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Cells Aug 2020Previously, we demonstrated that the homeoprotein Msx1 interaction with p53 inhibited tumor growth by inducing apoptosis. However, Msx1 can exert its tumor suppressive...
Previously, we demonstrated that the homeoprotein Msx1 interaction with p53 inhibited tumor growth by inducing apoptosis. However, Msx1 can exert its tumor suppressive effect through the inhibition of angiogenesis since growth of the tumor relies on sufficient blood supply from the existing vessels to provide oxygen and nutrients for tumor growth. We hypothesized that the inhibition of tumor growth by Msx1 might be due to the inhibition of angiogenesis. Here, we explored the role of Msx1 in angiogenesis. Overexpression of Msx1 in HUVECs inhibited angiogenesis, and silencing of Msx1 by siRNA abrogated its anti-angiogenic effects. Furthermore, forced expression of Msx1 in mouse muscle tissue inhibited vessel sprouting, and application of an Ad-Msx1-transfected conditioned medium onto the chicken chorioallantoic membrane (CAM) led to a significant inhibition of new vessel formation. To explore the underlying mechanism of Msx1-mediated angiogenesis, yeast two-hybrid screening was performed, and we identified PIASy (protein inhibitor of activated STAT Y) as a novel Msx1-interacting protein. We mapped the homeodomain of Msx1 and the C-terminal domain of PIASy as respective interacting domains. Consistent with its anti-angiogenic function, overexpression of Msx1 suppressed the reporter activity of VEGF. Interestingly, PIASy stabilized Msx1 protein, whereas deletion of the Msx1-interacting domain in PIASy abrogated the inhibition of tube formation and the stabilization of Msx1 protein. Our findings suggest the functional importance of PIASy-Msx1 interaction in Msx1-mediated angiogenesis inhibition.
Topics: Animals; Chick Embryo; Human Umbilical Vein Endothelial Cells; Humans; MSX1 Transcription Factor; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; Poly-ADP-Ribose Binding Proteins; Protein Binding; Protein Inhibitors of Activated STAT; Vascular Endothelial Growth Factor A
PubMed: 32784646
DOI: 10.3390/cells9081854 -
Cellular Physiology and Biochemistry :... 2017Calcium and integrin-binding protein 1 (CIB1) is an EF-hand calcium binding protein, which is involved in many cellular processes, including calcium signaling, cell... (Review)
Review
Calcium and integrin-binding protein 1 (CIB1) is an EF-hand calcium binding protein, which is involved in many cellular processes, including calcium signaling, cell survival and proliferation, cell migration, cell adhesion and apoptosis. A number of studies have found that CIB1 is ubiquitously expressed and is related to various human diseases, such as cancer, Alzheimer's disease (AD), cardiac hypertrophy and male infertility. The mechanism of CIB1 in human diseases is still not clear, although multiple functions of CIB1 are modulated by interacting with numerous interacting partners. As a calcium binding protein, the roles of CIB1 in calcium signaling by binding calcium or modulating some key modulators, such as calcineurin, integrin, inositol 1,4,5-trisphosphate receptor (IP3R) and taste 1 receptor member 2 (TAS1R2). The tumor promoting mechanisms of CIB1 have been described in different aspects, including promoting tumor cell cycle and proliferation, inhibiting tumor cell apoptosis, and mediating tumor cell migration and angiogenesis. In addition, multiple functions of CIB1, such as neural development, taste or gustation functions, and virus infection are also elucidated. These recent advances have significantly expanded our understanding of the knowledge of CIB1 and highlighted the potential mechanisms of CIB1 in tumor progression.
Topics: Animals; Calcium Signaling; Calcium-Binding Proteins; Cell Movement; Disease Progression; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 29017172
DOI: 10.1159/000481873 -
BMC Biology Apr 2023Angiogenesis plays important roles in physiological and pathologic conditions, but the mechanisms underlying this complex process often remain to be elucidated. In...
