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Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application
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Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 16995

Special Issue Editor

Prof. Dr. Marius L. Raica

E-Mail Website
Guest Editor
Department of Microscopic Morphology/Histology, Angiogenesis Research Center, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
Interests: head and neck cancer; otorhinolaryngology; molecular diagnosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

More than 50 years ago, Judah Folkman showed that malignant tumors cannot grow more than some millimeters in the absence of blood vessels, thus leading to the birth of modern angiogenesis. Since then, extensive research—especially in recent decades—has been dedicated to the discovery of specific growth factors, their cognate receptors, and the role of different biological substances that regulate this process through experimental models. Various drugs, mainly inhibitors of angiogenesis, have already been introduced in the medical practice. Both inhibition and stimulation of angiogenesis are of practical relevance in a broad spectrum of human diseases, which is why molecular mechanisms of normal and pathological angiogenesis are of major importance in order to better understand this process and to create a basis for new drug discovery. On the other hand, it has not been possible for all data found in preclinical experiments to be translated into the clinic. Indeed, there have been many excellent results obtained in the lab that could not be confirmed or were not applicable in medical practice. Many unclear, undiscovered, and confusing results persist concerning the molecular regulation of both excessive and deficient angiogenesis, and this is the reason we aim to explore the mechanisms of this process in particular in the current Special Issue of the International Journal of Molecular Sciences.

We have been aware of the concept of lymphangiogenesis for more than a century, but extensive studies on this topic only began to be carried out after the discovery of lymphatic endothelial cell-specific markers. Interest in this field is related in particular to the spread of malignant cells via lymphatic routes during the metastatic cascade. Similar to angiogenesis, there are some known growth factors that stimulate lymphangiogenesis. Opposite to angiogenesis, however, there are no known specific substances that can effectively inhibit lymphangiogenesis in human diseases, and in particular in patients with cancer. Only a few experiments that investigate humanized antibodies against the lymphatic endothelium are currently in progress. Therefore, we strongly encourage the publication of original papers and reviews that could contribute to a better knowledge of these two fascinating processes: angiogenesis and lymphangiogenesis.

Prof. Dr. Marius L. Raica
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • Lymphangiogenesis
  • Notch signalling
  • Angiogenic growth factors
  • PROX
  • Lymphatic endothelial cell differentiation

Published Papers (8 papers)

