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Angiogenesis in Cancer
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Angiogenesis in Cancer

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 November 2019) | Viewed by 102421

Special Issue Editor

Prof. Dr. Nader Rahimi

E-Mail Website
Guest Editor
Department of Pathology, Boston University, 670 Albany St. Room 510, Boston, MA 02118, USA
Interests: angiogenesis; vascular biology; cancer biology; cell–cell adhesion; post-translational modifications; signal transduction; endothelial dysfunction; COVID-19
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Angiogenesis is a coordinated cascade of numerous complex cellular processes, including endothelial cell migration, proliferation, sprouting, and lumen formation, which ultimately leads to the formation of new vessels. These coordinated cellular events are regulated by various cell surface receptors and soluble ligands. The ability of endothelial cells to form capillary tubes is a prerequisite for the establishment of a continuous vessel lumen that routes the blood flow. Several key receptor tyrosine kinases, such as vascular endothelial growth factor (VEGF) receptor-1 (VEGFR-1), VEGFR-2, and VEGFR-3, and cell adhesion molecules (CAMs), including cadherins, integrins, selectins, immunoglobulin (Ig) superfamily proteins, and Notch receptors, are involved in the regulation of angiogenesis. Moreover, various post-translational modifications, including phosphorylation, methylation, ubiquitination, and glycosylation, play integral roles in the various aspects of angiogenesis. This Special Issue of Cells brings together the most recent advances in various aspects of angiogenesis, from basic science to applied therapeutic angiogenesis and will provide new insights into our understanding of angiogenesis.

Sincerely yours,

Prof. Nader Rahimi
Guest Editor

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Keywords

  • molecular mechanisms of tumor angiogenesis
  • post-translational modification and tumor angiogenesis
  • cell adhesion molecules and tumor angiogenesis
  • mechanotransduction signaling and angiogenesis
  • anti-angiogenesis therapy of cancer
  • metabolism and angiogenesis
  • therapeutic angiogenesis and beyond

Published Papers (15 papers)

