The Role of Angiogenesis in Cancer Treatment.

doi:10.3390/BIOMEDICINES5020034

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The Role of Angiogenesis in Cancer Treatment.

Journal Article•DOI•

The Role of Angiogenesis in Cancer Treatment.

Mehdi Rajabi¹, Shaker A. Mousa¹•Institutions (1)

Albany College of Pharmacy and Health Sciences¹

21 Jun 2017-Biomedicines (Multidisciplinary Digital Publishing Institute)-Vol. 5, Iss: 2, pp 34

TL;DR: Combinations of anti-angiogenic drugs and other anticancer strategies such as chemotherapy appear essential for optimal outcome in cancer patients.

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Abstract: A number of anti-angiogenesis drugs have been FDA-approved and are being used in cancer treatment, and a number of other agents are in different stages of clinical development or in preclinical evaluation. However, pharmacologic anti-angiogenesis strategies that arrest tumor progression might not be enough to eradicate tumors. Decreased anti-angiogenesis activity in single mechanism-based anti-angiogenic strategies is due to the redundancy, multiplicity, and development of compensatory mechanism by which blood vessels are remodeled. Improving anti-angiogenesis drug efficacy will require identification of broad-spectrum anti-angiogenesis targets. These strategies may have novel features, such as increased porosity, and are the result of complex interactions among endothelial cells, extracellular matrix proteins, growth factors, pericyte, and smooth muscle cells. Thus, combinations of anti-angiogenic drugs and other anticancer strategies such as chemotherapy appear essential for optimal outcome in cancer patients. This review will focus on the role of anti-angiogenesis strategies in cancer treatment.

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Journal Article•DOI•

Approaches to treat immune hot, altered and cold tumours with combination immunotherapies

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Jérôme Galon¹, Daniela Bruni¹•Institutions (1)

Paris Descartes University¹

01 Mar 2019-Nature Reviews Drug Discovery

TL;DR: A panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours is provided and the impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.

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Abstract: Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.

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1,680 citations

Journal Article•

Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis.

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Carmen Stanca Melincovici, Adina Bianca Boşca, Sergiu Susman, Mariana Mărginean, Carina Mihu, Mihnea Istrate, Ioana Maria Moldovan, Alexandra Roman, Carmen Mihaela Mihu - Show less +5 more

01 Jan 2018-Romanian Journal of Morphology and Embryology

TL;DR: This article aims to highlight the most recent data referring to the VEGF family and its receptors, as well as its implications in the angiogenesis process.

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Abstract: Vascular endothelial growth factor (VEGF) represents a growth factor with important pro-angiogenic activity, having a mitogenic and an anti-apoptotic effect on endothelial cells, increasing the vascular permeability, promoting cell migration, etc. Due to these effects, it actively contributes in regulating the normal and pathological angiogenic processes. In humans, the VEGF family is composed of several members: VEGF-A (which has different isoforms), VEGF-B, VEGF-C, VEGF-D, VEGF-E (viral VEGF), VEGF-F (snake venom VEGF), placenta growth factor (PlGF), and, recently, to this family has been added endocrine gland-derived vascular endothelial growth factor (EG-VEGF). VEGF binds to tyrosine kinase cell receptors (VEGFRs): VEGFR-1 [Fms-like tyrosine kinase 1 (Flt-1)], VEGFR-2 [kinase insert domain receptor (KDR) in human; fetal liver kinase 1 (Flk-1) in mouse] and VEGFR-3 [Fms-like tyrosine kinase 4 (Flt-4)]. While VEGFR-1 and VEGFR-2 are expressed predominantly on vascular endothelial cells, VEGFR-3 is expressed especially on lymphatic endothelial cells. VEGFR-2 has the strongest pro-angiogenic activity and a higher tyrosine kinase activity than VEGFR-1. Endothelial cells also express co-receptors, such as neuropilin-1 (NP-1) and neuropilin-2 (NP-2), which modulate tyrosine kinase receptor activity. Both VEGF and VEGFRs are expressed not only on endothelial cells, but also on non-endothelial cells. This article aims to highlight the most recent data referring to the VEGF family and its receptors, as well as its implications in the angiogenesis process. At present, blocking angiogenesis in cancer or in other pathological processes, using anti-VEGF and anti-VEGFRs therapies, is considered to be extremely important.

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524 citations

Journal Article•DOI•

Role of Matrix Metalloproteinases in Angiogenesis and Cancer.

