Submit to JCM Review for JCM Propose a Special Issue

Journal Browser

Targeting Angiogenesis and the Immune System in Cancer: Current Challenges

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (20 April 2020) | Viewed by 60871

Share This Special Issue

Special Issue Editor

Prof. Dr. Vito Racanelli

E-Mail
Guest Editor

Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
Interests: clinical immunology; tumor immunology; emergency medicine; pharmacotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is my pleasure to invite you to contribute to the upcoming Special Issue of the Journal of Clinical Medicine devoted to “Targeting Angiogenesis and the Immune System in Cancer: Current Challenges”. The intent of this issue is to provide up-to-date knowledge on the crucial mechanisms promoting angiogenesis and mediating immunosuppression during cancer development and progression. As is now well known, tumors grow and evolve through a constant crosstalk with the surrounding microenvironment, and emerging evidence indicates that angiogenesis and immunosuppression frequently occur simultaneously in response to this crosstalk. Accordingly, strategies combining anti-angiogenic therapy and immunotherapy seem to have the potential to tip the balance of the tumor microenvironment and improve treatment response.

Original research papers describing complete investigations, brief communications reporting timely and significant results, and review articles highlighting recent findings are welcome. All manuscripts will be peer-reviewed according to standard journal procedures and policies.

I do hope that you will be able to accept this invitation and contribute to the success of this Special Issue.

Thank you for considering this invitation.

Sincerely,

Prof. Dr. Vito Racanelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Angiogenesis
Immunosuppression
Immune escape
Tumor progression
Cancer therapy

Published Papers (11 papers)

Download All Papers

Research

Jump to: Review

17 pages, 2461 KiB

Open AccessArticle

A Minimal PKPD Interaction Model for Evaluating Synergy Effects of Combined NSCLC Therapies

by Clara Mihaela Ionescu, Maria Ghita, Dana Copot, Eric Derom and Dirk Verellen

J. Clin. Med. 2020, 9(6), 1832; https://doi.org/10.3390/jcm9061832 - 12 Jun 2020

Cited by 15 | Viewed by 2545

Abstract

This paper introduces a mathematical compartmental formulation of dose-effect synergy modelling for multiple therapies in non small cell lung cancer (NSCLC): antiangiogenic, immuno- and radiotherapy. The model formulates the dose-effect relationship in a unified context, with tumor proliferating rates and necrotic tissue volume progression as a function of therapy management profiles. The model accounts for inter- and intra-response variability by using surface model response terms. Slow acting peripheral compartments such as fat and muscle for drug distribution are not modelled. This minimal pharmacokinetic-pharmacodynamic (PKPD) model is evaluated with reported data in mice from literature. A systematic analysis is performed by varying only radiotherapy profiles, while antiangiogenesis and immunotherapy are fixed to their initial profiles. Three radiotherapy protocols are selected from literature: (1) a single dose 5 Gy once weekly; (2) a dose of 5 Gy × 3 days followed by a 2 Gy × 3 days after two weeks and (3) a dose of 5 Gy + 2 × 0.075 Gy followed after two weeks by a 2 Gy + 2 × 0.075 Gy dose. A reduction of 28% in tumor end-volume after 30 days was observed in Protocol 2 when compared to Protocol 1. No changes in end-volume were observed between Protocol 2 and Protocol 3, this in agreement with other literature studies. Additional analysis on drug interaction suggested that higher synergy among drugs affects up to three-fold the tumor volume (increased synergy leads to significantly lower growth ratio and lower total tumor volume). Similarly, changes in patient response indicated that increased drug resistance leads to lower reduction rates of tumor volumes, with end-volume increased up to 25–30%. In conclusion, the proposed minimal PKPD model has physiological value and can be used to study therapy management protocols and is an aiding tool in the clinical decision making process. Although developed with data from mice studies, the model is scalable to NSCLC patients. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

15 pages, 1158 KiB

Open AccessArticle

miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

by Markus Krebs, Antonio Giovanni Solimando, Charis Kalogirou, André Marquardt, Torsten Frank, Ioannis Sokolakis, Georgios Hatzichristodoulou, Susanne Kneitz, Ralf Bargou, Hubert Kübler, Bastian Schilling, Martin Spahn and Burkhard Kneitz

J. Clin. Med. 2020, 9(3), 670; https://doi.org/10.3390/jcm9030670 - 02 Mar 2020

Cited by 43 | Viewed by 3952

Abstract

Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

14 pages, 3903 KiB

Open AccessArticle

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma

by Giuseppe Di Lernia, Patrizia Leone, Antonio Giovanni Solimando, Alessio Buonavoglia, Ilaria Saltarella, Roberto Ria, Paolo Ditonno, Nicola Silvestris, Lucilla Crudele, Angelo Vacca and Vito Racanelli

J. Clin. Med. 2020, 9(2), 552; https://doi.org/10.3390/jcm9020552 - 18 Feb 2020

Cited by 36 | Viewed by 4276

Abstract

Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

17 pages, 6349 KiB

Open AccessArticle

Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis

by Ian J. Purvis, Janardhan Avilala, Maheedhara R. Guda, Sujatha Venkataraman, Rajeev Vibhakar, Andrew J. Tsung, Kiran K. Velpula and Swapna Asuthkar