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Research

Jump to: Review

15 pages, 1444 KiB  
Communication
Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology
by Rolando Campanella, Laura Guarnaccia, Chiara Cordiglieri, Elena Trombetta, Manuela Caroli, Giorgio Carrabba, Nicla La Verde, Paolo Rampini, Chiara Gaudino, Antonella Costa, Sabino Luzzi, Giovanna Mantovani, Marco Locatelli, Laura Riboni, Stefania Elena Navone and Giovanni Marfia
Cells 2020, 9(2), 294; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020294 - 25 Jan 2020
Cited by 52 | Viewed by 4517
Abstract
Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs [...] Read more.
Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of “tumor education”, characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network’s complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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27 pages, 9477 KiB  
Article
Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis
by Filipa Lopes-Coelho, Fernanda Silva, Sofia Gouveia-Fernandes, Carmo Martins, Nuno Lopes, Germana Domingues, Catarina Brito, António M Almeida, Sofia A Pereira and Jacinta Serpa
Cells 2020, 9(1), 107; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010107 - 01 Jan 2020
Cited by 32 | Viewed by 4794
Abstract
Bone marrow contains endothelial progenitor cells (EPCs) that, upon pro-angiogenic stimuli, migrate and differentiate into endothelial cells (ECs) and contribute to re-endothelialization and neo-vascularization. There are currently no reliable markers to characterize EPCs, leading to their inaccurate identification. In the past, we showed [...] Read more.
Bone marrow contains endothelial progenitor cells (EPCs) that, upon pro-angiogenic stimuli, migrate and differentiate into endothelial cells (ECs) and contribute to re-endothelialization and neo-vascularization. There are currently no reliable markers to characterize EPCs, leading to their inaccurate identification. In the past, we showed that, in a panel of tumors, some cells on the vessel wall co-expressed CD14 (monocytic marker) and CD31 (EC marker), indicating a putative differentiation route of monocytes into ECs. Herein, we disclosed monocytes as potential EPCs, using in vitro and in vivo models, and also addressed the cancer context. Monocytes acquired the capacity to express ECs markers and were able to be incorporated into blood vessels, contributing to cancer progression, by being incorporated in tumor neo-vasculature. Reactive oxygen species (ROS) push monocytes to EC differentiation, and this phenotype is reverted by cysteine (a scavenger and precursor of glutathione), which indicates that angiogenesis is controlled by the interplay between the oxidative stress and the scavenging capacity of the tumor microenvironment. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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14 pages, 3199 KiB  
Article
Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study
by Chung-Sheng Shi, Kuan-Lin Kuo, Mei-Sin Chen, Po-Ming Chow, Shing-Hwa Liu, Yu-Wei Chang, Wei-Chou Lin, Shih-Ming Liao, Chen-Hsun Hsu, Fu-Shun Hsu, Hong-Chiang Chang and Kuo-How Huang
Cells 2019, 8(11), 1469; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8111469 - 19 Nov 2019
Cited by 9 | Viewed by 3401
Abstract
Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. [...] Read more.
Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. In this study, we investigated the role and therapeutic potential of CDK7 in regulating the angiogenic activity of endothelial cells and human renal cell carcinoma (RCC). Our results revealed that vascular endothelial growth factor (VEGF), a critical activator of angiogenesis, upregulated the expression of CDK7 and RNAPII, and the phosphorylation of RNAPII at serine 5 and 7 in human umbilical vein endothelial cells (HUVECs), indicating the transcriptional activity of CDK7 may be involved in VEGF-activated angiogenic activity of endothelium. Furthermore, through suppressing CDK7 activity, THZ1 suppressed VEGF-activated proliferation and migration, as well as enhanced apoptosis of HUVECs. Moreover, THZ1 inhibited VEGF-activated capillary tube formation and CDK7 knockdown consistently diminished tube formation in HUVECs. Additionally, THZ1 reduced VEGF expression in human RCC cells (786-O and Caki-2), and THZ1 treatment inhibited tumor growth, vascularity, and angiogenic marker (CD31) expression in RCC xenografts. Our results demonstrated that CDK7-mediated transcription was involved in the angiogenic activity of endothelium and human RCC. THZ1 suppressed VEGF-mediated VEGFR2 downstream activation of angiogenesis, providing a new perspective for antitumor therapy in RCC patients. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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13 pages, 6923 KiB  
Article
Dynamic Interplay between Pericytes and Endothelial Cells during Sprouting Angiogenesis
by Giulia Chiaverina, Laura di Blasio, Valentina Monica, Massimo Accardo, Miriam Palmiero, Barbara Peracino, Marianela Vara-Messler, Alberto Puliafito and Luca Primo
Cells 2019, 8(9), 1109; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091109 - 19 Sep 2019
Cited by 45 | Viewed by 5132
Abstract
Vascular physiology relies on the concerted dynamics of several cell types, including pericytes, endothelial, and vascular smooth muscle cells. The interactions between such cell types are inherently dynamic and are not easily described with static, fixed, experimental approaches. Pericytes are mural cells that [...] Read more.
