellular distribution of OCT-Lcn2-Lipo in MCF-7 and MDA-MB-231 and MCF-12A cells demonstrated higher uptake for the OCT-targeted liposomes at 6 h by flow cytometry and confocal microscopy. OCT-Lcn2-lipo could achieve approximately 55−60% silencing of Lcn2 mRNA in MCF-7 and MDA-MB-231 cells. OCT-Lcn2-Lipo also demonstrated in vitro anti-angiogenic effects in MCF-7 and MDA-MB-231 cells by reducing VEGF-A and reducing the endothelial cells (HUVEC) migration levels. This approach may be useful in inhibiting angiogenesis in MBC.

Epithelial ovarian cancer (EOC) is the deadliest female malignancy. The Wnt/β-catenin pathway plays critical roles in regulating embryonic development and physiological processes. This pathway is tightly regulated to ensure its proper activity. In the absence of Wnt ligands, β-catenin is degraded by a destruction complex. When the pathway is stimulated by a Wnt ligand, β-catenin dissociates from the destruction complex and translocates into the nucleus where it interacts with TCF/LEF transcription factors to regulate target gene expression. Aberrant activation of this pathway, which leads to the hyperactivity of β-catenin, has been reported in ovarian cancer. Specifically, mutations of CTNNB1, AXIN, or APC, have been observed in the endometrioid and mucinous subtypes of EOC. In addition, upregulation of the ligands, abnormal activation of the receptors or intracellular mediators, disruption of the β-catenin destruction complex, inhibition of the association of β-catenin/E-cadherin on the cell membrane, and aberrant promotion of the β-catenin/TCF transcriptional activity, have all been reported in EOC, especially in the high grade serous subtype. Furthermore, several non-coding RNAs have been shown to regulate EOC development, in part, through the modulation of Wnt/β-catenin signalling. The Wnt/β-catenin pathway has been reported to promote cancer stem cell self-renewal, metastasis, and chemoresistance in all subtypes of EOC. Emerging evidence also suggests that the pathway induces ovarian tumor angiogenesis and immune evasion. Taken together, these studies demonstrate that the Wnt/β-catenin pathway plays critical roles in EOC development and is a strong candidate for the development of targeted therapies. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis plays an important role during breast tumor growth. However, conventional Doppler has limited sensitivity to detect small blood vessels, resulting in a large overlap of Doppler features between benign and malignant tumors. An ultrasensitive ultrasound microvessel imaging (UMI) technique was recently developed. To evaluate the performance of UMI, we studied 44 patients with 51 breast masses. Tumor pathology served as the gold standard: 28 malignancies and 23 benignities. UMI provided a significant improvement in depicting smaller vessels compared with conventional Doppler. The microvessel morphologies observed on UMI were associated with tumor benign/malignant classification. The diagnostic accuracy of correct Breast Imaging Reporting and Data System (BI-RADS) classification rate (BI-RADS ≥4a: test positive; BI-RADS ≤3: test negative) as a fraction of total mass population was improved by 16% after combining conventional ultrasound with UMI compared with using conventional ultrasound alone. This improvement indicates the potential of UMI in reducing unnecessary benign biopsies and avoiding missed malignant biopsies. [ABSTRACT FROM AUTHOR]

Chimeric inhibitors, which merge two drug pharmacophores in a single molecule have become a prominent approach for the design of novel anticancer compounds. Here, we examined animacroxam, which combines histone deacetylase (HDAC) inhibitory and cytoskeleton‐interfering pharmacophores, in testicular germ cell tumors (TGCT). The effectiveness of animacroxam was compared to that of the commonly applied chemotherapeutic cisplatin as well as the clinically approved HDAC inhibitor vorinostat. The antineoplastic and antiangiogenic effects of animacroxam on TGCT in vivo were assessed through exploratory animal studies and a modified chorioallantoic membrane assay, revealing that animacroxam has significant antitumor activity in TGCT. A novel positron emission tomography/MR‐imaging approach was applied to determine tumor volume and glucose [2‐fluoro‐2‐deoxy‐d‐glucose (18F‐FDG)] uptake in TGCT tumors, revealing reduced glucose uptake in animacroxam‐treated TGCTs and showing a dose‐dependent suppression of glycolytic enzymes, which led to a breakdown in glycolytic energy production. Furthermore, the observed antiangiogenic effects of animacroxam were related to its ability to inhibit endothelial cell–cell communication, as the expression of gap junction‐forming connexin 43 was strongly suppressed, and gap‐junctional intercellular mass transport was reduced. Our data suggest that the chimeric HDAC inhibitor animacroxam may become a promising candidate for the treatment of solid cancers and may serve as an interesting alternative to platinum‐based therapies. [ABSTRACT FROM AUTHOR]

