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Acta Pharmacologica Sinica Oct 2015Angiogenesis, the formation of new blood vessels from the pre-existing vasculature is essential for embryonic development and tissue homeostasis. It also plays critical... (Review)
Review
Angiogenesis, the formation of new blood vessels from the pre-existing vasculature is essential for embryonic development and tissue homeostasis. It also plays critical roles in diseases such as cancer and retinopathy. A delicate balance between pro- and anti-angiogenic factors ensures normal physiological homeostasis. Endogenous angiogenesis inhibitors are proteins or protein fragments that are formed in the body and have the ability to limit angiogenesis. Many endogenous angiogenesis inhibitors have been discovered, and the list continues to grow. Endogenous protein/peptide inhibitors are relatively less toxic, better tolerated and have a lower risk of drug resistance, which makes them attractive as drug candidates. In this review, we highlight ten novel endogenous protein angiogenesis inhibitors discovered within the last five years, including ISM1, FKBPL, CHIP, ARHGAP18, MMRN2, SOCS3, TAp73, ZNF24, GPR56 and JWA. Although some of these proteins have been well characterized for other biological functions, we focus on their new and specific roles in angiogenesis inhibition and discuss their potential for therapeutic application.
Topics: Angiogenesis Inhibitors; Animals; Drug Discovery; Humans; Neoplasms; Neovascularization, Pathologic; Proteins
PubMed: 26364800
DOI: 10.1038/aps.2015.73 -
Biochemistry. Biokhimiia Jul 2008Tissue activity of angiogenesis depends on the balance of many stimulating or inhibiting factors. The key signaling system that regulates proliferation and migration of... (Review)
Review
Tissue activity of angiogenesis depends on the balance of many stimulating or inhibiting factors. The key signaling system that regulates proliferation and migration of endothelial cells forming the basis of any vessel are vascular endothelium growth factors (VEGF) and their receptors. The VEGF-dependent signaling system is necessary for formation of the embryonic vascular system. Neoangiogenesis during tumor growth is also associated with activation of this signaling system. The biological significance of the effect of such system on the cells depends on the content in tissue of various factors of the VEGF family and their receptors, while in the case of VEGFA it is defined by the ratio of different isoforms of this growth factor. A number of other signaling systems are also involved in regulation of the main steps of vessel formation. The signaling system Dll4/Notch regulates selection of endothelial cells for beginning of angiogenic expansion by endowing particular properties to endothelial cells leading in this process. An important step in vessel stabilization and maturation is vascular wall formation. Signaling system PDGFB/PDGFRbeta as well as angiopoietins Ang1, Ang2, and their receptor Tie2 are involved in recruiting mural cells (pericytes and smooth muscle cells). Identification of key molecules involved in the regulation of angiogenesis may provide new possibilities for development of drugs suitable for inhibition of angiogenesis or its stimulation in various pathologies.
Topics: Angiopoietins; Animals; Capillaries; Endothelium, Vascular; Humans; Mice; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Neuropilins; Receptors, TIE; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A
PubMed: 18707583
DOI: 10.1134/s0006297908070031 -
BMC Cancer Aug 2022Lycorine (Lyc) is a natural alkaloid derived from medicinal plants of the Amaryllidaceae family. Lyc has been reported to inhibit the recurrence and metastasis of...
Lycorine (Lyc) is a natural alkaloid derived from medicinal plants of the Amaryllidaceae family. Lyc has been reported to inhibit the recurrence and metastasis of different kinds of tumors. However, Lyc's effect on angiogenesis and its specific mechanism are still not clear. This study was designed to test the antiangiogenesis effect of Lyc and to explore the possible mechanisms. We performed cell experiments to confirm Lyc's inhibitory effect on angiogenesis and employed sunitinib as a positive control. Moreover, the synergistic effect of Lyc and sunitinib was also explored. Next, we conducted bioinformatics analyses to predict the potential targets of Lyc and verified them by western blotting and immunofluorescence. Molecular docking, kinase activity assays, Biacore assays and cellular thermal shift assays (CETSAs) were applied to elucidate the mechanism by which Lyc inhibited target activity. Lyc inhibited angiogenesis in human umbilical vein endothelial cells (HUVECs). Employing bioinformatics, we found that Lyc's target was PDGFRα and that Lyc attenuated PDGFRα phosphorylation. We also found that Lyc inhibited PDGFRα activation by docking to it to restrain its activity. Additionally, Lyc significantly inhibited PDGF-AA-induced angiogenesis. This study provides new insights into the molecular functions of Lyc and indicates its potential as a therapeutic agent for tumor angiogenesis.
