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12 pages, 2352 KiB

Open AccessArticle

Pentraxin 3 Inhibits the Angiogenic Potential of Multiple Myeloma Cells

by Roberto Ronca, Sara Taranto, Michela Corsini, Chiara Tobia, Cosetta Ravelli, Sara Rezzola, Mirella Belleri, Floriana De Cillis, Annamaria Cattaneo, Marco Presta and Arianna Giacomini

Cancers 2021, 13(9), 2255; https://doi.org/10.3390/cancers13092255 - 8 May 2021

Cited by 6 | Viewed by 2673

Abstract

During multiple myeloma (MM) progression the activation of the angiogenic process represents a key step for the formation of the vascular niche, where different stromal components and neoplastic cells collaborate and foster tumor growth. Among the different pro-angiogenic players, Fibroblast Growth Factor 2 [...] Read more.

During multiple myeloma (MM) progression the activation of the angiogenic process represents a key step for the formation of the vascular niche, where different stromal components and neoplastic cells collaborate and foster tumor growth. Among the different pro-angiogenic players, Fibroblast Growth Factor 2 (FGF2) plays a pivotal role in BM vascularization occurring during MM progression. Long Pentraxin 3 (PTX3), a natural FGF antagonist, is able to reduce the activation of stromal components promoted by FGF2 in various in vitro models. An increased FGF/PTX3 ratio has also been found to occur during MM evolution, suggesting that restoring the “physiological” FGF/PTX3 ratio in plasma cells and BM stromal cells (BMSCs) might impact MM. In this work, taking advantage of PTX3-inducible human MM models, we show that PTX3 produced by tumor cells is able to restore a balanced FGF/PTX3 ratio sufficient to prevent the activation of the FGF/FGFR system in endothelial cells and to reduce the angiogenic capacity of MM cells in different in vivo models. As a result of this anti-angiogenic activity, PTX3 overexpression causes a significant reduction of the tumor burden in both subcutaneously grafted and systemic MM models. These data pave the way for the exploitation of PTX3-derived anti-angiogenic approaches in MM. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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20 pages, 3625 KiB

Open AccessArticle

Anti-Angiogenic Properties of Ginsenoside Rg3 Epimers: In Vitro Assessment of Single and Combination Treatments

by Maryam Nakhjavani, Eric Smith, Kenny Yeo, Helen M. Palethorpe, Yoko Tomita, Tim J. Price, Amanda R. Townsend and Jennifer E. Hardingham

Cancers 2021, 13(9), 2223; https://doi.org/10.3390/cancers13092223 - 6 May 2021

Cited by 19 | Viewed by 2746

Abstract

Tumour angiogenesis plays a key role in tumour growth and progression. The application of current anti-angiogenic drugs is accompanied by adverse effects and drug resistance. Therefore, finding safer effective treatments is needed. Ginsenoside Rg3 (Rg3) has two epimers, 20(S)-Rg3 (SRg3) and 20(R)-Rg3 (RRg3), [...] Read more.

Tumour angiogenesis plays a key role in tumour growth and progression. The application of current anti-angiogenic drugs is accompanied by adverse effects and drug resistance. Therefore, finding safer effective treatments is needed. Ginsenoside Rg3 (Rg3) has two epimers, 20(S)-Rg3 (SRg3) and 20(R)-Rg3 (RRg3), with stereoselective activities. Using response surface methodology, we optimised a combination of these two epimers for the loop formation of human umbilical vein endothelial cell (HUVEC). The optimised combination (C3) was tested on HUVEC and two murine endothelial cell lines. C3 significantly inhibited the loop formation, migration, and proliferation of these cells, inducing apoptosis in HUVEC and cell cycle arrest in all of the cell lines tested. Using molecular docking and vascular endothelial growth factor (VEGF) bioassay, we showed that Rg3 has an allosteric modulatory effect on vascular endothelial growth factor receptor 2 (VEGFR2). C3 also decreased the VEGF expression in hypoxic conditions, decreased the expression of aquaporin 1 and affected AKT signaling. The proteins that were mostly affected after C3 treatment were those related to mammalian target of rapamycin (mTOR). Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) was one of the important targets of C3, which was affected in both hypoxic and normoxic conditions. In conclusion, these results show the potential of C3 as a novel anti-angiogenic drug. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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16 pages, 57801 KiB

Open AccessArticle

Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation

by Sara Sabatasso, Cristian Fernandez-Palomo, Ruslan Hlushchuk, Jennifer Fazzari, Stefan Tschanz, Paolo Pellicioli, Michael Krisch, Jean A. Laissue and Valentin Djonov

Cancers 2021, 13(9), 2103; https://doi.org/10.3390/cancers13092103 - 27 Apr 2021

Cited by 16 | Viewed by 3433

Abstract

Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which [...] Read more.

Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. Methods: the developing CAM was exposed to planar-microbeams of 75 Gy peak dose with Synchrotron X-rays. Similarly, mice harboring human glioblastoma xenografts were exposed to peak microbeam doses of 150 Gy, followed by treatment with Cisplatin. Tumor progression was documented by Magnetic Resonance Imaging (MRI) and caliper measurements. Results: CAM exposed to MRT exhibited vascular permeability, beginning 15 min post-irradiation, reaching its peak from 45 min to 2 h, and ending by 4 h. We have deemed this period the “permeability window”. Morphological analysis showed partially fragmented endothelial walls as the cause of the increased transport of FITC-Dextran into the surrounding tissue and the extravasation of 100 nm microspheres (representing the upper range of nanoparticles). In the human glioblastoma xenografts, MRI measurements showed that the combined treatment dramatically reduced the tumor size by 2.75-fold and 5.25-fold, respectively, compared to MRT or Cisplatin alone. Conclusions: MRT provides a novel mechanism for drug delivery by increasing vascular transpermeability while preserving vessel integrity. This permeability window increases the therapeutic index of currently available chemotherapeutics and could be combined with other therapeutic agents such as Nanoparticles/Antibodies/etc. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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13 pages, 2279 KiB

Open AccessArticle

Diagnostic Value of VEGF-A, VEGFR-1 and VEGFR-2 in Feline Mammary Carcinoma

by Catarina Nascimento, Andreia Gameiro, João Ferreira, Jorge Correia and Fernando Ferreira

Cancers 2021, 13(1), 117; https://doi.org/10.3390/cancers13010117 - 1 Jan 2021

Cited by 17 | Viewed by 3142

Abstract

Vascular endothelial growth factor (VEGF-A) plays an essential role in tumor-associated angiogenesis, exerting its biological activity by binding and activating membrane receptors, as vascular endothelial growth factor receptor 1 and 2 (VEGFR-1, VEGFR-2). In this study, serum VEGF-A, VEGFR-1, and VEGFR-2 levels were [...] Read more.

Vascular endothelial growth factor (VEGF-A) plays an essential role in tumor-associated angiogenesis, exerting its biological activity by binding and activating membrane receptors, as vascular endothelial growth factor receptor 1 and 2 (VEGFR-1, VEGFR-2). In this study, serum VEGF-A, VEGFR-1, and VEGFR-2 levels were quantified in 50 cats with mammary carcinoma and 14 healthy controls. The expression of these molecules in tumor-infiltrating lymphocytes (TILs) and in cancer cells was evaluated and compared with its serum levels. Results obtained showed that serum VEGF-A levels were significantly higher in cats with HER2-positive and Triple Negative (TN) Normal-Like subtypes, when compared to control group (p = 0.001, p = 0.020). Additionally, serum VEGFR-1 levels were significantly elevated in cats presenting luminal A, HER2-positive and TN Normal-Like tumors (p = 0.011, p = 0.048, p = 0.006), as serum VEGFR-2 levels (p = 0.010, p = 0.046, p = 0.005). Moreover, a positive interaction was found between the expression of VEGF-A, VEGFR-1, and VEGFR-2 in TILs and their serum levels (p = 0.002, p = 0.003, p = 0.003). In summary, these findings point to the usefulness of VEGF-A and its serum receptors assessment in clinical evaluation of cats with HER2-positive and TN Normal-Like tumors, suggesting that targeted therapies against these molecules may be effective for the treatment of these animals, as described in human breast cancer. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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21 pages, 7324 KiB

Open AccessArticle

Resveratrol Promotes Tumor Microvessel Growth via Endoglin and Extracellular Signal-Regulated Kinase Signaling Pathway and Enhances the Anticancer Efficacy of Gemcitabine against Lung Cancer

by San-Hai Qin, Andy T. Y. Lau, Zhan-Ling Liang, Heng Wee Tan, Yan-Chen Ji, Qiu-Hua Zhong, Xiao-Yun Zhao and Yan-Ming Xu

Cancers 2020, 12(4), 974; https://doi.org/10.3390/cancers12040974 - 15 Apr 2020

Cited by 17 | Viewed by 3530

Abstract

The synergistic anticancer effect of gemcitabine (GEM) and resveratrol (RSVL) has been noted in certain cancer types. However, whether the same phenomenon would occur in lung cancer is unclear. Here, we uncovered the molecular mechanism by which RSVL enhances the anticancer effect of [...] Read more.

