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Experimental and Therapeutic Medicine Mar 2020Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation,... (Review)
Review
Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.
PubMed: 32104259
DOI: 10.3892/etm.2020.8454 -
Signal Transduction and Targeted Therapy May 2023Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in... (Review)
Review
Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.
Topics: Humans; Vascular Endothelial Growth Factor A; Neoplasms; Neovascularization, Pathologic; Angiogenesis Inhibitors; Signal Transduction
PubMed: 37169756
DOI: 10.1038/s41392-023-01460-1 -
Oncology Letters Jul 2018When Folkman first suggested a theory about the association between angiogenesis and tumor growth in 1971, the hypothesis of targeting angiogenesis to treat cancer was... (Review)
Review
When Folkman first suggested a theory about the association between angiogenesis and tumor growth in 1971, the hypothesis of targeting angiogenesis to treat cancer was formed. Since then, various studies conducted across the world have additionally confirmed the theory of Folkman, and numerous efforts have been made to explore the possibilities of curing cancer by targeting angiogenesis. Among them, anti-angiogenic gene therapy has received attention due to its apparent advantages. Although specific problems remain prior to cancer being fully curable using anti-angiogenic gene therapy, several methods have been explored, and progress has been made in pre-clinical and clinical settings over previous decades. The present review aimed to provide up-to-date information concerning tumor angiogenesis and gene delivery systems in anti-angiogenic gene therapy, with a focus on recent developments in the study and application of the most commonly studied and newly identified anti-angiogenic candidates for anti-angiogenesis gene therapy, including interleukin-12, angiostatin, endostatin, tumstatin, anti-angiogenic metargidin peptide and endoglin silencing.
PubMed: 29963134
DOI: 10.3892/ol.2018.8733 -
Journal of Cancer Research and Clinical... Dec 2021The development of blood vessels, referred to as angiogenesis, is an intricate process regulated spatially and temporally through a delicate balance between the... (Review)
Review
The development of blood vessels, referred to as angiogenesis, is an intricate process regulated spatially and temporally through a delicate balance between the qualitative and quantitative expression of pro and anti-angiogenic molecules. As angiogenesis is a prerequisite for solid tumors to grow and metastasize, a variety of tumor angiogenesis models have been formulated to better understand the underlying mechanisms and associated clinical applications. Studies have demonstrated independent mechanisms inducing angiogenesis in tumors such as (a) HIF-1/VEGF mediated paracrine interactions between a cancer cell and endothelial cells, (b) recruitment of progenitor endothelial cells, and (c) vasculogenic mimicry. Moreover, single-cell sequencing technologies have indicated endothelial cell heterogeneity among organ systems including tumor tissues. However, existing angiogenesis models often rely upon normal endothelial cells which significantly differ from tumor endothelial cells exhibiting distinct (epi)genetic and metabolic signatures. Besides, the existence of intra-individual variations necessitates the development of improved tumor vascular model systems for personalized medicine. In the present review, we summarize recent advancements of 3D tumor vascular model systems which include (a) tissue engineering-based tumor models; (b) vascular organoid models, and (c) organ-on-chips and their importance in replicating the tumor angiogenesis along with the associated challenges to design improved models.
Topics: Animals; Humans; Neoplasms; Neovascularization, Pathologic; Organoids; Tissue Engineering
PubMed: 34613483
DOI: 10.1007/s00432-021-03814-0 -
Nature Reviews. Cancer Aug 2017Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic... (Review)
Review
Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
Topics: Adipocytes; Animals; Blood Platelets; Cancer-Associated Fibroblasts; Eosinophils; Extracellular Matrix; Extracellular Vesicles; Humans; Lymphocytes; Macrophages; Mast Cells; Myeloid Cells; Neoplasms; Neovascularization, Pathologic; Neutrophils; Pericytes; Tumor Microenvironment
PubMed: 28706266
DOI: 10.1038/nrc.2017.51 -
Theranostics 2019By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into...
By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood. The GEPIA database and hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated and . Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs. miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway. These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.
Topics: Angiogenesis Inducing Agents; Exosomes; Female; Humans; MicroRNAs; Neoplasm Metastasis; Neovascularization, Pathologic; Ovarian Neoplasms
PubMed: 31754391
DOI: 10.7150/thno.37455 -
International Journal of Biological... Nov 2022Angiogenesis forms new vessels from existing ones. Abnormal angiogenesis, which is what gives tumor microenvironments their distinctive features, is characterised by... (Review)
Review
Angiogenesis forms new vessels from existing ones. Abnormal angiogenesis, which is what gives tumor microenvironments their distinctive features, is characterised by convoluted, permeable blood vessels with a variety of shapes and high perfusion efficiency. Tumor angiogenesis controls cancer growth by allowing invasion and metastasis and is highly controlled by signalling networks. Therapeutic techniques targeting VEGF, PDGF, FGF Notch, Angiopoietin, and HGF signalling restrict the tumor's vascular supply. Numerous pathways regulate angiogenesis, and when one of those processes is blocked, the other pathways may step in to help. VEGF signalling inhibition alone has limits as an antiangiogenic therapy, and additional angiogenic pathways such as FGF, PDGF, Notch, angiopoietin, and HGF are important. For the treatment of advanced solid tumors, there are also new, emerging medicines that target multiple angiogenic pathways. Recent therapies block numerous signalling channels concurrently. This study focuses on 'alternative' methods to standard antiangiogenic medicines, such as cyclooxygenase-2 blocking, oligonucleotide binding complementary sites to noncoding RNAs to regulate mRNA target, matrix metalloproteinase inhibition and CRISPR/Cas9 based gene edition and dissecting alternative angiogenesis mechanism in tumor microenvironment.
