• BMB Reports
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• v.39 no.5
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• pp.469-478
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• 2006

Vascular endothelial growth factor (VEGF)-A, a major regulator for angiogenesis, binds and activates two tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). These receptors regulate physiological as well as pathological angiogenesis. VEGFR2 has strong tyrosine kinase activity, and transduces the major signals for angiogenesis. However, unlike other representative tyrosine kinase receptors which use the Ras pathway, VEGFR2 mostly uses the Phospholipase-$C{\gamma}$-Protein kinase-C pathway to activate MAP-kinase and DNA synthesis. VEGFR2 is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR2 itself and the signaling appear to be critical targets for the suppression of these diseases. VEGFR1 plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGF-A, and a positive role in adulthood in a tyrosine kinase-dependent manner. VEGFR1 is expressed not only in endothelial cells but also in macrophage-lineage cells, and promotes tumor growth, metastasis, and inflammation. Furthermore, a soluble form of VEGFR1 was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction. Therefore, VEGFR1 is also an important target in the treatment of human diseases. Recently, the VEGFR2-specific ligand VEGF-E (Orf-VEGF) was extensively characterized. Interestingly, the activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGF-A, suggesting VEGF-E to be a novel material for pro-angiogenic therapy.

• Bulletin of the Korean Chemical Society
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• v.25 no.9
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• pp.1331-1335
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• 2004

Angiogenesis is essential for the growth and persistence of solid tumors. Their metastases, anti-angiogenesis could lead to the suppression of tumor growth. One of the main strategies of cancer treatment is developing molecules of anti-angiogenic activity. In this study, two angiogenic inhibitors, Ang3 (KLFDF) and Ang4 (XLFDF) derived from KLYDY, which is the sequence of angiostatin active sites kringle 5, were designed and synthesized. Previously we reported the activities and structures of two inhibitors, Ang1 (KLYDY) and Ang2 (KLWDF). In order to investigate the effect of Phe substitution, Ang3 was designed with a sequence of KLFDF. In order to reduce conformational flexibility of side chain in Lys, Ang4 was designed with a sequence of XLFDF, where X has amino substituted phenyl ring. Solution structures of those inhibitors were investigated using NMR spectroscopy and their activities as angiogenesis inhibitors were studied. Ang1 and Ang2 show angiogenic activities, while Ang3 and Ang4 have no activities and have extended structures compared to Ang1 and Ang2. Therefore, Phe rings do not have effective hydrophobic interactions with other aromatic residues in Ang3 and Ang4. The representative structure of Ang2 has a stable intramolecular hydrogen bond. Therefore, intramolecular hydrogen bonding might be more important in stabilizing the structure than the hydrophobic interactions in these inhibitors. More rigid structure, which can be expected to have higher activities and better match with the receptor bound conformations, can be obtained with a constrained cyclic structure. Further peptidomimetic approaches should be tried to develop angiogenesis inhibitors.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.869-874
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• 2015

Background: The prognostic value of microvessel density (MVD), reflecting angiogenesis, detected in ovarian cancer is currently controversial. Here we performed a meta-analysis of all relevant eligible studies. Materials and Methods: A comprehensive search of online PubMed, Medline, EMBASE and Sciencedirect was performed to identify all related articles. The search strategy was designed as 'microvessel density', 'ovarian cancer', 'ovarian neoplasm', 'CD34' and 'angiogenesis'. Results: The studies were categorized by author/year, number of patients, FIGO stage, histology, cutoff value for microvessel density, types of survival analysis, methods of hazard rations (HR) estimation, HR and its 95% confidence interval (CI). Combined hazard ratios suggested that high MVD was associated with poor overall survival (OS) and progression-free survival (PFS), with HR and 95% CIs of 1.84 (1.33-2.35) and 1.36 (1.06-1.66), respectively. Subgroup analysis showed that high MVD detected by CD34 was relevant for OS [HR=1.67 (1.36-2.35)], but not MVD detected with other antibodies [HR=2.11 (0.90-3.31)]. Another subgroup analysis indicated that high MVD in patients without pre-chemotherapy, but not with pre-chemotherapy, was associated with OS [HR=1.88(1.59-2.18 and HR=1.70 (-0.18-3.59)]. Conclusions: The OS and PFS with high MVD were significant poorer than with low MVD in ovarian cancer patients. However, high MVD detected by CD34 seems to be more associated with survival for patients without pre-chemotherapy.