The synergistic anticancer effect of gemcitabine (GEM) and resveratrol (RSVL) has been noted in certain cancer types. However, whether the same phenomenon would occur in lung cancer is unclear. Here, we uncovered the molecular mechanism by which RSVL enhances the anticancer effect of GEM against lung cancer cells both in vitro and in vivo. We established human lung adenocarcinoma HCC827 xenografts in nude mice and treated them with GEM and RSVL to detect their synergistic effect in vivo. Tumor tissue sections from nude mice were subjected to hematoxylin and eosin staining for blood vessel morphological observation, and immunohistochemistry was conducted to detect CD31-positive staining blood vessels. We also established the HCC827-human umbilical vein endothelial cell (HUVEC) co-culture model to observe the tubule network formation. Human angiogenesis antibody array was used to screen the angiogenesis-related proteins in RSVL-treated HCC827. RSVL suppressed the expression of endoglin (ENG) and increased tumor microvessel growth and blood perfusion into tumor. Co-treatment of RSVL and GEM led to more tumor growth suppression than treatment of GEM alone. Mechanistically, using the HCC827-HUVEC co-culture model, we showed that RSVL-suppressed ENG expression was accompanied with augmented levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and increased tubule network formation, which may explain why RSVL promoted tumor microvessel growth in vivo. RSVL promoted tumor microvessel growth via ENG and ERK and enhanced the anticancer efficacy of GEM. Our results suggest that intake of RSVL may be beneficial during lung cancer chemotherapy. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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21 pages, 2160 KiB

Open AccessArticle

Retinol-Binding Protein 4 Accelerates Metastatic Spread and Increases Impairment of Blood Flow in Mouse Mammary Gland Tumors

by Diana Papiernik, Anna Urbaniak, Dagmara Kłopotowska, Anna Nasulewicz-Goldeman, Marcin Ekiert, Marcin Nowak, Joanna Jarosz, Monika Cuprych, Aleksandra Strzykalska, Maciej Ugorski, Rafał Matkowski and Joanna Wietrzyk

Cancers 2020, 12(3), 623; https://doi.org/10.3390/cancers12030623 - 7 Mar 2020

Cited by 20 | Viewed by 4533

Abstract

Retinol-binding protein 4 (RBP4) is proposed as an adipokine that links obesity and cancer. We analyzed the role of RBP4 in metastasis of breast cancer in patients and in mice bearing metastatic 4T1 and nonmetastatic 67NR mammary gland cancer. We compared the metastatic [...] Read more.

Retinol-binding protein 4 (RBP4) is proposed as an adipokine that links obesity and cancer. We analyzed the role of RBP4 in metastasis of breast cancer in patients and in mice bearing metastatic 4T1 and nonmetastatic 67NR mammary gland cancer. We compared the metastatic and angiogenic potential of these cells transduced with Rbp4 (4T1/RBP4 and 67NR/RBP4 cell lines). Higher plasma levels of RBP4 were observed in breast cancer patients with metastatic tumors than in healthy donors and patients with nonmetastatic cancer. Increased levels of RBP4 were observed in plasma, tumor tissue, liver, and abdominal fat. Moreover, the blood vessel network was highly impaired in mice bearing 4T1 as compared to 67NR tumors. RBP4 transductants showed further impairment of blood flow and increased metastatic potential. Exogenous RBP4 increased lung settlement by 67NR and 4T1 cells. In vitro studies showed increased invasive and clonogenic potential of cancer cells treated with or overexpressing RBP4. This effect is not dependent on STAT3 phosphorylation. RBP4 enhances the metastatic potential of breast cancer tumors through a direct effect on cancer cells and through increased endothelial dysfunction and impairment of blood vessels within the tumor. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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Review

Jump to: Research

18 pages, 1150 KiB

Open AccessReview

Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer

by Fatema Tuz Zahra, Md. Sanaullah Sajib and Constantinos M. Mikelis

Cancers 2021, 13(6), 1422; https://doi.org/10.3390/cancers13061422 - 20 Mar 2021

Cited by 39 | Viewed by 6592

Abstract

Anti-angiogenic approaches targeting the vascular endothelial growth factor (VEGF) signaling pathway have been a significant research focus during the past decades and are well established in clinical practice. Despite the expectations, their benefit is ephemeral in several diseases, including specific cancers. One of [...] Read more.