Topics: Humans; Vascular Endothelial Growth Factor A; Angiopoietins; Neovascularization, Pathologic; Signal Transduction; Angiogenesis Inhibitors; Neoplasms; Tumor Microenvironment; Hepatocyte Growth Factor
PubMed: 36122781
DOI: 10.1016/j.ijbiomac.2022.09.129 -
Neuro-oncology May 2023Tumor angiogenesis is essential for solid tumor progression, invasion and metastasis. The aim of this study was to identify potential signaling pathways involved in...
BACKGROUND
Tumor angiogenesis is essential for solid tumor progression, invasion and metastasis. The aim of this study was to identify potential signaling pathways involved in tumor angiogenesis.
METHODS
Genetically engineered mouse models were used to investigate the effects of endothelial ARL13B(ADP-ribosylation factor-like GTPase 13B) over-expression and deficiency on retinal and cerebral vasculature. An intracranially transplanted glioma model and a subcutaneously implanted melanoma model were employed to examine the effects of ARL13B on tumor growth and angiogenesis. Immunohistochemistry was used to measure ARL13B in glioma tissues, and scRNA-seq was used to analyze glioma and endothelial ARL13B expression. GST-fusion protein-protein interaction and co-immunoprecipitation assays were used to determine the ARL13B-VEGFR2 interaction. Immunobloting, qPCR, dual-luciferase reporter assay and functional experiments were performed to evaluate the effects of ARL13B on VEGFR2 activation.
RESULTS
Endothelial ARL13B regulated vascular development of both the retina and brain in mice. Also, ARL13B in endothelial cells regulated the growth of intracranially transplanted glioma cells and subcutaneously implanted melanoma cells by controlling tumor angiogenesis. Interestingly, this effect was attributed to ARL13B interaction with VEGFR2, through which ARL13B regulated the membrane and ciliary localization of VEGFR2 and consequently activated its downstream signaling in endothelial cells. Consistent with its oncogenic role, ARL13B was highly expressed in human gliomas, which was well correlated with the poor prognosis of glioma patients. Remarkably, ARL13B, transcriptionally regulated by ZEB1, enhanced the expression of VEGFA by activating Hedgehog signaling in glioma cells.
CONCLUSIONS
ARL13B promotes angiogenesis and tumor growth by activating VEGFA-VEGFR2 signaling. Thus, targeting ARL13B might serve as a potential approach for developing an anti-glioma or anti-melanoma therapy.
Topics: Humans; Mice; Animals; Endothelial Cells; Hedgehog Proteins; Signal Transduction; Glioma; Neovascularization, Pathologic; Cell Proliferation; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor A; ADP-Ribosylation Factors
PubMed: 36322624
DOI: 10.1093/neuonc/noac245 -
Cold Spring Harbor Perspectives in... Jan 2023The formation of new blood and lymphatic vessels is essential for both the development of multicellular organisms and (patho)physiological processes like wound repair... (Review)
Review
The formation of new blood and lymphatic vessels is essential for both the development of multicellular organisms and (patho)physiological processes like wound repair and tumor growth. In the 1990s, circulating blood platelets were first postulated to regulate tumor angiogenesis by interacting with the endothelium and releasing angiogenic regulators from specialized α granules. Since then, many studies have validated the contributions of platelets to tumor angiogenesis, while uncovering novel roles for platelets in other angiogenic processes like wound resolution and retinal vascular disease. Although the majority of (lymph)angiogenesis occurs during development, platelets appear necessary for lymphatic but not vascular growth, implying their particular importance in pathological cases of adult angiogenesis. Future work is required to determine whether drugs targeting platelet production or function offer a clinically relevant tool to limit detrimental angiogenesis.
Topics: Humans; Blood Platelets; Neovascularization, Physiologic; Neovascularization, Pathologic; Neoplasms; Lymphatic Vessels
PubMed: 35534208
DOI: 10.1101/cshperspect.a041174 -
Cell Research Jul 2022Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1...
Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na-dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na/Ca exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.
Topics: Animals; Endothelial Cells; Excitatory Amino Acid Transporter 3; Glutarates; Isocitrate Dehydrogenase; Mice; Mitochondria; Mutation; Neoplasms; Tumor Microenvironment
PubMed: 35459936
DOI: 10.1038/s41422-022-00650-w