Topics: Amaryllidaceae Alkaloids; Angiogenesis Inhibitors; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Humans; Molecular Docking Simulation; Neoplasms; Neovascularization, Pathologic; Phenanthridines; Receptor, Platelet-Derived Growth Factor alpha; Sunitinib
PubMed: 35948939
DOI: 10.1186/s12885-022-09929-y -
Cells Mar 2021Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads... (Review)
Review
Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.
Topics: Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 33805699
DOI: 10.3390/cells10030639 -
Journal of Translational Medicine Feb 2023In the past decades studies on anti-tumoral drugs inhibiting matrix metalloproteinase (MMPs) were disappointing. Recently, we demonstrated that mature endothelial cells...
BACKGROUND
In the past decades studies on anti-tumoral drugs inhibiting matrix metalloproteinase (MMPs) were disappointing. Recently, we demonstrated that mature endothelial cells (ECs) and endothelial colony forming cells (ECFCs) can switch between invasion modes to cope with challenging environments, performing the "amoeboid angiogenesis" in the absence of proteases activity.
METHODS
We first set out to investigate by ELISA if the inhibitors of the main protease family involved in angiogenesis were differently expressed during breast cancer progression. We used Marimastat, a broad-spectrum MMP inhibitor, as a means of inducing amoeboid characteristics and studied VEGF role in amoeboid angiogenesis. Thus, we performed invasion and capillary morphogenesis assay, morphological, cell signaling and in vivo mouse studies.
RESULTS
Our data showed that TIMP1, TIMP2, alpha2-antiplasmin, PAI-1 and cystatin increase in breast cancer serum of patients with primary cancer and lymph node positive compared to healthy women. In vitro results revealed that the most high-powered protease inhibitors able to induce amoeboid invasion of ECFCs were TIMP1, 2 and 3. Surprisingly, Marimastat promotes ECFC invasion and tubular formation in vitro and in vivo, inducing amoeboid characteristics. We observed that the combination of Marimastat plus VEGF doesn't boost neither cell invasion nor vessel formation capacity. Moreover, inhibition of VEGF activity with Bevacizumab in the presence of Marimastat confirmed that amoeboid angiogenesis is independent from the stimulus of the main vascular growth factor, VEGF.
CONCLUSIONS
We underline the importance to consider the amoeboid mechanism of endothelial and cancer cell invasion, probably responsible for the failure of synthetic metalloproteinase inhibitors as cancer therapy and tumor resistance to VEGF-targeted therapies, to set-up new drugs to be used in cancer therapy.
Topics: Animals; Female; Mice; Amoeba; Angiogenesis Inhibitors; Endothelial Cells; Matrix Metalloproteinases; Morphogenesis; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Vascular Endothelial Growth Factor A; MAP Kinase Signaling System
PubMed: 36759828
DOI: 10.1186/s12967-023-03954-6 -
Journal of Hematology & Oncology Sep 2021Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes...
BACKGROUND
Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes and clarified its underlying mechanism and clinical significance.
METHODS
Herein, we found Kai1 knockout mice showed significantly enhanced angiogenesis. Then, we investigated the anti-angiogenic roll of Kai1 in vitro and in vivo.
RESULTS
KAI1 was mainly expressed in pericytes rather than in endothelial cells. It localized at the membrane surface after palmitoylation by zDHHC4 enzyme and induced LIF through the Src/p53 pathway. LIF released from pericytes in turn suppressed angiogenic factors in endothelial cells as well as in pericytes themselves, leading to inhibition of angiogenesis. Interestingly, KAI1 had another mechanism to inhibit angiogenesis: It directly bound to VEGF and PDGF and inhibited activation of their receptors. In the two different in vivo cancer models, KAI1 supplementation significantly inhibited tumor angiogenesis and growth. A peptide derived from the large extracellular loop of KAI1 has been shown to have anti-angiogenic effects to block the progression of breast cancer and retinal neovascularization in vivo.