Vascular physiology relies on the concerted dynamics of several cell types, including pericytes, endothelial, and vascular smooth muscle cells. The interactions between such cell types are inherently dynamic and are not easily described with static, fixed, experimental approaches. Pericytes are mural cells that support vascular development, remodeling, and homeostasis, and are involved in a number of pathological situations including cancer. The dynamic interplay between pericytes and endothelial cells is at the basis of vascular physiology and few experimental tools exist to properly describe and study it. Here we employ a previously developed ex vivo murine aortic explant to study the formation of new blood capillary-like structures close to physiological situation. We develop several mouse models to culture, identify, characterize, and follow simultaneously single endothelial cells and pericytes during angiogenesis. We employ microscopy and image analysis to dissect the interactions between cell types and the process of cellular recruitment on the newly forming vessel. We find that pericytes are recruited on the developing sprout by proliferation, migrate independently from endothelial cells, and can proliferate on the growing capillary. Our results help elucidating several relevant mechanisms of interactions between endothelial cells and pericytes. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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15 pages, 7764 KiB  
Article
Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer
by Saori Yoshida, Hotaka Kawai, Takanori Eguchi, Shintaro Sukegawa, May Wathone Oo, Chang Anqi, Kiyofumi Takabatake, Keisuke Nakano, Kuniaki Okamoto and Hitoshi Nagatsuka
Cells 2019, 8(7), 761; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8070761 - 22 Jul 2019
Cited by 18 | Viewed by 6040
Abstract
CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis, thereby supporting tumor survival in OSCC. Immunohistochemistry on [...] Read more.
CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis, thereby supporting tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To uncover the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as tumor angiogenic inhibition triggered necrosis (TAITN), which was induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic areas with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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17 pages, 3729 KiB  
Article
Improved Antitumor Efficacy of Combined Vaccine Based on the Induced HUVECs and DC-CT26 Against Colorectal Carcinoma
by Qiushuang Zhang, Chao Xie, Dongyu Wang, Yi Yang, Hangfan Liu, Kangdong Liu, Jimin Zhao, Xinhuan Chen, Xiaoyan Zhang, Wanjing Yang, Xiang Li, Fang Tian, Ziming Dong and Jing Lu
Cells 2019, 8(5), 494; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050494 - 22 May 2019
Cited by 10 | Viewed by 4338
Abstract
Angiogenesis is essential for the development, growth, and metastasis of solid tumors. Vaccination with viable human umbilical vein endothelial cells (HUVECs) has been used for antitumor angiogenesis. However, the limited immune response induced by HUVECs hinders their clinical application. In the present study, [...] Read more.
Angiogenesis is essential for the development, growth, and metastasis of solid tumors. Vaccination with viable human umbilical vein endothelial cells (HUVECs) has been used for antitumor angiogenesis. However, the limited immune response induced by HUVECs hinders their clinical application. In the present study, we found that HUVECs induced by a tumor microenvironment using the supernatant of murine CT26 colorectal cancer cells exerted a better antiangiogenic effect than HUVECs themselves. The inhibitory effect on tumor growth in the induced HUVEC group was significantly better than that of the HUVEC group, and the induced HUVEC group showed a strong inhibition in CD31-positive microvessel density in the tumor tissues. Moreover, the level of anti-induced HUVEC membrane protein antibody in mouse serum was profoundly higher in the induced HUVEC group than in the HUVEC group. Based on this, the antitumor effect of a vaccine with a combination of induced HUVECs and dendritic cell-loading CT26 antigen (DC-CT26) was evaluated. Notably, the microvessel density of tumor specimens was significantly lower in the combined vaccine group than in the control groups. Furthermore, the spleen index, the killing effect of cytotoxic T lymphocytes (CTLs), and the concentration of interferon-γ in the serum were enhanced in the combined vaccine group. Based on these results, the combined vaccine targeting both tumor angiogenesis and tumor cells may be an attractive and effective cancer immunotherapy strategy. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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18 pages, 8193 KiB  
Article
Altered VEGF Splicing Isoform Balance in Tumor Endothelium Involves Activation of Splicing Factors Srpk1 and Srsf1 by the Wilms’ Tumor Suppressor Wt1
by Kay-Dietrich Wagner, Mounir El Maï, Michael Ladomery, Tareg Belali, Nathalie Leccia, Jean-François Michiels and Nicole Wagner
Cells 2019, 8(1), 41; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8010041 - 11 Jan 2019
Cited by 33 | Viewed by 5546
Abstract
Angiogenesis is one hallmark of cancer. Vascular endothelial growth factor (VEGF) is a known inducer of angiogenesis. Many patients benefit from antiangiogenic therapies, which however have limitations. Although VEGF is overexpressed in most tumors, different VEGF isoforms with distinct angiogenic properties are produced [...] Read more.
Angiogenesis is one hallmark of cancer. Vascular endothelial growth factor (VEGF) is a known inducer of angiogenesis. Many patients benefit from antiangiogenic therapies, which however have limitations. Although VEGF is overexpressed in most tumors, different VEGF isoforms with distinct angiogenic properties are produced through alternative splicing. In podocytes, the Wilms’ tumor suppressor 1 (WT1) suppresses the Serine/arginine-rich protein-specific splicing factor kinase (SRPK1), and indirectly Serine/arginine-rich splicing factor 1 (Srsf1) activity, and alters VEGF splicing. We analyzed VEGF isoforms, Wt1, Srpk1, and Srsf1 in normal and tumor endothelium. Wt1, Srpk1, Srsf1, and the angiogenic VEGF164a isoform were highly expressed in tumor endothelium compared to normal lung endothelium. Nuclear expression of Srsf1 was detectable in the endothelium of various tumor types, but not in healthy tissues. Inducible conditional vessel-specific knockout of Wt1 reduced Wt1, Srpk1, and Srsf1 expression in endothelial cells and induced a shift towards the antiangiogenic VEGF120 isoform. Wt1(−KTS) directly binds and activates both the promoters of Srpk1 and Srsf1 in endothelial cells. In conclusion, Wt1 activates Srpk1 and Srsf1 and induces expression of angiogenic VEGF isoforms in tumor endothelium. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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Review