BACKGROUND
Angiogenesis plays important roles in physiological and pathologic conditions, but the mechanisms underlying this complex process often remain to be elucidated. In recent years, liquid-liquid phase separation (LLPS) has emerged as a new concept to explain many cellular functions and diseases. However, whether LLPS is involved in angiogenesis has not been studied until now. Here, we investigated the potential role of LLPS in angiogenesis and endothelial function.
RESULTS
We found 1,6-hexanediol (1,6-HD), an inhibitor of LLPS, but not 2,5-hexanediol (2,5-HD) dramatically decreases neovascularization of Matrigel plug and angiogenesis response of murine corneal in vivo. Moreover, 1,6-HD but not 2,5-HD inhibits microvessel outgrowth of aortic ring and endothelial network formation. The endothelial function of migration, proliferation, and cell growth is suppressed by 1,6-HD. Global transcriptional analysis by RNA-sequencing reveals that 1,6-HD specifically blocks cell cycle and downregulates cell cycle-related genes including cyclin A1. Further experimental data show that 1,6-HD treatment greatly reduces the expression of cyclin A1 but with minimal effect on cyclin D1, cyclin E1, CDK2, and CDK4. The inhibitory effect of 1,6-HD on cyclin A1 is mainly through transcriptional regulation because proteasome inhibitors fail to rescue its expression. Furthermore, overexpression of cyclin A1 in HUVECs largely rescues the dysregulated tube formation upon 1,6-HD treatment.
CONCLUSIONS
Our data reveal a critical role of LLPS inhibitor 1,6-HD in angiogenesis and endothelial function, which specifically affects endothelial G1/S transition through transcriptional suppression of CCNA1, implying LLPS as a possible novel player to modulate angiogenesis, and thus, it might represent an interesting therapeutic target to be investigated in clinic angiogenesis-related diseases in future.
Topics: Humans; Mice; Animals; Cyclin A1; Human Umbilical Vein Endothelial Cells; Cell Movement; Neovascularization, Pathologic; Cell Proliferation
PubMed: 37024934
DOI: 10.1186/s12915-023-01580-8 -
TheScientificWorldJournal 2018Notch signaling pathway is a vital parameter of the mammalian vascular system. In this review, the authors summarize the current knowledge about the impact of the Notch... (Review)
Review
OBJECTIVE
Notch signaling pathway is a vital parameter of the mammalian vascular system. In this review, the authors summarize the current knowledge about the impact of the Notch signaling pathway in breast cancer progression and the therapeutic role of Notch's inhibition.
METHODS
The available literature in MEDLINE, PubMed, and Scopus, regarding the role of the Notch pathway in breast cancer progression was searched for related articles from about 1973 to 2017 including terms such as "Notch," "Breast Cancer," and "Angiogenesis." . Notch signaling controls the differentiation of breast epithelial cells during normal development. Studies confirm that the Notch pathway has a major participation in breast cancer progression through overexpression and/or abnormal genetic type expression of the notch receptors and ligands that determine angiogenesis. The cross-talk of Notch and estrogens, the effect of Notch in breast cancer stem cells formation, and the dependable Notch overexpression during breast tumorigenesis have been studied enough and undoubtedly linked to breast cancer development. The already applied therapeutic inhibition of Notch for breast cancer can drastically change the course of the disease.
CONCLUSION
Current data prove that Notch pathway has a major participation and multiple roles during breast tumor progression. Inhibition of Notch receptors and ligands provides innovative therapeutic results and could become the therapy of choice in the next few years, even though further research is needed to reach safe conclusions.