CONCLUSIONS
KAI1 from PC is a novel molecular regulator that counterbalances the effect of angiogenic factors.
Topics: Animals; Female; Kangai-1 Protein; Male; Membrane Microdomains; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A; Mice
PubMed: 34530889
DOI: 10.1186/s13045-021-01147-6 -
Phytomedicine : International Journal... Jan 2023Hypoxia is a characteristic feature of many solid tumors. As an adaptive response to hypoxia, tumor cells activate hypoxia-inducible factor-1α (HIF-1α). Under hypoxic...
BACKGROUND
Hypoxia is a characteristic feature of many solid tumors. As an adaptive response to hypoxia, tumor cells activate hypoxia-inducible factor-1α (HIF-1α). Under hypoxic conditions, angiogenesis mediated by HIF-1α is involved in the growth and metastasis of tumor cells. During the angiogenic process, differentiated tip endothelial cells (ECs) characterized by high expression of DLL4 promote angiogenic germination through filopodia. Inhibitors of HIF-1α or DLL4 have been widely studied PURPOSE: We tried to find inhibitors targeting both HIF-1α and DLL4 in tumor which have not yet been developed.
STUDY DESIGN
In this study, we examined a natural compound that inhibits sprouting angiogenesis and tumor growth by targeting both HIF-1α and DLL4 under hypoxic conditions.
METHODS
After examining cell viability of 70 selected natural compounds, we assessed the effects of compounds on HIF-1α and DLL4 transcriptional activity using a dual-luciferase reporter assay. Western blot analysis, immunofluoresecnt assay and real-time qPCR were performed to identify expression of proteins, such as HIF-1α and DLL4, as well as HIF-1α target genes under hypoxic conditions. In vitro angiogenesis assay and in vivo allograft tumor experiment were performed to investigate inhibition of tumor growth through anti-angiogenic activity.
RESULTS
Among these compounds, steppogenin, which is extracted from the root bark of Morus alba l, respectively inhibited the transcriptional activity of HIF-1α under hypoxic conditions in HEK293T cells and vascular endothelial growth factor (VEGF)-induced DLL4 expression in vascular ECs in a dose-dependent manner. In tumor cells and retinal pigment epithelial cells, steppogenin significantly suppressed HIF-1α protein levels under hypoxic conditions as well as VEGF-induced DLL4 expression in ECs. Furthermore, steppogenin suppressed hypoxia-induced vascular EC proliferation and migration as well as VEGF-induced sprouting of EC spheroids.
CONCLUSION
These results suggest that the natural compound steppogenin could potentially be used to treat angiogenic diseases, such as those involving solid tumors, because of its dual inhibition of HIF-1α and DLL4.
Topics: Humans; Adaptor Proteins, Signal Transducing; Calcium-Binding Proteins; Cell Hypoxia; Cell Line, Tumor; Endothelial Cells; Endothelium; HEK293 Cells; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A
PubMed: 36332389
DOI: 10.1016/j.phymed.2022.154513 -
Biological Chemistry Nov 2017Kallistatin, via its two structural elements - an active site and a heparin-binding domain - displays a double-edged function in angiogenesis, apoptosis and oxidative... (Review)
Review
Kallistatin, via its two structural elements - an active site and a heparin-binding domain - displays a double-edged function in angiogenesis, apoptosis and oxidative stress. First, kallistatin has both anti-angiogenic and pro-angiogenic effects. Kallistatin treatment attenuates angiogenesis and tumor growth in cancer-bearing mice. Kallistatin via its heparin-binding site inhibits angiogenesis by blocking vascular endothelial growth factor (VEGF)-induced growth, migration and adhesion of endothelial cells. Conversely, kallistatin via the active site promotes neovascularization by stimulating VEGF levels in endothelial progenitor cells. Second, kallistatin inhibits or induces apoptosis depending on cell types. Kallistatin attenuates organ injury and apoptosis in animal models, and its heparin-binding site is essential for blocking tumor necrosis factor (TNF)-α-induced apoptosis in endothelial cells. However, kallistatin via its active site induces apoptosis in breast cancer cells by up-regulating miR-34a and down-regulating miR-21 and miR-203 synthesis. Third, kallistatin can act as an antioxidant or pro-oxidant. Kallistatin treatment inhibits oxidative stress and tissue damage in animal models and cultured cells. Kallistatin via the heparin-binding domain antagonizes TNF-α-induced oxidative stress, whereas its active site is crucial for stimulating antioxidant enzyme expression. In contrast, kallistatin provokes oxidant formation, leading to blood pressure reduction and bacterial killing. Kallistatin-mediated vasodilation is partly mediated by H2O2, as the effect is abolished by the antioxidant enzyme catalase. Moreover, kallistatin exerts a bactericidal effect by stimulating superoxide production in neutrophils of mice with microbial infection as well as in cultured immune cells. Thus, kallistatin's dual roles in angiogenesis, apoptosis and oxidative stress contribute to its beneficial effects in various diseases.