• Blocking the sympathetic signaling arrests tumor growth of lung cancer cells. • Adrenergic-stimulated macrophages tend to exhibit an M2-like phenotype. • Catecholamine-stimulated macrophages contribute to angiogenesis. • Catecholamines regulate tumor microenvironment by affecting the innate immune cells. Elevated catecholamines in the tumor microenvironment often correlate with tumor development. However, the mechanisms by which catecholamines modulate lung cancer growth are still poorly understood. This study is aimed at examining the functions and mechanisms of catecholamine-induced macrophage polarization in angiogenesis and tumor development. We established in vitro and in vivo models to investigate the relationship between catecholamines and macrophages in lung cancer. Flow cytometry, cytokine detection, tube formation assay, immunofluorescence, and western blot analysis were performed, and animal models were also used to explore the underlying mechanism of catecholamine-induced macrophage polarization and host immunological response. Catecholamines were shown to be secreted into tumor under the control of the sympathetic nerve system to maintain the pro-tumoral microenvironment. In vivo , the chemical depletion of the natural catecholamine stock with 6OHDA could reduce the release of catecholamines within tumor tissues, restrain the function of alternatively activated M2 macrophage, attenuate tumor neovascularization, and inhibit tumor growth. In vitro , catecholamine treatment triggered the M2 polarization of macrophages, enhanced the expression of VEGF, promoted tumor angiogenesis, and these catecholamine-stimulated effects could be reversed by the adrenergic receptor antagonist propranolol. In addition to regulating tumor-associated macrophages (TAM) recruitment, decreasing catecholamine levels could also shift the immunosuppressive microenvironment by decreasing myeloid-derived suppressor cells' (MDSCs) recruitment and facilitating dendritic cells' (DCs) activation, potentially resulting in a positive antitumor immune response. Our study demonstrates the potential of adrenergic stress and catecholamine-driven adrenergic signaling of TAMs to regulate the immune status of a tumor microenvironment and provides promising targets for anticancer therapies. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in American men. Androgen deprivation therapy (ADT) has become a standard treatment strategy for advanced PCa. Although a majority of patients initially respond to ADT well, most of them will eventually develop castration-resistant PCa (CRPC). Previous studies suggest that ADT-induced changes in the immune microenvironment (mE) in PCa might be responsible for the failures of various therapies. However, the role of the immune system in CRPC development remains unclear. To systematically understand the immunity leading to CRPC progression and predict the optimal treatment strategy in silico, we developed a 3D Hybrid Multi-scale Model (HMSM), consisting of an ODE system and an agent-based model (ABM), to manipulate the tumor growth in a defined immune system. Based on our analysis, we revealed that the key factors (e.g. WNT5A, TRAIL, CSF1, etc.) mediated the activation of PC-Treg and PC-TAM interaction pathways, which induced the immunosuppression during CRPC progression. Our HMSM model also provided an optimal therapeutic strategy for improving the outcomes of PCa treatment. [ABSTRACT FROM AUTHOR]

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Objective: To explore the use of Contrast-enhanced Ultrasound (CEUS) in evaluating angiogenesis in a xenograft nasopharyngeal carcinoma (NPC) model in nude mice and the evolution of CEUS parameters according to the growth of NPC. Methods: Nude mice were divided into three groups according to experiments conducted at various times from tumor implantation (8 mice/group; group A: 4 weeks from implantation; group B:6 weeks from implantation; group C:8 weeks from implantation). CNE-2 cells were transplanted in 24 nude mice and CEUS evaluations of the tumors were performed at 4, 6 or 8 weeks from implantation. CEUS parametric perfusion images and pathological findings were recorded. R version 3.4.4 software was used to analyze the CEUS parameters and pathological findings. Results: One-way anova analysis indicated statistically significant differences among the three groups with the parameters of peak intensity (PI) (p<0.001), area wash in (AWI) (p<0.001), area wash out (AWO) (p<0.001) and tumor volumes (p<0.001).Pearson correlation coefficient analysis indicated that microvessel density (MVD) was correlated with tumor volume (r = 0.644, p = 0.001), PI (r = 0.904, p<0.0001), AWI (r = 0.547, p = 0.008) and AWO (r = 0.744, P<0.0001). Tumor volume was correlated with MVD (r = 0.644, p = 0.001), PI (r = 0.625, p = 0.002), AWI (r = 0.528, p = 0.012) and AWO (r = 0.784, p<0.001). The percentage of necrosis in histological sections was correlated with the percentage of CEUS unperfused area (r = 0.446,p = 0.038). Spearman rank correlation coefficient analysis indicated that vascular endothelial growth factor (VEGF) was correlated with PI (r = 0.462, P = 0.032). Welch t test indicated PI, AWI and AWO parameters were significantly lower than that of kidneys (p<0.001, p = 0.009, p = 0.005). Conclusions: The CEUS parameters PI, AWI and AWO indirectly reflect the MVD and the tumor volume in our model of subcutaneous transplanted NPC in nude mice, providing precious information on angiogenesis and tumor growth. VEGF may play a role in promoting angiogenesis of NPC. [ABSTRACT FROM AUTHOR]

Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of ApcΔ716 mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC. Laser capture microdissection and in situ hybridization analysis show almost exclusive expression of Dio2 in the stroma of ApcΔ716 polyps in the proximity of the COX‐2‐positive areas. Treatment with iopanoic acid, a deiodinase inhibitor, or chemical thyroidectomy suppresses tumor formation in ApcΔ716 mice, accompanied by reduced tumor cell proliferation and angiogenesis. Dio2 expression in ApcΔ716 polyps is strongly suppressed by treatment with the COX‐2 inhibitor meloxicam. Analysis of The Cancer Genome Atlas data shows upregulation of DIO2 in CRC clinical samples and a close association of its expression pattern with the stromal component, consistently with almost exclusive expression of DIO2 in the stroma of human CRC as revealed by in situ hybridization. These results indicate essential roles of stromal DIO2 and thyroid hormone signaling in promoting the growth of intestinal tumors. [ABSTRACT FROM AUTHOR]

Cancers exhibit spatially heterogeneous, unique vascular architectures across individual samples, cell-lines and patients. This inherently disorganised collection of leaky blood vessels contribute significantly to suboptimal treatment efficacy. Preclinical tools are urgently required which incorporate the inherent variability and heterogeneity of tumours to optimise and engineer anti-cancer therapies. In this study, we present a novel computational framework which incorporates whole, realistic tumours extracted ex vivo to efficiently simulate vascular blood flow and interstitial fluid transport in silico for validation against in vivo biomedical imaging. Our model couples Poiseuille and Darcy descriptions of vascular and interstitial flow, respectively, and incorporates spatially heterogeneous blood vessel lumen and interstitial permeabilities to generate accurate predictions of tumour fluid dynamics. Our platform enables highly-controlled experiments to be performed which provide insight into how tumour vascular heterogeneity contributes to tumour fluid transport. We detail the application of our framework to an orthotopic murine glioma (GL261) and a human colorectal carcinoma (LS147T), and perform sensitivity analysis to gain an understanding of the key biological mechanisms which determine tumour fluid transport. Finally we mimic vascular normalization by modifying parameters, such as vascular and interstitial permeabilities, and show that incorporating realistic vasculatures is key to modelling the contrasting fluid dynamic response between tumour samples. Contrary to literature, we show that reducing tumour interstitial fluid pressure is not essential to increase interstitial perfusion and that therapies should seek to develop an interstitial fluid pressure gradient. We also hypothesise that stabilising vessel diameters and permeabilities are not key responses following vascular normalization and that therapy may alter interstitial hydraulic conductivity. Consequently, we suggest that normalizing the interstitial microenvironment may provide a more effective means to increase interstitial perfusion within tumours. [ABSTRACT FROM AUTHOR]