J. Clin. Med. 2019, 8(8), 1158; https://doi.org/10.3390/jcm8081158 - 02 Aug 2019

Cited by 34 | Viewed by 4840

Abstract

Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is highly expressed and is associated with lower overall survival in MYC⁺ MB’s. Evidence for a direct transcriptional role of MYC on the B7-H3 gene promoter was confirmed by MYC inhibition and anti-MYC antibody ChIP analysis. Interestingly, MYC inhibition not only downregulated the B7-H3 protein expression, but also rescued miR-29 expression, thus indicating a triangular regulatory relationship between MYC, miR-29, and B7-H3 in Group 3 MB cells. From RNA seq and IPAD assay, we observed a negative feedback loop between miR-29 and MYC that may control B7-H3 expression levels in MB cells. Our studies show that B7-H3 expression levels play a crucial role in promoting MB angiogenesis which can be inhibited by miR-29 overexpression via miR-29-mediated B7-H3 downregulation. The tumor suppressor role of miR-29 is mediated by the activation of JAK/STAT1 signaling that further plays a role in MYC-B7-H3 downregulation in MB. This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

Review

Jump to: Research

19 pages, 743 KiB

Open AccessReview

Anti-angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

by Antonella Argentiero, Antonio Giovanni Solimando, Markus Krebs, Patrizia Leone, Nicola Susca, Oronzo Brunetti, Vito Racanelli, Angelo Vacca and Nicola Silvestris

J. Clin. Med. 2020, 9(5), 1594; https://doi.org/10.3390/jcm9051594 - 24 May 2020

Cited by 49 | Viewed by 4326

Abstract

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

11 pages, 767 KiB

Open AccessReview

Angiogenesis and Immunity in Renal Carcinoma: Can We Turn an Unhappy Relationship into a Happy Marriage?

by Alessia Mennitto, Veronica Huber, Raffaele Ratta, Pierangela Sepe, Filippo de Braud, Giuseppe Procopio, Valentina Guadalupi, Mélanie Claps, Marco Stellato, Elena Daveri, Licia Rivoltini and Elena Verzoni

J. Clin. Med. 2020, 9(4), 930; https://doi.org/10.3390/jcm9040930 - 28 Mar 2020

Cited by 24 | Viewed by 3592

Abstract

The frontline treatment options for patients with metastatic renal cell carcinoma (mRCC) are evolving rapidly since the approval of combination immunotherapies by the U.S. Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). In particular, in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) have significantly improved the outcome of patients with mRCC compared to TKI monotherapy. Here, we review the preclinical data supporting the combination of ICIs with VEGFR TKIs. The VEGF-signaling inhibition could ideally sustain immunotherapy through a positive modulation of the tumor microenvironment (TME). Antiangiogenetics, in fact, with their inhibitory activity on myelopoiesis that indirectly reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells’ (Tregs) frequency and function, could have a role in determining an effective anti-tumor immune response. These findings are relevant for the challenges posed to clinicians concerning the clinical impact on treatment strategies for mRCC. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

21 pages, 700 KiB

Open AccessReview

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

by Raluca Ioana Teleanu, Cristina Chircov, Alexandru Mihai Grumezescu and Daniel Mihai Teleanu

J. Clin. Med. 2020, 9(1), 84; https://doi.org/10.3390/jcm9010084 - 29 Dec 2019

Cited by 291 | Viewed by 12544

Abstract

Angiogenesis is the process through which novel blood vessels are formed from pre-existing ones and it is involved in both physiological and pathological processes of the body. Furthermore, tumor angiogenesis is a crucial factor associated with tumor growth, progression, and metastasis. In this manner, there has been a great interest in the development of anti-angiogenesis strategies that could inhibit tumor vascularization. Conventional approaches comprise the administration of anti-angiogenic drugs that target and block the activity of proangiogenic factors. However, as their efficacy is still a matter of debate, novel strategies have been focusing on combining anti-angiogenic agents with chemotherapy or immunotherapy. Moreover, nanotechnology has also been investigated for the potential of nanomaterials to target and release anti-angiogenic drugs at specific sites. The aim of this paper is to review the mechanisms involved in angiogenesis and tumor vascularization and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

20 pages, 821 KiB

Open AccessReview

Insights into the Regulation of Tumor Angiogenesis by Micro-RNAs

by Patrizia Leone, Alessio Buonavoglia, Rossella Fasano, Antonio Giovanni Solimando, Valli De Re, Sebastiano Cicco, Angelo Vacca and Vito Racanelli

J. Clin. Med. 2019, 8(12), 2030; https://doi.org/10.3390/jcm8122030 - 20 Nov 2019

Cited by 60 | Viewed by 3885

Abstract

One of the hallmarks of cancer is angiogenesis, a series of events leading to the formation of the abnormal vascular network required for tumor growth, development, progression, and metastasis. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs whose functions include modulation of the expression of pro- and anti-angiogenic factors and regulation of the function of vascular endothelial cells. Vascular-associated microRNAs can be either pro- or anti-angiogenic. In cancer, miRNA expression levels are deregulated and typically vary during tumor progression. Experimental data indicate that the tumor phenotype can be modified by targeting miRNA expression. Based on these observations, miRNAs may be promising targets for the development of novel anti-angiogenic therapies. This review discusses the role of various miRNAs and their targets in tumor angiogenesis, describes the strategies and challenges of miRNA-based anti-angiogenic therapies and explores the potential use of miRNAs as biomarkers for anti-angiogenic therapy response. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