Topics: Animals; Apoptosis; Humans; Neovascularization, Pathologic; Oxidative Stress; Serpins
PubMed: 28742513
DOI: 10.1515/hsz-2017-0180 -
Experimental Cell Research May 2013Semaphorins (Semas) are a large family of traditional axon guidance molecules. Through interactions with their receptors, Plexins and Neuropilins, Semas play critical... (Review)
Review
Semaphorins (Semas) are a large family of traditional axon guidance molecules. Through interactions with their receptors, Plexins and Neuropilins, Semas play critical roles in a continuously growing list of diverse biological systems. In this review, we focus on their function in regulating vascular development. In addition, over the past few years a number of findings have shown the crucial role that Semas and their receptors play in the regulation of cancer progression and tumor angiogenesis. In particular, Semas control tumor progression by directly influencing the behavior of cancer cells or, indirectly, by modulating angiogenesis and the function of other cell types in the tumor microenvironment (i.e., inflammatory cells and fibroblasts). Some Semas can activate or inhibit tumor progression and angiogenesis, while others may have the opposite effect depending on specific post-translational modifications. Here we will also discuss the diverse biological effects of Semas and their receptor complexes on cancer progression as well as their impact on the tumor microenvironment.
Topics: Animals; Cell Adhesion Molecules; Humans; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Nerve Tissue Proteins; Neuropilins; Semaphorins; Signal Transduction; Tumor Microenvironment
PubMed: 23422037
DOI: 10.1016/j.yexcr.2013.02.003 -
Cancer Reports (Hoboken, N.J.) Apr 2019IL-37 is a newly identified IL-1 family cytokine. Unlike other members in IL-1 family, IL-37 has been demonstrated to be an anti-inflammatory cytokine in many... (Review)
Review
BACKGROUND
IL-37 is a newly identified IL-1 family cytokine. Unlike other members in IL-1 family, IL-37 has been demonstrated to be an anti-inflammatory cytokine in many inflammatory and autoimmune diseases. IL-37 is regarded as a dual-function cytokine as both the extracellular and intracellular IL-37 are biologically functional. Extracellular IL-37 can bind to IL-18Rα and IL-1R8 to form a triple complex, regulating the downstream STAT3 and PTEN signaling. Intracellular IL-37 can interact with Smad3, translocate into nucleus, and regulate downstream target gene expressions. Recently, the role of IL-37 in tumor development has been extensively studied.
RECENT FINDINGS
IL-37 has been found to play an antitumor role in various types of tumors, such as non-small cell lung cancer, hepatocellular carcinoma, and renal cell carcinoma. Many mechanism studies have been carried out to elaborate the possible effects of IL-37 on tumor growth, immune responses, and tumor angiogenesis. More importantly, the function of IL-37 may be dependent on its concentration and receptor expression. It can form dimers at high concentrations to be inactivated, thus inhibiting its anti-inflammatory function. We focused on the role of IL-37 in various tumor types and provided the hypothesis regarding the underlying mechanisms.
CONCLUSION
IL-37 may affect tumor development through multiple mechanisms: (1) IL-37 directly influences tumor cell viability; (2) IL-37 regulates the immune response to promote the antitumor immunity; and (3) IL-37 suppresses tumor angiogenesis in the tumor microenvironment. Future studies are warranted to further investigate the mechanisms of these multifaceted functions of IL-37 in animal models and cancer patients.
Topics: Animals; Humans; Interleukin-1; Neoplasms; Neovascularization, Pathologic; Recombinant Proteins; Signal Transduction; Tumor Microenvironment
PubMed: 32935478
DOI: 10.1002/cnr2.1151