• Anti-angiogenic treatment has been recently shown to be beneficial for mesothelioma patients. • Angiopoietins-1 and -2 are key regulators of tumor angiogenesis. • Ang-1 promotes mesothelioma angiogenesis and growth. • The effect of Ang-2 is context-dependent. • Low Ang-1 levels in human mesotheliomas are associated with epitheloid subtype. • Tumors of high Ang-1, or high Ang-2 and VEGF expression present high PECAM-1 and CDH5 expression. Anti-angiogenic treatment has been recently shown to be clinically beneficial for mesothelioma patients. Angiopoietins-1 and -2 are key regulators of tumor angiogenesis. Ang-1 is mainly known to promote angiogenesis and vessel stability, while Ang-2 could serve as an antagonist of Ang-1 causing vessel regression and destabilization or enhance angiogenesis in a context-dependent manner. We hypothesized that Ang-1 would promote and Ang2 would halt experimental mesothelioma by affecting tumor angiogenesis. To examine the effects of angiopoietins in mesothelioma angiogenesis and in vivo growth we constructed Ang-1 or Ang-2 overexpressing AE17 and AB1 mesothelioma cells and implanted them in the respective syngeneic animals. We also explored the clinical relevance of our observations using the human tumoral mRNAseq data available in the TCGA database. Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 is context-dependent. Low Ang-1 levels in human mesotheliomas are associated with the epitheloid subtype. Tumors of high Ang-1, or concurrent high Ang-2 and VEGF expression present high PECAM-1 and CDH5 expression, markers of vascularity and vascular stability, respectively. Our results highlight the importance of angiopoietins in mesothelioma pathophysiology and pave the way for the clinical development of novel anti-angiogenic strategies. [ABSTRACT FROM AUTHOR]

The anti-cancer role of local anesthetics has garnered attention in recent years because increasing evidence show that local anesthetics reduce the risk of tumor metastasis and recurrence. Angiogenesis, the formation of new blood vessels, is fundamental for tumor growth and metastasis. The role of local anesthetics on tumor angiogenesis still remains unknown. Using human lung tumor-associated endothelial cell (HLT-EC) and angiogenesis models, our work shows that ropivacaine at the clinically relevant concentration is active against multiple biological functions of HLT-EC but not lung tumor cells. Ropivacaine inhibits HLT-EC capillary network formation, growth and survival. The anti-angiogenic activity of ropivacaine is further confirmed in in vivo angiogenesis mouse model. Mechanistically, we show that ropivacaine inhibits HLT-EC mitochondrial respiration via specifically targeting mitochondrial respiratory complex II. As a consequence of mitochondrial respiration inhibition, we observe the energy depletion, oxidative stress and damage in HLT-EC after ropivacaine exposure. Additionally, an antioxidant agent completely reverses the inhibitory effects of ropivacaine, suggesting that oxidative stress is required for the action of ropivacaine in HLT-EC. Interestingly, mitochondrial dysfunction and oxidative stress induced by ropivacaine is sodium channel-independent. Our work demonstrates the potent inhibitory effects of ropivacaine in lung tumor angiogenesis by inducing mitochondrial dysfunction. These findings provide significant insight into the potential mechanisms by which local anaesthetics may negatively affect tumor reoccurrence and metastasis. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis, the formation of blood vessel, is required for invasive tumor growth and metastasis. In this study, the effects of lidocaine, an amide-link local anesthetic, on angiogenesis and tumor growth were investigated.Methods: In vitro angiogenesis assays were conducted using human umbilical vascular endothelial cell (HUVEC). Essential molecules involved in vascular endothelial growth factor (VEGF) signaling were analyzed. Tumor angiogenesis was analyzed using in vivo mouse tumor model.Results: Lidocaine at clinically relevant concentrations inhibited angiogenesis. Lidocaine inhibited endothelial cell in vitro capillary network formation on Matrigel through interfering early stage of angiogenesis. In addition, lidocaine inhibited vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration and proliferation without affecting cell adhesion. Lidocaine also induced endothelial cell apoptosis in the presence of VEGF. Lidocaine suppressed VEGF-activated phosphorylation of VEGF receptor 2 (VEGFR2), PLCγ-PKC-MAPK and FAK-paxillin in endothelial cells, demonstrating that VEGF, PLC, MAPK and FAK-paxillin suppression is associated with the antiangiogenic effect of lidocaine. Importantly, the in vitro observations were translatable to in vivo B16 melanoma mouse model. Lidocaine significantly inhibited tumor angiogenesis, leading to delay of tumor growth.Conclusions: This study is the first to report that lidocaine acts as an angiogenesis inhibitor. The findings provide preclinical evidence into the potential mechanisms by which lidocaine may negatively affect cancer growth and metastasis. [ABSTRACT FROM AUTHOR]