Anti-angiogenic approaches targeting the vascular endothelial growth factor (VEGF) signaling pathway have been a significant research focus during the past decades and are well established in clinical practice. Despite the expectations, their benefit is ephemeral in several diseases, including specific cancers. One of the most prominent side effects of the current, VEGF-based, anti-angiogenic treatments remains the development of resistance, mostly due to the upregulation and compensatory mechanisms of other growth factors, with the basic fibroblast growth factor (bFGF) being at the top of the list. Over the past decade, several anti-angiogenic approaches targeting simultaneously different growth factors and their signaling pathways have been developed and some have reached the clinical practice. In the present review, we summarize the knowledge regarding resistance mechanisms upon anti-angiogenic treatment, mainly focusing on bFGF. We discuss its role in acquired resistance upon prolonged anti-angiogenic treatment in different tumor settings, outline the reported resistance mechanisms leading to bFGF upregulation, and summarize the efforts and outcome of combined anti-angiogenic approaches to date. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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14 pages, 865 KiB

Open AccessReview

Angiogenesis in the Normal Adrenal Fetal Cortex and Adrenocortical Tumors

by Sofia S. Pereira, Sofia Oliveira, Mariana P. Monteiro and Duarte Pignatelli

Cancers 2021, 13(5), 1030; https://doi.org/10.3390/cancers13051030 - 1 Mar 2021

Cited by 8 | Viewed by 2517

Abstract

Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC [...] Read more.

Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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15 pages, 858 KiB

Open AccessFeature PaperReview

Targeting E-selectin to Tackle Cancer Using Uproleselan

by Barbara Muz, Anas Abdelghafer, Matea Markovic, Jessica Yavner, Anupama Melam, Noha Nabil Salama and Abdel Kareem Azab

Cancers 2021, 13(2), 335; https://doi.org/10.3390/cancers13020335 - 18 Jan 2021

Cited by 38 | Viewed by 5719

Abstract

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties [...] Read more.

E-selectin is a vascular adhesion molecule expressed mainly on endothelium, and its primary role is to facilitate leukocyte cell trafficking by recognizing ligand surface proteins. E-selectin gained a new role since it was demonstrated to be involved in cancer cell trafficking, stem-like properties and therapy resistance. Therefore, being expressed in the tumor microenvironment, E-selectin can potentially be used to eradicate cancer. Uproleselan (also known as GMI-1271), a specific E-selectin antagonist, has been tested on leukemia, myeloma, pancreatic, colon and breast cancer cells, most of which involve the bone marrow as a primary or as a metastatic tumor site. This novel therapy disrupts the tumor microenvironment by affecting the two main steps of metastasis—extravasation and adhesion—thus blocking E-selectin reduces tumor dissemination. Additionally, uproleselan mobilized cancer cells from the protective vascular niche into the circulation, making them more susceptible to chemotherapy. Several preclinical and clinical studies summarized herein demonstrate that uproleselan has favorable safety and pharmacokinetics and is a tumor microenvironment-disrupting agent that improves the efficacy of chemotherapy, reduces side effects such as neutropenia, intestinal mucositis and infections, and extends overall survival. This review highlights the critical contribution of E-selectin and its specific antagonist, uproleselan, in the regulation of cancer growth, dissemination, and drug resistance in the context of the bone marrow microenvironment. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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15 pages, 1334 KiB

Open AccessReview

Potential Roles of Tumor Cell- and Stroma Cell-Derived Small Extracellular Vesicles in Promoting a Pro-Angiogenic Tumor Microenvironment

by Nils Ludwig, Dominique S. Rubenich, Łukasz Zaręba, Jacek Siewiera, Josquin Pieper, Elizandra Braganhol, Torsten E. Reichert and Mirosław J. Szczepański

Cancers 2020, 12(12), 3599; https://doi.org/10.3390/cancers12123599 - 2 Dec 2020

Cited by 20 | Viewed by 2902

Abstract

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of [...] Read more.