Jump to: Research

12 pages, 944 KiB  
Review
Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy
by Dennis Jones
Cells 2020, 9(3), 762; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030762 - 20 Mar 2020
Cited by 27 | Viewed by 3878
Abstract
Metastasis is the primary cause of cancer-related mortality. Cancer cells primarily metastasize via blood and lymphatic vessels to colonize lymph nodes and distant organs, leading to worse prognosis. Thus, strategies to limit blood and lymphatic spread of cancer have been a focal point [...] Read more.
Metastasis is the primary cause of cancer-related mortality. Cancer cells primarily metastasize via blood and lymphatic vessels to colonize lymph nodes and distant organs, leading to worse prognosis. Thus, strategies to limit blood and lymphatic spread of cancer have been a focal point of cancer research for several decades. Resistance to FDA-approved anti-angiogenic therapies designed to limit blood vessel growth has emerged as a significant clinical challenge. However, there are no FDA-approved drugs that target tumor lymphangiogenesis, despite the consequences of metastasis through the lymphatic system. This review highlights several of the key resistance mechanisms to anti-angiogenic therapy and potential challenges facing anti-lymphangiogenic therapy. Blood and lymphatic vessels are more than just conduits for nutrient, fluid, and cancer cell transport. Recent studies have elucidated how these vasculatures often regulate immune responses. Vessels that are abnormal or compromised by tumor cells can lead to immunosuppression. Therapies designed to improve lymphatic vessel function while limiting metastasis may represent a viable approach to enhance immunotherapy and limit cancer progression. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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21 pages, 943 KiB  
Review
The Tumor Vessel Targeting Strategy: A Double-Edged Sword in Tumor Metastasis
by Xiaobo Li, Yong Li, Weijin Lu, Minfeng Chen, Wencai Ye and Dongmei Zhang
Cells 2019, 8(12), 1602; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121602 - 10 Dec 2019
Cited by 23 | Viewed by 3973
Abstract
Tumor vessels provide essential paths for tumor cells to escape from the primary tumor and form metastatic foci in distant organs. The vessel targeting strategy has been widely used as an important clinical cancer chemotherapeutic strategy for patients with metastatic tumors. Our review [...] Read more.
Tumor vessels provide essential paths for tumor cells to escape from the primary tumor and form metastatic foci in distant organs. The vessel targeting strategy has been widely used as an important clinical cancer chemotherapeutic strategy for patients with metastatic tumors. Our review introduces the contribution of angiogenesis to tumor metastasis and summarizes the application of Food and Drug Administration (FDA)-approved vessel targeting drugs for metastatic tumors. We recommend the application and mechanisms of vascular targeting drugs for inhibiting tumor metastasis and discuss the risk and corresponding countermeasures after vessel targeting treatment. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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Graphical abstract