• Journal of Life Science
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• v.34 no.2
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• pp.128-137
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• 2024

This review discusses the pivotal role of vascular endothelial growth factors (VEGF) in angiogenesis and lymphangiogenesis, vital processes influencing vascular permeability, endothelial cell recruitment, and the maintenance of tumor-associated blood and lymphatic vessels. VEGF exerts its effects through tyrosine-kinase receptors, VEGFR-1, VEGFR-2, and VEGFR-3. This VEGF-VEGFR system is central not only to cancer but also to diseases arising from abnormal blood vessel and lymphatic vessel formation. In the context of cancer, VEGF and its receptors are essential for the development of tumor-associated vessels, making them attractive targets for therapeutic intervention. Various approaches, such as anti-VEGF antibodies, receptor antagonists, and VEGF receptor function inhibitors, are being explored to interfere with tumor growth. However, the clinical efficacy of anti-angiogenic agents remains uncertain and necessitates further refinement. The article also highlights the physiological role of VEGFs, emphasizing their involvement in endothelial cell functions, survival, and vascular permeability. The identification of five distinct VEGFs in humans (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PLGF) is discussed, along with the classification of VEGFRs as typical receptor tyrosine kinases with distinct signaling systems. The family includes VEGFR-1 and VEGFR-2, crucial in tumor biology and angiogenesis, and VEGFR-3, specifically involved in lymphangiogenesis. Overall, this review has provided a comprehensive overview of VEGF and VEGFR, detailing their roles in various diseases, including cancer. This is expected to further facilitate the utilization of VEGF and VEGFR as therapeutic targets.

• Toxicological Research
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• v.35 no.4
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• pp.361-369
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• 2019

1,2-Dichloropropane (1,2-DCP) has been used as an industrial solvent and a chemical intermediate, as well as in soil fumigants. Human exposure may occur during its production and industrial use. The target organs of 1,2-DCP are the eyes, respiratory system, liver, kidneys, central nervous system, and skin. Repeated or prolonged contact may cause skin sensitization. In this study, 1,2-DCP was dissolved in corn oil at 0, 2.73, 5.75, and 8.75 mL/kg. The skin of mice treated with 1,2-DCP was investigated using western blotting, hematoxylin and eosin staining, and immunohistochemistry. 1,2-DCP was applied to the dorsal skin and both ears of C57BL/6J mice. The thickness of ears and the epidermis increased significantly following treatment, and the appearance of blood vessels was observed in the dorsal skin. Additionally, the expression of vascular endothelial growth factor, which is tightly associated with neovascularization, increased significantly. The levels of protein kinase-B (PKB), phosphorylated PKB, mammalian target of rapamycin (mTOR), and phosphorylated mTOR, all of which are key components of the phosphoinositide 3-kinase/PKB/mTOR signaling pathway, were also enhanced. Taken together, 1,2-DCP induced angiogenesis in dermatitis through the PI3K/PKB/mTOR pathway in the skin.

• Journal of Nutrition and Health
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• v.55 no.2
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• pp.240-249
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• 2022

Purpose: Glabridin (GD) is a bio-available isoflavane isolated from the root extract of licorice (Glycyrrhiza glabra L.). It exhibits a variety of pharmacological activities such as anti-inflammatory and anti-oxidant activities. However, extracellular vesicles (EVs) secretion and the anti-cancer mechanism of action remains largely unknown. The present study investigates the anticancer effects of GD by determining the inhibition of EVs secretion in the human breast cancer cell line, MDA-MB-231. Methods: Cell viability, reactive oxygen species (ROS) production, migration, invasion rate, and vascular endothelial growth factor (VEGF) concentration were assessed in MDA-MB-231 cells treated with increasing concentrations of GD (0.1, 1, 5, 10, 20 µM). Subsequently, EV secretion and exosomal DEL-1 protein expression were evaluated to determine the anticancer effects of GD. Results: The results showed that GD significantly inhibited the cell proliferation of MDA-MB-231 cells in a dose- or time-dependent manner. Also, ROS production and apoptosis marker protein cleaved caspase-3 were significantly increased in GD-treated MDA-MB-231, compared to control. Furthermore, GD exposure resulted in significantly decreased not only migration and invasion rates but also the VEGF concentration, thereby contributing to a reduction in angiogenesis. Interestingly, the concentration and number of EVs as well as EV marker proteins, such as CD63 and TSG101, were decreased in GD-treated MDA-MB-231 cells. Markedly, extracellular matrix protein DEL-1 as angiogenesis factor was decreased in EVs from GD-treated MDA-MB-231 cells. Conclusion: This study identifies that the anti-cancer molecular mechanism of GD is exerted via inhibition of angiogenesis and EVs secretion, indicating the potential of GD as a chemotherapeutic agent for breast cancer.

