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Journal Article•DOI•

Angiopoietins in angiogenesis.

Ernesta Fagiani1, Gerhard Christofori1•
University of Basel1
01 Jan 2013-Cancer Letters (Elsevier)-Vol. 328, Iss: 1, pp 18-26
TL;DR: Its central role in the regulation of physiological and pathological angiogenesis makes the angiopoietin/Tie signaling pathway a therapeutically attractive target for the treatment of vascular disease and cancer.
About: This article is published in Cancer Letters.The article was published on 2013-01-01. It has received 528 citations till now. The article focuses on the topics: Angiopoietin & Angiopoietin receptor.
Citations
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Journal Article•DOI•
Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer

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Jonathan Welti1, Sonja Loges, Stefanie Dimmeler, Peter Carmeliet•
Katholieke Universiteit Leuven1
01 Aug 2013-Journal of Clinical Investigation
TL;DR: Recent discoveries of new mechanisms underlying angiogenesis are examined, successes and challenges of current antiangiogenic therapy are discussed, and emerging antiangIogenic paradigms are highlighted.
Abstract: Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.

537 citations

Cites background from "Angiopoietins in angiogenesis."

  • ...org Volume 123 Number 8 August 2013 3193 Ang2 on tumor progression upon over- or underexpression are complex and often divergent (26)....

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Journal Article•DOI•
Diabetes and Wound Angiogenesis.

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Uzoagu A. Okonkwo1, Luisa A. DiPietro1•
University of Illinois at Chicago1
03 Jul 2017-International Journal of Molecular Sciences
TL;DR: This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis and considers therapeutics that may offer promise to better wound healing outcomes.
Abstract: Diabetes Mellitus Type II (DM2) is a growing international health concern with no end in sight. Complications of DM2 involve a myriad of comorbidities including the serious complications of poor wound healing, chronic ulceration, and resultant limb amputation. In skin wound healing, which has definite, orderly phases, diabetes leads to improper function at all stages. While the etiology of chronic, non-healing diabetic wounds is multi-faceted, the progression to a non-healing phenotype is closely linked to poor vascular networks. This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis. Additionally, this review considers therapeutics that may offer promise to better wound healing outcomes.

484 citations

Cites background from "Angiopoietins in angiogenesis."

  • ...In addition to PEDF and SPRY2, another group of factors known to influence the normal progression of wound capillary growth and remodeling are the angiopoietins 1 and 2, which work in concert with the Tie2 receptor [63]....

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Journal Article•DOI•
Small molecules in targeted cancer therapy: advances, challenges, and future perspectives.

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Lei Zhong1, Y. Li1, Liang Xiong1, Wen-Jing Wang1, Ming Wu1, Ting Yuan2, Wei Yang1, Chenyu Tian1, Zhuang Miao1, Tianqi Wang1, Shengyong Yang1 •
Sichuan University1, University of Electronic Science and Technology of China2
31 May 2021-Signal Transduction and Targeted Therapy
TL;DR: A comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification is conducted, which presents all the approved drugs as well as important drug candidates in clinical trials for each target, and discusses the current challenges.
Abstract: Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

398 citations

Journal Article•DOI•
Macro- and microvascular endothelial dysfunction in diabetes

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Yi Shi1, Paul M. Vanhoutte2•
Fudan University1, Li Ka Shing Faculty of Medicine, University of Hong Kong2
01 May 2017-Journal of Diabetes
TL;DR: This reviews pays special attention to microRNAs and their modulatory role in diabetes‐induced vascular dysfunction and some therapeutic strategies for preventing and restoring diabetic endothelial dysfunction are highlighted.
Abstract: Endothelial cells, as well as their major products nitric oxide (NO) and prostacyclin, play a key role in the regulation of vascular homeostasis. Diabetes mellitus is an important risk factor for cardiovascular disease. Diabetes-induced endothelial dysfunction is a critical and initiating factor in the genesis of diabetic vascular complications. The present review focuses on both large blood vessels and the microvasculature. The endothelial dysfunction in diabetic macrovascular complications is characterized by reduced NO bioavailability, poorly compensated for by increased production of prostacyclin and/or endothelium-dependent hyperpolarizations, and increased production or action of endothelium-derived vasoconstrictors. The endothelial dysfunction of microvascular complications is primarily characterized by decreased release of NO, enhanced oxidative stress, increased production of inflammatory factors, abnormal angiogenesis, and impaired endothelial repair. In addition, non-coding RNAs (microRNAs) have emerged as participating in numerous cellular processes. Thus, this reviews pays special attention to microRNAs and their modulatory role in diabetes-induced vascular dysfunction. Some therapeutic strategies for preventing and restoring diabetic endothelial dysfunction are also highlighted.

318 citations

Cites background from "Angiopoietins in angiogenesis."