35 pages, 1887 KiB  
Review
Trends and Challenges in Tumor Anti-Angiogenic Therapies
by József Jászai and Mirko H.H. Schmidt
Cells 2019, 8(9), 1102; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8091102 - 18 Sep 2019
Cited by 147 | Viewed by 14135
Abstract
Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling [...] Read more.
Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling has quickly become one of the most promising anti-angiogenic therapeutic targets in oncology. Nevertheless, the clinical efficacy of this approach is severely limited in certain tumor types or shows only transient efficacy in patients. Acquired or intrinsic therapy resistance associated with anti-VEGF monotherapeutic approaches indicates the necessity of a paradigm change when targeting neoangiogenesis in solid tumors. In this context, the elaboration of the conceptual framework of “vessel normalization” might be a promising approach to increase the efficacy of anti-angiogenic therapies and the survival rates of patients. Indeed, the promotion of vessel maturation instead of regressing tumors by vaso-obliteration could result in reduced tumor hypoxia and improved drug delivery. The implementation of such anti-angiogenic strategies, however, faces several pitfalls due to the potential involvement of multiple pro-angiogenic factors and modulatory effects of the innate and adaptive immune system. Thus, effective treatments bypassing relapses associated with anti-VEGF monotherapies or breaking the intrinsic therapy resistance of solid tumors might use combination therapies or agents with a multimodal mode of action. This review enumerates some of the current approaches and possible future directions of treating solid tumors by targeting neovascularization. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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16 pages, 1546 KiB  
Review
Dual Roles of the AMP-Activated Protein Kinase Pathway in Angiogenesis
by Yuanjun Li, Ruipu Sun, Junrong Zou, Ying Ying and Zhijun Luo
Cells 2019, 8(7), 752; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8070752 - 19 Jul 2019
Cited by 72 | Viewed by 8997
Abstract
Angiogenesis plays important roles in development, stress response, wound healing, tumorigenesis and cancer progression, diabetic retinopathy, and age-related macular degeneration. It is a complex event engaging many signaling pathways including vascular endothelial growth factor (VEGF), Notch, transforming growth factor-beta/bone morphogenetic proteins (TGF-β/BMPs), and [...] Read more.
Angiogenesis plays important roles in development, stress response, wound healing, tumorigenesis and cancer progression, diabetic retinopathy, and age-related macular degeneration. It is a complex event engaging many signaling pathways including vascular endothelial growth factor (VEGF), Notch, transforming growth factor-beta/bone morphogenetic proteins (TGF-β/BMPs), and other cytokines and growth factors. Almost all of them eventually funnel to two crucial molecules, VEGF and hypoxia-inducing factor-1 alpha (HIF-1α) whose expressions could change under both physiological and pathological conditions. Hypoxic conditions stabilize HIF-1α, while it is upregulated by many oncogenic factors under normaxia. HIF-1α is a critical transcription activator for VEGF. Recent studies have shown that intracellular metabolic state participates in regulation of sprouting angiogenesis, which may involve AMP-activated protein kinase (AMPK). Indeed, AMPK has been shown to exert both positive and negative effects on angiogenesis. On the one hand, activation of AMPK mediates stress responses to facilitate autophagy which stabilizes HIF-1α, leading to increased expression of VEGF. On the other hand, AMPK could attenuate angiogenesis induced by tumor-promoting and pro-metastatic factors, such as the phosphoinositide 3-kinase /protein kinase B (Akt)/mammalian target of rapamycin (PI3K/Akt/mTOR), hepatic growth factor (HGF), and TGF-β/BMP signaling pathways. Thus, this review will summarize research progresses on these two opposite effects and discuss the mechanisms behind the discrepant findings. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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14 pages, 620 KiB  
Review
Pharmacogenetic-Based Interactions between Nutraceuticals and Angiogenesis Inhibitors
by Raffaele Di Francia, Massimiliano Berretta, Giulio Benincasa, Alfredo D’Avino, Sergio Facchini, Domenico Costagliola and Paola Rossi
Cells 2019, 8(6), 522; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8060522 - 30 May 2019
Cited by 12 | Viewed by 3608
Abstract
Background: Angiogenesis inhibitors (AIs) have become established as an effective cancer treatment. Whereas their interactions with antineoplastic drugs have extensively been investigated, little is known of the effect of their co-administration with nutraceuticals/dietary supplements (N/DSs), which are often self-prescribed. N/DSs comprise a wide [...] Read more.