Topics: Animals; Breast Neoplasms; Female; Humans; Neovascularization, Pathologic; Receptors, Notch; Signal Transduction
PubMed: 30111989
DOI: 10.1155/2018/2415489 -
The Keio Journal of Medicine Mar 2022The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular... (Review)
Review
The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular neovascularization and is seen in diabetic retinopathy, age-related macular degeneration, glaucoma and retinopathy of prematurity. Current treatments for these diseases include laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents and vitreoretinal surgery. Although strategies to inhibit VEGF have proved to be dramatically successful in some clinical studies, there remains the possibility of significant adverse effects regarding the blockade of crucial physiological roles of VEGF and the invasive nature of the treatments. Moreover, it is evident that other pro-angiogenic factors also play important roles in the development of these diseases, as seen in cases in which anti-VEGF therapies have failed. Therefore, new types of effective treatments are required. In this review, we discuss a promising strategy for the treatment of ocular neovascular diseases, i.e., the inhibition of hypoxia-inducible factor (HIF), a master regulator of angiogenesis. We also summarize promising recently investigated HIF inhibitors as treatments for ocular diseases. This review will facilitate more comprehensive approaches to understanding the protective aspects of HIF inhibition in the prevention of ocular diseases.
Topics: Eye; Humans; Infant, Newborn; Macular Degeneration; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 33840673
DOI: 10.2302/kjm.2021-0004-IR -
Medicina (Kaunas, Lithuania) Jul 2022Angiogenesis is the process of developing new blood vessels from pre-existing ones. This review summarizes the main features of physiological and pathological... (Review)
Review
Angiogenesis is the process of developing new blood vessels from pre-existing ones. This review summarizes the main features of physiological and pathological angiogenesis and those of angiogenesis activation and inhibition. In healthy adults, angiogenesis is absent apart from its involvement in female reproductive functions and tissue regeneration. Angiogenesis is a complex process regulated by the action of specific activators and inhibitors. In certain diseases, modulating the angiogenic balance can be a therapeutic route, either by inhibiting angiogenesis (for example in the case of tumor angiogenesis), or by trying to activate the process of new blood vessels formation, which is the goal in case of cardiac or peripheral ischemia.
Topics: Angiogenesis Inhibitors; Cardiovascular Diseases; Female; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 35888622
DOI: 10.3390/medicina58070903 -
International Journal of Molecular... May 2021Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and... (Review)
Review
Retinopathy of prematurity (ROP) is an ocular vascular disease affecting premature infants, characterized by pathological retinal neovascularization (RNV), dilated and tortuous retinal blood vessels, and retinal or vitreous hemorrhages that may lead to retinal detachment, vision impairment and blindness. Compared with other neovascular diseases, ROP is unique because of ongoing and concurrent physiological and pathological angiogenesis in the developing retina. While the disease is currently treated by laser or cryotherapy, anti-vascular endothelial growth factor (VEGF) agents have been extensively investigated but are not approved in the U.S. because of safety concerns that they negatively interfere with physiological angiogenesis of the developing retina. An ideal therapeutic strategy would selectively inhibit pathological but not physiological angiogenesis. Our group recently described a novel strategy that selectively and safely alleviates pathological RNV in animal models of ROP by targeting secretogranin III (Scg3), a disease-restricted angiogenic factor. The preclinical profile of anti-Scg3 therapy presents a high potential for next-generation disease-targeted anti-angiogenic therapy for the ROP indication. This review focuses on retinal vessel development in neonates, the pathogenesis of ROP and its underlying molecular mechanisms, including different animal models, and provides a summary of current and emerging therapies.
Topics: Animals; Animals, Newborn; Chromogranins; Humans; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; Oxygen; Retina; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A
PubMed: 34062733
DOI: 10.3390/ijms22094809 -
Journal of Translational Medicine Sep 2023Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development...
BACKGROUND
Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development of anti-angiogenic medications that target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), the occurrence of adverse reactions and drug resistance has somewhat impeded the widespread application of these drugs. Therefore, additional investigations are warranted to explore alternative therapeutic targets. In recent years, owing to the swift advancement of high-throughput sequencing technology, pan-cancer analysis and single-cell sequencing analysis have emerged as pivotal methodologies and focal areas within the domain of omics research, which is of great significance for us to find potential targets related to the regulation of pathological neovascularization.