• BMB Reports
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• v.46 no.3
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• pp.131-138
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• 2013

During cancer progression, bone marrow derived myeloid cells, including immature myeloid cells and macrophages, progressively accumulate at the primary tumour site where they contribute to the establishment of a tumour promoting microenvironment. A marked infiltration of macrophages into the stromal compartment and the generation of a desmoplastic stromal reaction is a particular characteristic of pancreatic ductal adenocarcinoma (PDA) and is thought to play a key role in disease progression and its response to therapy. Tumour associated macrophages (TAMs) foster PDA tumour progression by promoting angiogenesis, metastasis, and by suppressing an anti-tumourigenic immune response. Recent work also suggests that TAMs contribute to resistance to chemotherapy and to the emergence of cancer stem-like cells. Here we will review the current understanding of the biology and the pro-tumourigenic functions of TAMs in cancer and specifically in PDA, and highlight potential therapeutic strategies to target TAMs and to improve current therapies for pancreatic cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1667-1674
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• 2012

Objective: To explore the differential protein expression profile in EC304 gastric cancer cells induced by alphastatin. Methods: Cultured EC304 cells in the exponential phase of growth were randomly divided into alphastatin and control groups. Total proteins were extracted and the two dimensional electrophoresis (2-DE) technique was applied to analyze differences in expression with ImageMaster 2D Platinum 5.0 software. Proteins were identified using the MASCOT database and selected differently expressed proteins were characterised by western blotting and immunofluorescence. Results: $1350{\pm}90$ protein spots were detected by the ImageMaster software in the 2-DE gel images from the control and alphastatin groups. The match rate was about 72-80% for the spectrum profiles, with 29 significantly different protein spots being identified, 10 upregulated, 16 downregulated, two new and one lost. The MASCOT search scores were 64-666 and the peptide matching numbers were 3-27 with sequence coverage of 8-62%. Twenty-three proteins were checked by mass spectrometry, including decrease in Nm23 and profilin-2 isoform b associated with the regulation of actin multimerisation induced by extracellular signals. Conclusion: The proteome in EC304 cells is dramatically altered by alphastatin, which appears to play an important role in modulating cellular activity and anti-angiogenesis by regulating protein expression and signal transduction pathways through Nm23 and profilin-2 isoform b, providing new research directions for anti-angiogenic therapy of gastric cancer.

• Biomolecules & Therapeutics
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• v.27 no.1
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• pp.117-125
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• 2019

Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has recently been noted as a repositioning candidate for angiogenesis inhibition and cancer therapy. However, the definite anti-angiogenic mechanism of MBZ remains unclear. In this study, we explored the inhibitory mechanism of MBZ in endothelial cells (ECs) and developed a novel strategy to improve its anti-angiogenic therapy. Treatment of ECs with MBZ led to inhibition of EC proliferation in a dose-dependent manner in several culture conditions in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) or FBS, without selectivity of growth factors, although MBZ is known to inhibit VEGF receptor 2 kinase. Furthermore, MBZ inhibited EC migration and tube formation induced by either VEGF or bFGF. However, unexpectedly, treatment of MBZ did not affect FAK and ERK1/2 phosphorylation induced by these factors. Treatment with MBZ induced shrinking of ECs and caused G2-M arrest and apoptosis with an increased Sub-G1 fraction. In addition, increased levels of nuclear fragmentation, p53 expression, and active form of caspase 3 were observed. The marked induction of autophagy by MBZ was also noted. Interestingly, inhibition of autophagy through knocking down of Beclin1 or ATG5/7, or treatment with autophagy inhibitors such as 3-methyladenine and chloroquine resulted in marked enhancement of anti-proliferative and pro-apoptotic effects of MBZ in ECs. Consequently, we suggest that MBZ induces autophagy in ECs and that protective autophagy can be a novel target for enhancing the anti-angiogenic efficacy of MBZ in cancer treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5363-5369
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• 2012

High-risk human papillomavirus (HPV) especially HPV-16 and HPV-18 types are speculated to be important risk factors in non-smoking associated lung cancer in Asia. Increasing evidence has demonstrated that HPV oncoproteins may contribute to lung tumorigenesis and cell transformation. Importantly, HPV 16/18 E6 and E7 oncoproteins can mediate expression of multiple target genes and proteins, such as p53/pRb, VEGF, HIF-$1{\alpha}$, cIAP-2, and hTERT, and contribute to cell proliferation, angiogenesis and cell immortalization through different signaling pathways in lung cancer. This article provides an overview of experiment data on HPV-associated lung cancer, describes the main targets on which HPV E6/E7 oncoproteins act, and further discusses the potential signaling pathways in which HPV E6/E7 oncoproteins are involved. In addition, we also raise questions regarding existing problems with the study of HPV-associated lung cancer.