Special Issue "Angiogenesis in Cancer"

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

Deadline for manuscript submissions: 15 November 2019.

Special Issue Editor

Guest Editor
Assoc. Prof. Nader Rahimi

Department of Pathology, Boston University, 670 Albany St. Room 510, Boston, MA 02118, USA
Website | E-Mail
Interests: angiogenesis; vascular biology; cancer biology; cell-cell adhesion; posttranslational modifications; signal transduction

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

Manuscript Submission Information

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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 (9 papers)

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Research

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Open AccessArticle
Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer
Received: 27 June 2019 / Revised: 18 July 2019 / Accepted: 20 July 2019 / Published: 22 July 2019
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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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Open AccessArticle
Improved Antitumor Efficacy of Combined Vaccine Based on the Induced HUVECs and DC-CT26 Against Colorectal Carcinoma
Received: 24 April 2019 / Revised: 20 May 2019 / Accepted: 21 May 2019 / Published: 22 May 2019
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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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Open AccessArticle
Altered VEGF Splicing Isoform Balance in Tumor Endothelium Involves Activation of Splicing Factors Srpk1 and Srsf1 by the Wilms’ Tumor Suppressor Wt1
Received: 6 December 2018 / Revised: 27 December 2018 / Accepted: 8 January 2019 / Published: 11 January 2019
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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

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Open AccessReview
Dual Roles of the AMP-Activated Protein Kinase Pathway in Angiogenesis
Received: 25 June 2019 / Revised: 11 July 2019 / Accepted: 14 July 2019 / Published: 19 July 2019
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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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Open AccessReview
Glycosylation in the Tumor Microenvironment: Implications for Tumor Angiogenesis and Metastasis
Received: 14 May 2019 / Revised: 31 May 2019 / Accepted: 1 June 2019 / Published: 5 June 2019
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Abstract
Just as oncogene activation and tumor suppressor loss are hallmarks of tumor development, emerging evidence indicates that tumor microenvironment-mediated changes in glycosylation play a crucial functional role in tumor progression and metastasis. Hypoxia and inflammatory events regulate protein glycosylation in tumor cells and [...] Read more.
Just as oncogene activation and tumor suppressor loss are hallmarks of tumor development, emerging evidence indicates that tumor microenvironment-mediated changes in glycosylation play a crucial functional role in tumor progression and metastasis. Hypoxia and inflammatory events regulate protein glycosylation in tumor cells and associated stromal cells in the tumor microenvironment, which facilitates tumor progression and also modulates a patient’s response to anti-cancer therapeutics. In this review, we highlight the impact of altered glycosylation on angiogenic signaling and endothelial cell adhesion, and the critical consequences of these changes in tumor behavior. Full article
(This article belongs to the Special Issue Angiogenesis in Cancer)
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Open AccessReview
Pharmacogenetic-Based Interactions between Nutraceuticals and Angiogenesis Inhibitors
Received: 16 April 2019 / Revised: 20 May 2019 / Accepted: 24 May 2019 / Published: 30 May 2019
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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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Open AccessReview
c-Cbl: An Important Regulator and a Target in Angiogenesis and Tumorigenesis
Received: 7 April 2019 / Revised: 9 May 2019 / Accepted: 10 May 2019 / Published: 23 May 2019
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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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Open AccessReview
Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology
Received: 17 April 2019 / Revised: 6 May 2019 / Accepted: 16 May 2019 / Published: 17 May 2019
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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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Open AccessReview
Cholesterol Trafficking: An Emerging Therapeutic Target for Angiogenesis and Cancer
Received: 9 April 2019 / Revised: 19 April 2019 / Accepted: 23 April 2019 / Published: 28 April 2019
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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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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Author: Felisbina Queiroga

Tentative Title: Crosstalk between TGFβ, FoxP3 and angiogenesis in malignant canine mammary tumors: association with clinicopathological parameters and prognosis

Author: Ugo Cavallaro

Tentative Title: L1CAM and its multiple ways to (dys)regulate cancer vasculature

Author: Wen-Hui Fang, Mark Slevin and Shant Kumar

Tentative Title: The angiogenic activities of HIV-1 matrix protein p17 could contribute to AIDS-related lymphomas

Author: Lei Xu

Affiliation: Steele lab at Mass General Hospital, Harvard Medical School

Tentative Title: Vasculogenic mimicry in head and neck cancers

Author: József Jászai1, Mirko HH Schmidt2 

Tentative Title: Trends and challenges in tumor anti-angiogenic therapies

Author: Giuseppe Esposito

Tentative title: Antiangiogenic effect of rifaximin in human colon cancer organotypic coltures

Authors: Anca Maria Cimpean , Alexandru Nesiu,  Ioan Ioiart, Ahmed Adile , Dorin Novacescu , Alin Adrian Cumpanas, Marius Raica 

Tentative title: Gene expression heterogeneity of Platelet Derived Growth Factor pathway defines three distinct subgroups in renal cell carcinomas

Authors: Hotaka Kawai, Takanori Eguchi*, Hitoshi Nagatsuka

Tentative Title: Antagonizing CXCR4 declines intra-tumoral angiogenesis and induces tumor necrosis in oral cancer

Authors: Dongmei Zhang

Tentative Title: Tumor vascular targeting strategy: A double-sward in tumor metastasis

 


 

 

 

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