Background: Angiogenesis inhibitors (AIs) have become established as an effective cancer treatment. Whereas their interactions with antineoplastic drugs have extensively been investigated, little is known of the effect of their co-administration with nutraceuticals/dietary supplements (N/DSs), which are often self-prescribed. N/DSs comprise a wide range of products such as herbs, nutrients, vitamins, minerals, and probiotics. Assessment of their interactions with cancer drugs, particularly AIs, is hampered by the difficulty of gauging the amount of active substances patients actually take. Moreover, there is no agreement on which approach should be used to determine which N/DSs are most likely to influence AI treatment efficacy. We present a comprehensive review of the metabolic routes of the major AIs and their possible interactions with N/DSs. Methods: The PubMed and Cochrane databases were searched for papers describing the metabolic routes of the main AIs and N/DSs. Results: Data from the 133 studies thus identified were used to compile a diagnostic table reporting known and expected AI-N/DS interactions based on their metabolization pathways. AIs and N/DSs sharing the cytochrome P450 pathway are at risk of negative interactions. Conclusions: Recent advances in pharmacogenetics offer exceptional opportunities to identify prognostic and predictive markers to enhance the efficacy of individualized AI treatments. The table provides a guide to genotyping patients who are due to receive AIs and is a promising tool to prevent occult AI-N/DS interactions in poor metabolizers. N/DS use by cancer patients receiving AIs is a topical problem requiring urgent attention from the scientific community. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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14 pages, 4634 KiB  
Review
c-Cbl: An Important Regulator and a Target in Angiogenesis and Tumorigenesis
by Chimera L. Lyle, Mostafa Belghasem and Vipul C. Chitalia
Cells 2019, 8(5), 498; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050498 - 23 May 2019
Cited by 42 | Viewed by 7337
Abstract
Casitas B lineage lymphoma (c-Cbl) is a multifunctional protein with a ubiquitin E3 ligase activity capable of degrading diverse sets of proteins. Although previous work had focused mainly on c-Cbl mutations in humans with hematological malignancies, recent emerging evidence suggests a critical role [...] Read more.
Casitas B lineage lymphoma (c-Cbl) is a multifunctional protein with a ubiquitin E3 ligase activity capable of degrading diverse sets of proteins. Although previous work had focused mainly on c-Cbl mutations in humans with hematological malignancies, recent emerging evidence suggests a critical role of c-Cbl in angiogenesis and human solid organ tumors. The combination of its unique structure, modular function, and ability to channelize cues from a rich network of signaling cascades, empowers c-Cbl to assume a central role in these disease models. This review consolidates the structural and functional insights based on recent studies that highlight c-Cbl as a target with tantalizing therapeutic potential in various models of angiogenesis and tumorigenesis. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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19 pages, 1492 KiB  
Review
Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology
by Racheal G. Akwii, Md S. Sajib, Fatema T. Zahra and Constantinos M. Mikelis
Cells 2019, 8(5), 471; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050471 - 17 May 2019
Cited by 283 | Viewed by 17090
Abstract
Angiopoietins 1–4 (Ang1–4) represent an important family of growth factors, whose activities are mediated through the tyrosine kinase receptors, Tie1 and Tie2. The best characterized are angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2). Ang1 is a potent angiogenic growth factor signaling through Tie2, whereas Ang2 [...] Read more.
Angiopoietins 1–4 (Ang1–4) represent an important family of growth factors, whose activities are mediated through the tyrosine kinase receptors, Tie1 and Tie2. The best characterized are angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2). Ang1 is a potent angiogenic growth factor signaling through Tie2, whereas Ang2 was initially identified as a vascular disruptive agent with antagonistic activity through the same receptor. Recent data demonstrates that Ang2 has context-dependent agonist activities. Ang2 plays important roles in physiological processes and the deregulation of its expression is characteristic of several diseases. In this review, we summarize the activity of Ang2 on blood and lymphatic endothelial cells, its significance in human physiology and disease, and provide a current view of the molecular signaling pathways regulated by Ang2 in endothelial cells. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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11 pages, 1327 KiB  
Review
Cholesterol Trafficking: An Emerging Therapeutic Target for Angiogenesis and Cancer
by Junfang Lyu, Eun Ju Yang and Joong Sup Shim
Cells 2019, 8(5), 389; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8050389 - 28 Apr 2019
Cited by 42 | Viewed by 8299
Abstract
Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, [...] Read more.
Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, recent evidence suggests that cholesterol plays a key role in regulating angiogenesis. This review discusses the role of cholesterol in angiogenesis, with a particular emphasis on cholesterol trafficking in endothelial cell signaling. Small molecule inhibitors of cholesterol trafficking and their preclinical and clinical development targeting angiogenesis and cancer are also discussed. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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