25 pages, 1636 KiB

Open AccessReview

Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors

by Bin Ren, J. Bart Rose, Yehe Liu, Renata Jaskular-Sztul, Carlo Contreras, Adam Beck and Herbert Chen

J. Clin. Med. 2019, 8(11), 1980; https://doi.org/10.3390/jcm8111980 - 14 Nov 2019

Cited by 23 | Viewed by 7129

Abstract

Arteriogenesis supplies oxygen and nutrients in the tumor microenvironment (TME), which may play an important role in tumor growth and metastasis. Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic malignancy and are frequently metastatic on presentation. Nearly a third of pNETs secrete bioactive substances causing debilitating symptoms. Current treatment options for metastatic pNETs are limited. Importantly, these tumors are highly vascularized and heterogeneous neoplasms, in which the heterogeneity of vascular endothelial cells (ECs) and de novo arteriogenesis may be critical for their progression. Current anti-angiogenetic targeted treatments have not shown substantial clinical benefits, and they are poorly tolerated. This review article describes EC heterogeneity and heterogeneous tumor-associated ECs (TAECs) in the TME and emphasizes the concept of de novo arteriogenesis in the TME. The authors also emphasize the challenges of current antiangiogenic therapy in pNETs and discuss the potential of tumor arteriogenesis as a novel therapeutic target. Finally, the authors prospect the clinical potential of targeting the FoxO1-CD36-Notch pathway that is associated with both pNET progression and arteriogenesis and provide insights into the clinical implications of targeting plasticity of cancer stem cells (CSCs) and vascular niche, particularly the arteriolar niche within the TME in pNETs, which will also provide insights into other types of cancer, including breast cancer, lung cancer, and malignant melanoma. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

18 pages, 1673 KiB

Open AccessReview

Classical Hodgkin’s Lymphoma in the Era of Immune Checkpoint Inhibition

by Valli De Re, Laura Caggiari, Ombretta Repetto, Lara Mussolin and Maurizio Mascarin

J. Clin. Med. 2019, 8(10), 1596; https://doi.org/10.3390/jcm8101596 - 02 Oct 2019

Cited by 16 | Viewed by 4247

Abstract

The ligation of programmed cell death 1 (PD-1) with programmed cell death ligand PD-L activates the immune checkpoint leading to T-cell dysfunction, exhaustion, and tolerance, especially in Hodgkin lymphoma (HL) where the PD-L/ Janus kinase (Jak) signaling was frequently found altered. Anti-PD-1 or anti-PD-L1 monoclonal antibodies can reverse this immune checkpoint, releasing the brake on T-cell responses. The characterization of the mechanisms regulating both the expression of PD-1 and PD-L and their function(s) in HL is ongoing. We provide in this review the recent findings focused on this aim with special attention on the major research topics, such as adverse events and resistance to PD-1–PD-L1 inhibitor treatment, together with a part about angiogenesis, extracellular vesicles, and microbiome in HL pathogenesis. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures

Figure 1

26 pages, 2999 KiB

Open AccessReview

High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

by Antonio Giovanni Solimando, Matteo Claudio Da Vià, Sebastiano Cicco, Patrizia Leone, Giuseppe Di Lernia, Donato Giannico, Vanessa Desantis, Maria Antonia Frassanito, Arcangelo Morizio, Julia Delgado Tascon, Assunta Melaccio, Ilaria Saltarella, Giuseppe Ranieri, Roberto Ria, Leo Rasche, K. Martin Kortüm, Andreas Beilhack, Vito Racanelli, Angelo Vacca and Hermann Einsele

J. Clin. Med. 2019, 8(7), 997; https://doi.org/10.3390/jcm8070997 - 09 Jul 2019

Cited by 48 | Viewed by 8572

Abstract

Multiple myeloma (MM) is a genetically heterogeneous disease that includes a subgroup of 10–15% of patients facing dismal survival despite the most intensive treatment. Despite improvements in biological knowledge, MM is still an incurable neoplasia, and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. The aim of this review is to provide an integrated clinical and biological overview of high-risk MM, discussing novel therapeutic perspectives, targeting the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug-resistance can foster a better tailored clinical management of the high-risk profile and therapy-refractoriness. Among the current clinical difficulties in MM, patients’ management by manipulating the tumor niche represents a major challenge. The angiogenesis and the stromal infiltrate constitute pivotal mechanisms of a mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy, but variable and unpredictable responses in high-risk MM. The comprehensive understanding of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Here, we provide a broad outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better select candidates for dual immune/vasculogenesis targeting. Full article

(This article belongs to the Special Issue Targeting Angiogenesis and the Immune System in Cancer: Current Challenges)

► Show Figures