METHODS
Pan-cancer analysis and scRNA-seq data analysis were employed to forecast the association between Actin filament-associated protein 1 like 1 (AFAP1L1) and the development of tumors and endothelial cells. Tumor xenograft model and ocular pathological neovascularization model were constructed as well as Isolectin B4 (IsoB4) staining and immunofluorescence staining were used to assess the effects of AFAP1L1 on the progression of neoplasms and neovascular eye diseases in vivo. Transwell assay, wound scratch assay, tube forming assay, three-dimensional germination assay, and rhodamine-phalloidin staining were used to evaluate the impact of AFAP1L1 on human umbilical vein endothelial cells (HUVECs) function in vitro; Dual luciferase reporting, qRT-PCR and western blot were used to investigate the upstream and downstream mechanisms of pathological neovascularization mediated by AFAP1L1.
RESULTS
Our investigation revealed that AFAP1L1 plays a crucial role in promoting the development of various tumors and demonstrates a strong correlation with endothelial cells. Targeted suppression of AFAP1L1 specifically in endothelial cells in vivo proves effective in inhibiting tumor formation and ocular pathological neovascularization. Mechanistically, AFAP1L1 functions as a hypoxia-related regulatory protein that can be activated by HIF-1α. In vitro experiments demonstrated that reducing AFAP1L1 levels can reverse hypoxia-induced excessive angiogenic capacity in HUVECs. The principal mechanism of angiogenesis inhibition entails the regulation of tip cell behavior through the YAP-DLL4-NOTCH axis.
CONCLUSION
In conclusion, AFAP1L1, a newly identified hypoxia-related regulatory protein, can be activated by HIF-1α. Inhibiting AFAP1L1 results in the inhibition of angiogenesis by suppressing the germination of endothelial tip cells through the YAP-DLL4-NOTCH axis. This presents a promising therapeutic target to halt the progression of tumors and neovascular eye disease.
Topics: Humans; Adaptor Proteins, Signal Transducing; Angiogenesis Inhibitors; Calcium-Binding Proteins; Endothelial Cells; Neovascularization, Pathologic; Signal Transduction; Vascular Endothelial Growth Factor A; Animals
PubMed: 37737201
DOI: 10.1186/s12967-023-04503-x -
Cancer Research May 2009Among the regulators of angiogenesis, catecholamine neurotransmitters are of recent interest because of their opposite roles in the regulation of tumor... (Review)
Review
Among the regulators of angiogenesis, catecholamine neurotransmitters are of recent interest because of their opposite roles in the regulation of tumor neovascularization. Norepinephrine and epinephrine by acting through specific adrenoceptors increase the synthesis of proangiogenic factors, and thereby, promote tumor growth. In contrast, dopamine acting via its specific D(2) receptors inhibits tumor growth by suppressing the actions of vascular permeability factor/vascular endothelial growth factor-A on both tumor endothelial and bone marrow-derived endothelial progenitor cells. These reports identify novel endogenous regulators of tumor angiogenesis and also indicate a new and an inexpensive class of antiangiogenic drugs for the treatment of cancer.
Topics: Angiogenesis Inhibitors; Angiogenic Proteins; Animals; Catecholamines; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 19383906
DOI: 10.1158/0008-5472.CAN-08-4289 -
JCI Insight Jun 2023Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In...
Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In this study, we report that the antitumor peptide JP1 regulated mitochondrial metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improved the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibited the secretion of IL-8 by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature resulted in mature and regular blood vessels, which made the tumor microenvironment form a benign feedback loop consisting of vascular normalization, sufficient perfusion, and an oxygen-rich microenvironment, prevented tumor cells from entering the vasculature, and inhibited metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel maintained a certain vascular density in the tumor and promoted tumor vascular normalization, increasing the delivery of oxygen and drugs and enhancing the antitumor effect. Collectively, our work highlights the antitumor peptide JP1 as an inhibitor of metastasis initiation and its mechanism of action.
Topics: Humans; Interleukin-8; Neovascularization, Pathologic; Neoplasms; Paclitaxel; Oxygen; Tumor Microenvironment
PubMed: 37192004
DOI: 10.1172/jci.insight.161675