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. They are characterized by a distinct biogenesis and complex cargo composition, which reflects the cytosolic contents and cell-surface molecules of the parent cells. This cargo consists of proteins, nucleic acids, and lipids and is competent in inducing signaling cascades in recipient cells after surface interactions or in initiating the generation of a functional protein by delivering nucleic acids. Based on these characteristics, sEVs are now considered as important mediators of intercellular communication. One hallmark of sEVs is the promotion of angiogenesis. It was shown that sEVs interact with endothelial cells (ECs) and promote an angiogenic phenotype, ultimately leading to increased vascularization of solid tumors and disease progression. It was also shown that sEVs reprogram cells in the tumor microenvironment (TME) and act in a functionally cooperative fashion to promote angiogenesis by a paracrine mechanism involving the differential expression and secretion of angiogenic factors from other cell types. In this review, we will focus on the distinct functions of tumor-cell-derived sEVs (TEX) in promotion of angiogenesis and describe their potential as a therapeutic target for anti-angiogenic therapies. Also, we will focus on non-cancer stroma-cell-derived small extracellular vesicles and their potential role in stimulating a pro-angiogenic TME. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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24 pages, 2219 KiB

Open AccessReview

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling

by Antonio Giovanni Solimando, Simona De Summa, Angelo Vacca and Domenico Ribatti

Cancers 2020, 12(11), 3380; https://doi.org/10.3390/cancers12113380 - 15 Nov 2020

Cited by 77 | Viewed by 4822

Abstract

Cancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract [...] Read more.

Cancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial–neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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28 pages, 752 KiB

Open AccessReview

Old Player-New Tricks: Non Angiogenic Effects of the VEGF/VEGFR Pathway in Cancer

by Panagiotis Ntellas, Leonidas Mavroeidis, Stefania Gkoura, Ioanna Gazouli, Anna-Lea Amylidi, Alexandra Papadaki, George Zarkavelis, Davide Mauri, Georgia Karpathiou, Evangelos Kolettas, Anna Batistatou and George Pentheroudakis

Cancers 2020, 12(11), 3145; https://doi.org/10.3390/cancers12113145 - 27 Oct 2020

Cited by 48 | Viewed by 7634

Abstract

Angiogenesis has long been considered to facilitate and sustain cancer growth, making the introduction of anti-angiogenic agents that disrupt the vascular endothelial growth factor/receptor (VEGF/VEGFR) pathway an important milestone at the beginning of the 21st century. Originally research on VEGF signaling focused on [...] Read more.

Angiogenesis has long been considered to facilitate and sustain cancer growth, making the introduction of anti-angiogenic agents that disrupt the vascular endothelial growth factor/receptor (VEGF/VEGFR) pathway an important milestone at the beginning of the 21st century. Originally research on VEGF signaling focused on its survival and mitogenic effects towards endothelial cells, with moderate so far success of anti-angiogenic therapy. However, VEGF can have multiple effects on additional cell types including immune and tumor cells, by directly influencing and promoting tumor cell survival, proliferation and invasion and contributing to an immunosuppressive microenvironment. In this review, we summarize the effects of the VEGF/VEGFR pathway on non-endothelial cells and the resulting implications of anti-angiogenic agents that include direct inhibition of tumor cell growth and immunostimulatory functions. Finally, we present how previously unappreciated studies on VEGF biology, that have demonstrated immunomodulatory properties and tumor regression by disrupting the VEGF/VEGFR pathway, now provide the scientific basis for new combinational treatments of immunotherapy with anti-angiogenic agents. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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22 pages, 2746 KiB

Open AccessReview

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology

by Antonio Giovanni Solimando, Tiziana Annese, Roberto Tamma, Giuseppe Ingravallo, Eugenio Maiorano, Angelo Vacca, Giorgina Specchia and Domenico Ribatti

Cancers 2020, 12(7), 1869; https://doi.org/10.3390/cancers12071869 - 11 Jul 2020

Cited by 43 | Viewed by 5376

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases of NHL. Analysis of the tumor microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases of NHL. Analysis of the tumor microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we analyzed the role of different cellular components of the tumor microenvironment, including mast cells, macrophages, and lymphocytes, in the tumor progression of DLBCL. We examined several approaches to confront the available pieces of evidence, whereby three key points emerged. DLBCL is a disease of malignant B cells spreading and accumulating both at nodal and at extranodal sites. In patients with both nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. The DLBCL cell interaction with mature stromal cells and vessels confers tumor protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL–milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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18 pages, 2429 KiB

Open AccessEditor’s ChoiceReview

Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches

by Harman Saman, Syed Shadab Raza, Shahab Uddin and Kakil Rasul

Cancers 2020, 12(5), 1172; https://doi.org/10.3390/cancers12051172 - 6 May 2020

Cited by 105 | Viewed by 9566

Abstract

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the [...] Read more.

Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer. Full article

(This article belongs to the Special Issue Angiogenesis in Cancers)

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