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Biomedicines
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Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels...
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Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 13447

Special Issue Editors

Dr. Loredana Albonici

E-Mail Website
Guest Editor
1. Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
2. Department of Biomedical Sciences, “Our Lady of Good Counsel” University, Rruga Dritan Hoxha, 1000 Tirana, Albania
Interests: molecular mechanisms associated with tumor growth and progression linked to angiogenesis; molecular mechanisms associated with polarized immune cells in the tumor microenvironment; effects of angiogenic factors on vascular biology and immune response
Special Issues, Collections and Topics in MDPI journals
Dr. Camilla Palumbo

E-Mail Website
Guest Editor
Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
Interests: molecular and cellular oncology; anticancer drugs sensitivity and resistance; combination therapy in cancer treatment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumor angiogenesis is sustained by multiple growth factors, including vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), stromal-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). Accumulating evidence indicates that angiogenic growth factors (AGFs) are involved in tumor growth and progression via multiple mechanisms that go beyond their angiogenic role. Indeed, within the tumor microenvironment (TME), AGFs produced by tumor and inflammatory cells create a tolerogenic milieu that allows the escape of cancer cells from immune recognition and elimination. Therapeutic strategies targeting AGFs to restore vessel normalization have been found to improve antitumor immunity and, in turn, immune-mediated mechanisms can regulate the response to antiangiogenic therapy. Still, immunotherapy is effective only in a fraction of cancer patients, and combined antiangiogenic and immunotherapy approaches have not always yielded the expected clinical results. An in-depth characterization of the complex interplay between AGFs, cancer cells and immune cells in the TME is urgently needed to identify new targets that could promote or hinder the antitumor immune response.

In this Special Issue we welcome the submission of reviews, mini-reviews, and original research articles that can offer new insights into the following topics:

  • The multifaceted relationship between AGFs and cells of innate and adaptive immunity in the TME;
  • Reciprocal interplay between immune cell types in a TME characterized by AGFs upregulation;
  • Role of AGFs in endothelial–immune cell cross-talk during vascular inflammation and metastasis;
  • Prediction and optimization of cellular responses to therapeutic strategies based on AGF-targeting agents and immune-checkpoint inhibitors.

Dr. Loredana Albonici
Dr. Camilla Palumbo
Guest Editors

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. Biomedicines is an international peer-reviewed open access monthly 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

  • angiogenic growth factors (AGFs)
  • VEGF
  • PlGF
  • SDF-1
  • PDGF
  • FGF
  • AGFs-Receptors
  • tumor microenvironment
  • innate and adaptive immune cells

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 174 KiB  
Editorial
Editorial for the Special Issue “Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation”
by Camilla Palumbo and Loredana Albonici
Biomedicines 2024, 12(11), 2541; https://doi.org/10.3390/biomedicines12112541 - 7 Nov 2024
Viewed by 639
Abstract
A myriad of growth factors and receptors, whose effects are intertwined in complex interactions, do not only orchestrate tumor angiogenesis [...] Full article
(This article belongs to the Special Issue Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation)