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Saray Quintero-Fabián, Rodrigo Arreola, Enrique Becerril-Villanueva, Julio César Torres-Romero¹, Victor Arana-Argáez¹, Julio Lara-Riegos¹, Mario Alberto Ramírez-Camacho¹, María Elizbeth Alvarez-Sánchez² - Show less +4 more•Institutions (2)

Universidad Autónoma de Yucatán¹, Universidad Autónoma de la Ciudad de México²

06 Dec 2019-Frontiers in Oncology

TL;DR: This review analyzes recent knowledge on MMPs and their participation in angiogenesis through the modulation of the balance between pro- and anti-angiogenic factors and concludes that Matrix metalloproteinases participate in the disruption, tumor neovascularization, and subsequent metastasis.

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Abstract: During angiogenesis, new vessels emerge from existing endothelial lined vessels to promote the degradation of the vascular basement membrane and remodel the extracellular matrix (ECM), followed by endothelial cell migration, and proliferation and the new generation of matrix components. Matrix metalloproteinases (MMPs) participate in the disruption, tumor neovascularization, and subsequent metastasis while tissue inhibitors of metalloproteinases (TIMPs) downregulate the activity of these MMPs. Then, the angiogenic response can be directly or indirectly mediated by MMPs through the modulation of the balance between pro- and anti-angiogenic factors. This review analyzes recent knowledge on MMPs and their participation in angiogenesis.

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488 citations

Cites background from "The Role of Angiogenesis in Cancer ..."

...Subsequently, a wave of growth factors such as EGF, basic and acidic FGF, estrogen, prostaglandin E1 and E2, IL-8, TGF, TNF, neuropilins, and VEGF promotes the formation of a vascular network that ensures the exchange of oxygen and nutrients with the tumor (5, 31, 47, 48)....
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...New blood vessels require the dismantling of endothelial lined vessels via the “sprouting” of endothelial cells (ECs), expanding the vascular tree (31)....
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Journal Article•DOI•

Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook.

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Josep Garcia¹, Herbert Hurwitz², Alan Sandler², David Miles, Robert L. Coleman³, Regula Deurloo¹, Olivier Chinot⁴ - Show less +3 more•Institutions (4)

Hoffmann-La Roche¹, Genentech², University of Texas MD Anderson Cancer Center³, Aix-Marseille University⁴

01 Jun 2020-Cancer Treatment Reviews

TL;DR: Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.

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417 citations

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 - Show less +7 more•Institutions (2)

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.

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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.

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398 citations

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References

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Open Access

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Journal Article•DOI•

The biology of VEGF and its receptors.

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Napoleone Ferrara¹, Hans-Peter Gerber¹, Jennifer LeCouter¹•Institutions (1)

Genentech¹

01 Jun 2003-Nature Medicine

TL;DR: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions and is implicated in pathologicalAngiogenesis associated with tumors, intraocular neovascular disorders and other conditions.

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Abstract: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

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8,942 citations

Journal Article•DOI•

Targeting HIF-1 for cancer therapy

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Gregg L. Semenza¹•Institutions (1)

Johns Hopkins University School of Medicine¹

01 Oct 2003-Nature Reviews Cancer

TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.

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Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

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6,024 citations

"The Role of Angiogenesis in Cancer ..." refers background in this paper

...Each of the three isoforms of HIFα (HIF-1–3) can heterodimerize with the aryl hydrocarbon receptor nuclear translocator (HIFβ/ARNT) subunit to form an active transcriptional complex that initiates expression of hundreds of genes, including those regulating cell survival, metabolism, and angiogenesis [35]....
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Journal Article•DOI•

Mechanisms of angiogenesis

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Werner Risau¹•Institutions (1)

Max Planck Society¹

17 Apr 1997-Nature

TL;DR: Understanding of the molecular basis underlying angiogenesis, particularly from the study of mice lacking some of the signalling systems involved, has greatly improved, and may suggest new approaches for treating conditions such as cancer that depend onAngiogenesis.

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Abstract: After the developing embryo has formed a primary vascular plexus by a process termed vasculogenesis, further blood vessels are generated by both sprouting and non-sprouting angiogenesis, which are progressively pruned and remodelled into a functional adult circulatory system. Recent results, particularly from the study of mice lacking some of the signalling systems involved, have greatly improved our understanding of the molecular basis underlying these events, and may suggest new approaches for treating conditions such as cancer that depend on angiogenesis.