  • ...In cell culture, VEGF stimulation increases NO production by upregulating eNOS expression in endothelial cells,118–120 whereas VEGF-induced angiogenesis is antagonized by NG-nitro-L-arginine methyl ester (L-NAME; an inhibitor of eNOS).121 In diabetic rats, the number of CD34+ glomerular endothelial cells is increased, which is in line with the upregulation of VEGF, but renal nitrite levels are reduced.77 The reduced proteinuria caused by blockade of VEGF receptors in diabetic rats is reversed by LNAME treatment.77 In diabetic patients with retinopathy, high levels of VEGF are accompanied by eNOS uncoupling and augmented inflammation.122 The abnormal angiogenesis in diabetic retinopathy and nephropathy is probably due to increased oxidative stress84 and enhanced expression and/or activity of arginase.85,123 Taken together, the available data suggest that diabetes interrupts the coupling between VEGF and NO.76 Angiopoietins are vascular growth factors, participating in neovascular genesis and blood vessel repair.124 Angiopoietin (ANGPT) 1 stabilizes the vascular wall, whereas ANGPT2, competing with ANGPT1, destabilizes it125 by inducing cell apoptosis.68 In addition, ANGPT2 promotes neovascularization when binding to VEGF.126 In the porcine kidney and human retina, diabetes reduces the expression of ANGPT1,124,127,128 but increases the expression of ANGPT2,68,129,130 disturbing the balance between the two ANGPTs in favor of the latter.131,132 Treatment targeting ANGPTs reduces vascular damage and improves vascular integrity.127,133 Angiopoietin-like 4 (ANGPTL4) has beneficial effects on vascular permeability in diabetic retinopathy.134 This effect of ANGPTL4 is independent of VEGF because anti-VEGF treatment of the retina does not alter the vitreous concentration of ANGPTL4,135 which thus may represent a new target for the treatment of diabetic microvascular complications....

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  • ...ANGPT2 promotes neovascularization when binding to VEGF.(126) In the porcine kidney and human retina, diabetes reduces the expression of ANGPT1,(124,127,128) but increases the expression of ANGPT2,(68,129,130) disturbing the balance between the two ANGPTs in favor of the latter....

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Journal Article•DOI•
FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review)

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Masaru Katoh
01 Jul 2016-International Journal of Molecular Medicine
TL;DR: The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment.
Abstract: Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.

283 citations

Cites background from "Angiopoietins in angiogenesis."

  • ...ANGPT2 is secreted from endothelial cells and promotes the endothelial activation or sprouting through TIE2 signaling inhibition (92,93)....

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References
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Journal Article•DOI•
Hallmarks of cancer: the next generation.

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Douglas Hanahan1, Robert A. Weinberg2•
ISREC1, Massachusetts Institute of Technology2
04 Mar 2011-Cell
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

51,099 citations

Journal Article•DOI•
Isolation of putative progenitor endothelial cells for angiogenesis.

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Takayuki Asahara1, Toyoaki Murohara1, Alison Sullivan1, Marcy Silver1, Rien van der Zee1, Tong Li1, Bernhard Witzenbichler1, Gina C. Schatteman1, Jeffrey M. Isner1 •
Tufts University1
14 Feb 1997-Science
TL;DR: It is suggested that EC progenitors may be useful for augmenting collateral vessel growth to ischemic tissues (therapeutic angiogenesis) and for delivering anti- or pro-angiogenic agents, respectively, to sites of pathologic or utilitarianAngiogenesis.
Abstract: Putative endothelial cell (EC) progenitors or angioblasts were isolated from human peripheral blood by magnetic bead selection on the basis of cell surface antigen expression In vitro, these cells differentiated into ECs In animal models of ischemia, heterologous, homologous, and autologous EC progenitors incorporated into sites of active angiogenesis These findings suggest that EC progenitors may be useful for augmenting collateral vessel growth to ischemic tissues (therapeutic angiogenesis) and for delivering anti- or pro-angiogenic agents, respectively, to sites of pathologic or utilitarian angiogenesis

8,598 citations

Journal Article•DOI•
Hallmarks of Cancer: The Next Generation

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M.F. Roizen
01 Jan 2012-Yearbook of Anesthesiology and Pain Management

7,570 citations

"Angiopoietins in angiogenesis." refers background in this paper

  • ...They arise from both cancer cells and stromal cells in response to metabolic stress and/ or mechanical stress, genetic mutations, the immune response, but most prominently tissue hypoxia and autocrine and paracrine growth factor stimulation [21,22]....

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  • ...This angiogenic switch [23] provokes the expression of a variety of angiogenic factors by tumor cells and also by stromal cells, including VEGF-A, FGF, platelet-derived growth factors (PDGFs), lysophosphatic acid (LPA), and angiopoietins [21]....

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Journal Article•DOI•
Molecular mechanisms and clinical applications of angiogenesis

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Peter Carmeliet1, Rakesh K. Jain2•
Katholieke Universiteit Leuven1, Harvard University2
19 May 2011-Nature
TL;DR: Preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
Abstract: Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.

4,441 citations

Journal Article•DOI•
Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis

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Maisonpierre Peter C1, Chitra Suri1, Pamela F. Jones1, Sona Bartunkova1, Stanley J. Wiegand1, Czeslaw Radziejewski1, Debra L Compton1, Joyce Mcclain1, Aldrich Thomas H1, Nick Papadopoulos1, Thomas J. Daly1, Samuel Davis1, Thomas N. Sato1, George D. Yancopoulos1 •
Beth Israel Deaconess Medical Center1
04 Jul 1997-Science
TL;DR: The discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.
Abstract: Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.

3,552 citations

Related Papers (5)
Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis

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04 Jul 1997-Science
Maisonpierre Peter C, Chitra Suri, Pamela F. Jones, Sona Bartunkova, Stanley J. Wiegand, Czeslaw Radziejewski, Debra L Compton, Joyce Mcclain, Aldrich Thomas H, Nick Papadopoulos, Thomas J. Daly, Samuel Davis, Thomas N. Sato, George D. Yancopoulos 
Molecular mechanisms and clinical applications of angiogenesis

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19 May 2011-Nature
Peter Carmeliet, Rakesh K. Jain
Tumor Angiogenesis: Therapeutic Implications

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18 Nov 1971-The New England Journal of Medicine
Judah Folkman
The biology of VEGF and its receptors.

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01 Jun 2003-Nature Medicine
Napoleone Ferrara, Hans-Peter Gerber, Jennifer LeCouter
Hallmarks of cancer: the next generation.

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04 Mar 2011-Cell
Douglas Hanahan, Robert A. Weinberg