We report here the preparation, physico-chemical characterization, and biological evaluation of a new liposome formulation as a tool for tumor angiogenesis inhibition. Liposomes are loaded with sunitinib, a tyrosine kinase inhibitor, and decorated with cyclo-aminoprolineRGD units (cAmpRGD), efficient and selective ligands for integrin α V β 3. The RGD units play multiple roles since they target the nanovehicles at the integrin α V β 3 -overexpressing cells (e.g. activated endothelial cells), favor their active cell internalization, providing drug accumulation in the cytoplasm, and likely take part in the angiogenesis inhibition by interfering in the α V β 3 -VEGFR2 cross-talk. Both in vitro and in vivo studies show a better efficacy of this integrated antiangiogenic tool with respect to the free sunitinib and untargeted sunitinib-loaded liposomes. This system could allow a lower administration of the drug and, by increasing the vector specificity, reduce side-effects in a prolonged antiangiogenic therapy. Liposomes decorated with AmpRGD, an α V β 3 integrin-targeted ligand, and loaded with sunitinib, a known tyrosine-kinase inhibitor, were developed. This nanosized system was tested as an integrated antiangiogenic tool, and compared to free sunitinib and sunitinib-loaded untargeted liposomes, showing a potentiated activity both in vitro and in vivo. Unlabelled Image [ABSTRACT FROM AUTHOR]

The human UTP14a (hUTP14a) promotes degradation of p53 and RB. Moreover, hUTP14a stabilizes c-Myc and is associated with the metastasis of human colorectal cancer (CRC). Angiogenesis plays a key role in tumor growth and metastasis. However, how hUTP14a regulates angiogenesis is unknown. Here, we show that nucleolar expression of hUTP14a is positively associated with higher microvascular density (MVD) in the CRC tumor tissues. The conditioned medium (CM) from CRC cells HCT116 and LoVo with hUTP14a knockdown impairs tube formation and migration of human umbilical vein endothelial cells (HUVECs). RNA-seq analysis indicates that hUTP14a might regulate expression of angiogenic factors in tumor cells. We further demonstrate that hUTP14a upregulates transcription and secretion of platelet-derived growth factor subunit A (PDGFA) in CRC cells. The CRC-CM derived from hUTP14a-depleted cells inhibits the PDGFA-mediated signaling pathway and induces apoptosis in HUVECs. In contrast, the CRC-CM derived from cells expressing Flag-hUTP14a activates the PDGFA-mediated signaling pathway in HUVECs. Importantly, the CRC-CM derived from Flag-hUTP14a-expressing cells promotes angiogenesis in HUVECs, which is counteracted by PDGFR inhibitor imatinib. We thus demonstrate that hUTP14a promotes angiogenesis by upregulating expression and secretion of PDGFA. The in vivo Matrigel plug assay shows that depletion of hUTP14a dramatically decreased MVD in mice xenografts. Collectively, we demonstrate that hUTP14a promotes angiogenesis in CRC and indicate that targeting hUTP14a might improve the prognosis of the hUTP14a-expressing CRC patients. • Nucleolar hUTP14a is associated with high microvascular density in CRC tissues. • hUTP14a upregulates transcription and secretion of PDGFA in CRC cells. • hUTP14a enhances tube formation and migration of HUVECs in a paracrine manner. • hUTP14a promotes tumor angiogenesis in CRC in vivo. [ABSTRACT FROM AUTHOR]

Angiogenesis is central to a wide range of physiological and pathological processes including wound healing, macular degeneration, and cancer. Excessive or inappropriate vascular supply of tumors is one of the main targets for cancer therapy. Recently, critical and selective transcriptional factors such as yes-associated protein (YAP) that control the expression of angiogenesis factors have gained increasing attention in antiangiogenic therapy. In this study, we have identified and characterized a novel inhibitor of YAP, gambogic acid (GA), which exerted striking antiangiogenic effects both in vitro and in vivo. We demonstrated that GA remarkably inhibited a variety of vascular endothelial growth factor-induced angiogenesis processes including proliferation, migration, sprouting, and tube formation of endothelial cells in vitro. In addition, GA resulted in decreased neo-vessel formation in Matrigel plugs of mice and chick chorioallantoic membrane. More importantly, we showed that GA limited tumor growth via preventing tumor angiogenesis and vascular maturation. Further mechanistic studies illustrated that GA directly targeted YAP/STAT3 signaling axis, which is critical for the transcriptional regulation of a series of angiogenic factors. Taken together, these preclinical findings suggest that GA significantly repressed tumor angiogenesis and may serve as a promising drug candidate against cancer. [ABSTRACT FROM AUTHOR]