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5,793 citations

"The Role of Angiogenesis in Cancer ..." refers background in this paper

...The generation of new blood vessels is from pre-existing blood cells via the “sprouting” of endothelial cells, thus expanding the vascular tree (Figure 1A) [1,2]....
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Journal Article•DOI•

Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy

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Rakesh K. Jain¹•Institutions (1)

Harvard University¹

07 Jan 2005-Science

TL;DR: Emerging evidence supporting an alternative hypothesis is reviewed—that certain antiangiogenic agents can also transiently “normalize” the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery.

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Abstract: Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. The widely held view is that these antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Here, I review emerging evidence supporting an alternative hypothesis-that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. Drugs that induce vascular normalization can alleviate hypoxia and increase the efficacy of conventional therapies if both are carefully scheduled. A better understanding of the molecular and cellular underpinnings of vascular normalization may ultimately lead to more effective therapies not only for cancer but also for diseases with abnormal vasculature, as well as regenerative medicine, in which the goal is to create and maintain a functionally normal vasculature.

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4,952 citations

Journal Article•DOI•

Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.

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Michael S. O'Reilly¹, Thomas Boehm¹, Yuen Shing¹, Naomi Fukai², George Vasios, William S. Lane², Evelyn Flynn¹, James R Birkhead, Bjorn R. Olsen², Judah Folkman¹ - Show less +6 more•Institutions (2)

Boston Children's Hospital¹, Harvard University²

24 Jan 1997-Cell

TL;DR: This work has identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma, a 20 kDa C-terminal fragment of collagen XVIII that specifically inhibits endothelial proliferation and potently inhibitsAngiogenesis and tumor growth.

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4,613 citations

"The Role of Angiogenesis in Cancer ..." refers background in this paper

...Soluble VEGF-1 Decoy receptors for VEGF-B [5] Angio tatin Suppr ss EC adhesion, migration, proliferation [6] Thrombospondin-1 and -2 Suppress EC adhesion, migration, proliferation [7] Angiopoietin-2 Oppose Angiopoietin 1 [8] Platelet Factor-4 Inhibit bFGF (FGF2) and VEGF binding [9,10] Endostatin Suppress EC adhesion, migration, proliferation [6,11] Anti-thrombin I I Fragment Suppress EC adhesion, migration, proliferation [12] Osteopontin Serve as ligand for integrin binding [13] Collagen Substrate for MMPs [14,15] Kininogen Domains Suppress EC adhesion, migration, proliferation [16] Tissue Factor Pathways Inhibitor Antagonist for Tissue Factor [17] Vasostatin Suppress EC adhesion [18,19] Calreticulin Suppress EC adhesion [20] TIMPs Suppress EC adhesion [21,22] A cartilage-derived angiogenesis inhibitor Suppress EC adhesion [23] Meth-1 and Meth-2 Suppress EC adhesion [24] Maspin Inhibits proteases [25] Laminin 511 Suppresses metastases [26,27] CCN3 Suppresses EC adhesion [28] Endorepellin Suppresses EC adhesion [29] MULTIMERIN2 (Endoglyx-1) Suppresses EC migration [30]...
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...Endogenous Angiogenesis Inhibitors Mechanisms Reference Soluble VEGF-1 Decoy receptors for VEGF-B [5] Angiostatin Suppress EC adhesion, migration, proliferation [6] Thrombospondin-1 and -2 Suppress EC adhesion, migration, proliferation [7] Angiopoietin-2 Oppose Angiopoietin 1 [8] Platelet Factor-4 Inhibit bFGF (FGF2) and VEGF binding [9,10] Endostatin Suppress EC adhesion, migration, proliferation [6,11] Anti-thrombin III Fragment Suppress EC adhesion, migration, proliferation [12] Osteopontin Serve as ligand for integrin binding [13] Collagen Substrate for MMPs [14,15] Kininogen Domains Suppress EC adhesion, migration, proliferation [16] Tissue Factor Pathways Inhibitor Antagonist for Tissue Factor [17] Vasostatin Suppress EC adhesion [18,19] Calreticulin Suppress EC adhesion [20] TIMPs Suppress EC adhesion [21,22] A cartilage-derived angiogenesis inhibitor Suppress EC adhesion [23] Meth-1 and Meth-2 Suppress EC adhesion [24] Maspin Inhibits proteases [25] Laminin 511 Suppresses metastases [26,27] CCN3 Suppresses EC adhesion [28] Endorepellin Suppresses EC adhesion [29] MULTIMERIN2 (Endoglyx-1) Suppresses EC migration [30]...
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