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Cellular and Molecular Life Sciences :... May 2020Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously... (Review)
Review
Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.
Topics: Angiogenesis Inhibitors; Animals; Humans; Neoplasms; Neovascularization, Pathologic; Signal Transduction
PubMed: 31690961
DOI: 10.1007/s00018-019-03351-7 -
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 -
Nature Reviews. Clinical Oncology Dec 2021Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer... (Review)
Review
Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer progression through complex interactions with other cell types in the tumour microenvironment. As well as generating extracellular matrix components that contribute to the structure and function of the tumour stroma, CAFs undergo epigenetic changes to produce secreted factors, exosomes and metabolites that influence tumour angiogenesis, immunology and metabolism. Because of their putative pro-oncogenic functions, CAFs have long been considered an attractive therapeutic target; however, clinical trials of treatment strategies targeting CAFs have mostly ended in failure and, in some cases, accelerated cancer progression and resulted in inferior survival outcomes. Importantly, CAFs are heterogeneous cells and their characteristics and interactions with other cell types might change dynamically as cancers evolve. Studies involving single-cell RNA sequencing and novel mouse models have increased our understanding of CAF diversity, although the context-dependent roles of different CAF populations and their interchangeable plasticity remain largely unknown. Comprehensive characterization of the tumour-promoting and tumour-restraining activities of CAF subtypes, including how these complex bimodal functions evolve and are subjugated by neoplastic cells during cancer progression, might facilitate the development of novel diagnostic and therapeutic approaches. In this Review, the clinical relevance of CAFs is summarized with an emphasis on their value as prognosis factors and therapeutic targets.
Topics: Cancer-Associated Fibroblasts; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Tumor Microenvironment
PubMed: 34489603
DOI: 10.1038/s41571-021-00546-5 -
The Journal of Clinical Investigation Oct 2023Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing...
Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1-overexpressing cells and decreased in BACH1-knockout cells in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HIF1A-knockout and WT cells. BACH1 was found to be a transcriptional target of HIF1α, but BACH1's ability to stimulate angiogenesis gene expression was HIF1α independent. Antioxidants increased tumor vascularity in vivo in a BACH1-dependent fashion, and overexpressing BACH1 rendered tumors sensitive to antiangiogenesis therapy. BACH1 expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor.
Topics: Humans; Antioxidants; Basic-Leucine Zipper Transcription Factors; Hypoxia; Lung Neoplasms; Neovascularization, Pathologic; Animals; Mice
PubMed: 37651203
DOI: 10.1172/JCI169671 -
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 -
Frontiers in Oncology 2021Early growth response factor 1 (EGR1) is a transcription factor that is mainly involved in the processes of tissue injury, immune responses, and fibrosis. Recent studies... (Review)
Review
Early growth response factor 1 (EGR1) is a transcription factor that is mainly involved in the processes of tissue injury, immune responses, and fibrosis. Recent studies have shown that EGR1 is closely related to the initiation and progression of cancer and may participate in tumor cell proliferation, invasion, and metastasis and in tumor angiogenesis. Nonetheless, the specific mechanism whereby EGR1 modulates these processes remains to be elucidated. This review article summarizes possible mechanisms of action of EGR1 in tumorigenesis and tumor progression and may serve as a reference for clinical efficacy predictions and for the discovery of new therapeutic targets.
PubMed: 33842351
DOI: 10.3389/fonc.2021.642547 -
Journal of Experimental & Clinical... Sep 2020Tumor angiogenesis is necessary for the continued survival and development of tumor cells, and plays an important role in their growth, invasion, and metastasis. The... (Review)
Review
Tumor angiogenesis is necessary for the continued survival and development of tumor cells, and plays an important role in their growth, invasion, and metastasis. The tumor microenvironment-composed of tumor cells, surrounding cells, and secreted cytokines-provides a conducive environment for the growth and survival of tumors. Different components of the tumor microenvironment can regulate tumor development. In this review, we have discussed the regulatory role of the microenvironment in tumor angiogenesis. High expression of angiogenic factors and inflammatory cytokines in the tumor microenvironment, as well as hypoxia, are presumed to be the reasons for poor therapeutic efficacy of current anti-angiogenic drugs. A combination of anti-angiogenic drugs and antitumor inflammatory drugs or hypoxia inhibitors might improve the therapeutic outcome.
Topics: Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 32993787
DOI: 10.1186/s13046-020-01709-5 -
Cell Metabolism Apr 2020Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known...
Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.
Topics: Animals; Endothelial Cells; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms; Macular Degeneration; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 32268117
DOI: 10.1016/j.cmet.2020.03.009 -
Cell Metabolism May 2020While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels...
While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFκB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A first-in-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis.
Topics: Animals; Cells, Cultured; Female; GTP Phosphohydrolases; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; NF-kappa B; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Zebrafish
PubMed: 32315597
DOI: 10.1016/j.cmet.2020.04.007