Research

Jump to: Editorial, Review

14 pages, 5434 KiB  
Article
Prognostic Value of PlGF Upregulation in Prostate Cancer
by Manuel Scimeca, Erica Giacobbi, Francesca Servadei, Valeria Palumbo, Camilla Palumbo, Enrico Finazzi-Agrò, Simone Albisinni, Alessandro Mauriello and Loredana Albonici
Biomedicines 2024, 12(10), 2194; https://doi.org/10.3390/biomedicines12102194 - 26 Sep 2024
Viewed by 1280
Abstract
Background: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide, with metastasis, particularly to bone, being the primary cause of mortality. Currently, prognostic markers like PSA levels and Gleason classification are limited in predicting metastasis, emphasizing the need for [...] Read more.
Background: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide, with metastasis, particularly to bone, being the primary cause of mortality. Currently, prognostic markers like PSA levels and Gleason classification are limited in predicting metastasis, emphasizing the need for novel clinical biomarkers. New molecules predicting tumor progression have been identified over time. Some, such as the immune checkpoint inhibitors (ICIs) PD-1/PD-L1, have become valid markers as theranostic tools essential for prognosis and drug target therapy. However, despite the success of ICIs as an anti-cancer therapy for solid tumors, their efficacy in treating bone metastases has mainly proven ineffective, suggesting intrinsic resistance to this therapy in the bone microenvironment. This study explores the potential of immunological intratumoral biomarkers, focusing on placental growth factor (PlGF), Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), and Programmed Cell Death Protein 1 (PD-1), in predicting bone metastasis formation. Methods: we analyzed PCa samples from patients with and without metastasis by immunohistochemical analysis. Results: Results revealed that PlGF expression is significantly higher in primary tumors of patients that developed metastasis within five years from the histological diagnosis. Additionally, PlGF expression correlates with increased VEGFR1 and PD-1 levels, as well as the presence of intratumoral M2 macrophages. Conclusions: These findings suggest that PlGF contributes to an immunosuppressive environment, thus favoring tumor progression and metastatic process. Results here highlight the potential of integrating these molecular markers with existing prognostic tools to enhance the accuracy of metastasis prediction in PCa. By identifying patients at risk for metastasis, clinicians can tailor treatment strategies more effectively, potentially improving survival outcomes and quality of life. This study underscores the importance of further research into the role of intratumoral biomarkers in PCa management. Full article
(This article belongs to the Special Issue Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation)
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20 pages, 4905 KiB  
Article
Angiopoietin-2 and the Vascular Endothelial Growth Factor Promote Migration and Invasion in Hepatocellular Carcinoma- and Intrahepatic Cholangiocarcinoma-Derived Spheroids
by Adriana Romanzi, Fabiola Milosa, Gemma Marcelli, Rosina Maria Critelli, Simone Lasagni, Isabella Gigante, Francesco Dituri, Filippo Schepis, Massimiliano Cadamuro, Gianluigi Giannelli, Luca Fabris and Erica Villa
Biomedicines 2024, 12(1), 87; https://doi.org/10.3390/biomedicines12010087 - 30 Dec 2023
Cited by 5 | Viewed by 2351
Abstract
Aggressive hepatocellular carcinoma (HCC) overexpressing Angiopoietin-2 (ANG-2) (a protein linked with angiogenesis, proliferation, and epithelial–mesenchymal transition (EMT)), shares 95% of up-regulated genes and a similar poor prognosis with the proliferative subgroup of intrahepatic cholangiocarcinoma (iCCA). We analyzed the pro-invasive effect of ANG-2 and [...] Read more.
Aggressive hepatocellular carcinoma (HCC) overexpressing Angiopoietin-2 (ANG-2) (a protein linked with angiogenesis, proliferation, and epithelial–mesenchymal transition (EMT)), shares 95% of up-regulated genes and a similar poor prognosis with the proliferative subgroup of intrahepatic cholangiocarcinoma (iCCA). We analyzed the pro-invasive effect of ANG-2 and its regulator vascular endothelial growth factor (VEGF) on HCC and CCA spheroids to uncover posUsible common ways of response. Four cell lines were used: Hep3B and HepG2 (HCC), HuCC-T1 (iCCA), and EGI-1 (extrahepatic CCA). We treated the spheroids with recombinant human (rh) ANG-2 and/or VEGF and then observed the changes at the baseline, after 24 h, and again after 48 h. Proangiogenic stimuli increased migration and invasion capability in HCC- and iCCA-derived spheroids and were associated with a modification in EMT phenotypic markers (a decrease in E-cadherin and an increase in N-cadherin and Vimentin), especially at the migration front. Inhibitors targeting ANG-2 (Trebananib) and the VEGF (Bevacizumab) effectively blocked the migration ability of spheroids that had been stimulated with rh-ANG-2 and rh-VEGF. Overall, our findings highlight the critical role played by ANG-2 and the VEGF in enhancing the ability of HCC- and iCCA-derived spheroids to migrate and invade, which are key processes in cancer progression. Full article
(This article belongs to the Special Issue Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation)
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16 pages, 33442 KiB  
Article
VEGFA Status as a Predictive Marker of Therapy Outcome in Metastatic Gastric Cancer Patients Following Ramucirumab-Based Treatment
by Annalisa Schirizzi, Aram Arshadi, Doron Tolomeo, Laura Schirosi, Anna Maria Valentini, Giampiero De Leonardis, Maria Grazia Refolo, Rossella Donghia, Clelia Tiziana Storlazzi, Alfredo Zito, Angela Dalia Ricci, Simona Vallarelli, Carmela Ostuni, Maria Bencivenga, Giovanni De Manzoni, Caterina Messa, Raffaele Armentano, Gianluigi Giannelli, Claudio Lotesoriere and Rosalba D’Alessandro
Biomedicines 2023, 11(10), 2721; https://doi.org/10.3390/biomedicines11102721 - 7 Oct 2023
Cited by 3 | Viewed by 1926
Abstract
Metastatic gastric cancer (mGC) often has a poor prognosis and may benefit from a few targeted therapies. Ramucirumab-based anti-angiogenic therapy targeting the VEGFR2 represents a milestone in the second-line treatment of mGC. Several studies on different cancers are focusing on the major VEGFR2 [...] Read more.
Metastatic gastric cancer (mGC) often has a poor prognosis and may benefit from a few targeted therapies. Ramucirumab-based anti-angiogenic therapy targeting the VEGFR2 represents a milestone in the second-line treatment of mGC. Several studies on different cancers are focusing on the major VEGFR2 ligand status, meaning VEGFA gene copy number and protein overexpression, as a prognostic marker and predictor of response to anti-angiogenic therapy. Following this insight, our study aims to examine the role of VEGFA status as a predictive biomarker for the outcome of second-line therapy with Ramucirumab and paclitaxel in mGC patients. To this purpose, the copy number of the VEGFA gene, by fluorescence in situ hybridization experiments, and its expression in tumor tissue as well as the density of micro-vessels, by immunohistochemistry experiments, were assessed in samples derived from mGC patients. This analysis found that amplification of VEGFA concomitantly with VEGFA overexpression and overexpression of VEGFA with micro-vessels density are more represented in patients showing disease control during treatment with Ramucirumab. In addition, in the analyzed series, it was found that amplification was not always associated with overexpression of VEGFA, but overexpression of VEGFA correlates with high micro-vessel density. In conclusion, overexpression of VEGFA could emerge as a potential biomarker to predict the response to anti-angiogenic therapy. Full article
(This article belongs to the Special Issue Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation)
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21 pages, 3787 KiB  
Article
Nonlinear Adaptive Optimal Controller Design for Anti-Angiogenic Tumor Treatment
by Nitendra Nath, Irfan Kil, Ugur Hasirci, Richard E. Groff and Timothy C. Burg
Biomedicines 2023, 11(2), 497; https://doi.org/10.3390/biomedicines11020497 - 8 Feb 2023
Viewed by 1754
Abstract
Angiogenesis is an important process in tumor growth as it represents the regime when the tumor recruits blood vessels from the surrounding tissue to support further tumor growth. Anti-angiogenic treatments aim to shrink the tumor by interrupting the vascularization of the tumor; however, [...] Read more.
Angiogenesis is an important process in tumor growth as it represents the regime when the tumor recruits blood vessels from the surrounding tissue to support further tumor growth. Anti-angiogenic treatments aim to shrink the tumor by interrupting the vascularization of the tumor; however, the anti-angiogenic agents are costly and the tumor response to these agents is nonlinear. Simple dosing schemes, e.g., a constant dose, may yield higher cost or lower efficacy than an approach that considers the tumor system dynamics. Hence, in this study, the administration of anti-angiogenic treatment is considered as a nonlinear control problem. The main aim of the controller design is to optimize the anti-angiogenic tumor therapy, specifically, to minimize the tumor volume and drug dose. Toward this aim, two nonlinear optimal controllers are presented. The first controller ensures exponential tracking of a desired, optimal tumor volume profile under the assumption that all parameters in the system model are known. The second controller, on the other hand, assumes all the parameters are unknown and provides asymptotic tracking. Both controllers take pharmacokinetics and pharmacodynamics into account, as well as the carrying capacity of the vascular network. Lyapunov based arguments are used to design the controllers, using stability arguments, and numerical simulation results are presented to demonstrate the effectiveness of the proposed method. Full article
(This article belongs to the Special Issue Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation)
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Review

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22 pages, 3585 KiB  
Review
Combination of Anti-Angiogenics and Immunotherapies in Renal Cell Carcinoma Show Their Limits: Targeting Fibrosis to Break through the Glass Ceiling?
by Manon Teisseire, Sandy Giuliano and Gilles Pagès
Biomedicines 2024, 12(2), 385; https://doi.org/10.3390/biomedicines12020385 - 7 Feb 2024
Cited by 1 | Viewed by 1922
Abstract
This review explores treating metastatic clear cell renal cell carcinoma (ccRCC) through current therapeutic modalities—anti-angiogenic therapies and immunotherapies. While these approaches represent the forefront, their limitations and variable patient responses highlight the need to comprehend underlying resistance mechanisms. We specifically investigate the role [...] Read more.
This review explores treating metastatic clear cell renal cell carcinoma (ccRCC) through current therapeutic modalities—anti-angiogenic therapies and immunotherapies. While these approaches represent the forefront, their limitations and variable patient responses highlight the need to comprehend underlying resistance mechanisms. We specifically investigate the role of fibrosis, prevalent in chronic kidney disease, influencing tumour growth and treatment resistance. Our focus extends to unravelling the intricate interplay between fibrosis, immunotherapy resistance, and the tumour microenvironment for effective therapy development. The analysis centres on connective tissue growth factor (CTGF), revealing its multifaceted role in ccRCC—promoting fibrosis, angiogenesis, and cancer progression. We discuss the potential of targeting CTGF to address the problem of fibrosis in ccRCC. Emphasising the crucial relationship between fibrosis and the immune system in ccRCC, we propose that targeting CTGF holds promise for overcoming obstacles to cancer treatment. However, we recognise that an in-depth understanding of the mechanisms and potential limitations is imperative and, therefore, advocate for further research. This is an essential prerequisite for the successful integration of CTGF-targeted therapies into the clinical landscape. Full article
(This article belongs to the Special Issue Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation)
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16 pages, 1107 KiB  
Review
Metamorphic Effect of Angiogenic Switch in Tumor Development: Conundrum of Tumor Angiogenesis Toward Progression and Metastatic Potential
by Daniel Leon Moshe, Leili Baghaie, Fleur Leroy, Elizabeth Skapinker and Myron R. Szewczuk
Biomedicines 2023, 11(8), 2142; https://doi.org/10.3390/biomedicines11082142 - 29 Jul 2023
Cited by 6 | Viewed by 2486
Abstract
Our understanding of angiogenesis has significantly expanded over the past five decades. More recently, research has focused on this process at a more molecular level, looking at it through the signaling pathways that activate it and its non-direct downstream effects. This review discusses [...] Read more.
Our understanding of angiogenesis has significantly expanded over the past five decades. More recently, research has focused on this process at a more molecular level, looking at it through the signaling pathways that activate it and its non-direct downstream effects. This review discusses current findings in molecular angiogenesis, focusing on its impact on the immune system. Moreover, the impairment of this process in cancer progression and metastasis is highlighted, and current anti-angiogenic treatments and their effects on tumor growth are discussed. Full article
(This article belongs to the Special Issue Angiogenic Growth Factors in Tumor Development: Beyond New Blood Vessels Formation)
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