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Research

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16 pages, 3907 KiB  
Article
Single-Cell Transcriptome of Wet AMD Patient-Derived Endothelial Cells in Angiogenic Sprouting
by Natalie Jia Ying Yeo, Vanessa Wazny, Nhi Le Uyen Nguyen, Chun-Yi Ng, Kan Xing Wu, Qiao Fan, Chui Ming Gemmy Cheung and Christine Cheung
Int. J. Mol. Sci. 2022, 23(20), 12549; https://doi.org/10.3390/ijms232012549 - 19 Oct 2022
Cited by 1 | Viewed by 2237
Abstract
Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. ‘Wet’ AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial [...] Read more.
Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. ‘Wet’ AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our ‘activated’ BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome has been created to facilitate further discovery research. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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28 pages, 5516 KiB  
Article
WNK1–OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy
by Chia-Ying Hou, Chung-Yung Ma, Yu-Ju Lin, Chou-Long Huang, Horng-Dar Wang and Chiou-Hwa Yuh
Int. J. Mol. Sci. 2022, 23(20), 12100; https://doi.org/10.3390/ijms232012100 - 11 Oct 2022
Cited by 7 | Viewed by 2727
Abstract
Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b (osr1b) is upregulated in endothelial cells in [...] Read more.
Lysine-deficient protein kinase-1 (WNK1) is critical for both embryonic angiogenesis and tumor-induced angiogenesis. However, the downstream effectors of WNK1 during these processes remain ambiguous. In this study, we identified that oxidative stress responsive 1b (osr1b) is upregulated in endothelial cells in both embryonic and tumor-induced angiogenesis in zebrafish, accompanied by downregulation of protein phosphatase 2A (pp2a) subunit ppp2r1bb. In addition, wnk1a and osr1b are upregulated in two liver cancer transgenic fish models: [tert x p53−/−] and [HBx,src,p53−/−,RPIA], while ppp2r1bb is downregulated in [tert x p53−/−]. Furthermore, using HUVEC endothelial cells co-cultured with HepG2 hepatoma cells, we confirmed that WNK1 plays a critical role in the induction of hepatoma cell migration in both endothelial cells and hepatoma cells. Moreover, overexpression of OSR1 can rescue the reduced cell migration caused by shWNK1 knockdown in HUVEC cells, indicating OSR1 is downstream of WNK1 in endothelial cells promoting hepatoma cell migration. Overexpression of PPP2R1A can rescue the increased cell migration caused by WNK1 overexpression in HepG2, indicating that PPP2R1A is a downstream effector in hepatoma. The combinatorial treatment with WNK1 inhibitor (WNK463) and OSR1 inhibitor (Rafoxanide) plus oligo-fucoidan via oral gavage to feed [HBx,src,p53−/−,RPIA] transgenic fish exhibits much more significant anticancer efficacy than Regorafenib for advanced HCC. Importantly, oligo-fucoidan can reduce the cell senescence marker-IL-1β expression. Furthermore, oligo-fucoidan reduces the increased cell senescence-associated β-galactosidase activity in tert transgenic fish treated with WNK1-OSR1 inhibitors. Our results reveal the WNK1–OSR1–PPP2R1A axis plays a critical role in both endothelial and hepatoma cells during tumor-induced angiogenesis promoting cancer cell migration. By in vitro and in vivo experiments, we further uncover the molecular mechanisms of WNK1 and its downstream effectors during tumor-induced angiogenesis. Targeting WNK1–OSR1-mediated anti-angiogenesis and anti-cancer activity, the undesired inflammation response caused by inhibiting WNK1–OSR1 can be attenuated by the combination therapy with oligo-fucoidan and may improve the efficacy. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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21 pages, 3652 KiB  
Article
Evaluation of Circulating MicroRNAs and Adipokines in Breast Cancer Survivors with Arm Lymphedema
by Khairunnisa’ Md Yusof, Kira Groen, Rozita Rosli, Maha Abdullah, Rozi Mahmud and Kelly A. Avery-Kiejda
Int. J. Mol. Sci. 2022, 23(19), 11359; https://doi.org/10.3390/ijms231911359 - 26 Sep 2022
Cited by 6 | Viewed by 1838
Abstract
Breast cancer-related lymphedema (BCRL) is a form of secondary lymphedema that is characterized by abnormal swelling of one or both arms due to the accumulation of lymph fluid in the interstitial tissue spaces, resulting from obstruction of the lymphatic vessels due to surgery [...] Read more.
Breast cancer-related lymphedema (BCRL) is a form of secondary lymphedema that is characterized by abnormal swelling of one or both arms due to the accumulation of lymph fluid in the interstitial tissue spaces, resulting from obstruction of the lymphatic vessels due to surgery insults, radiotherapy, or chemotherapy. Due to the multifactorial nature of this condition, the pathogenesis of secondary lymphedema remains unclear and the search for molecular factors associated with the condition is ongoing. This study aimed to identify serum microRNAs and adipokines associated with BCRL. Blood was collected from 113 breast cancer survivors and processed to obtain serum for small RNA-sequencing (BCRL vs. non-BCRL, n = 7 per group). MicroRNAs that were differentially expressed (fold change >1.5, p < 0.05) between lymphedema cases and those without lymphedema were further quantified in a validation cohort through quantitative reverse transcription PCR (BCRL n = 16, non-BCRL, n = 83). Leptin and adiponectin levels were measured in a combined cohort (BCRL n = 23, non-BCRL n = 90) using enzyme-linked immunosorbent assays. Two of the most significantly upregulated microRNAs, miR-199a-3p and miR-151a-3p, were strongly correlated with the onset of lymphedema and diabetes mellitus in the BCRL group. Leptin levels were higher in the BCRL cohort compared to the non-BCRL cohort (p < 0.05). A metabolic syndrome biomarker, the adiponectin/leptin ratio, was found to be lower in the BCRL group than in the non-BCRL group (median: 0.28 vs. 0.41, p < 0.05). Extensive studies on the mechanisms of the identified microRNAs and association of leptin with arm lymphedema may provide new insights on the potential biomarkers for lymphedema that should be followed up in a prospective cohort study. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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20 pages, 8594 KiB  
Article
HTRA1 Regulates Subclinical Inflammation and Activates Proangiogenic Response in the Retina and Choroid
by Waseem Ahamed, Richard Ming Chuan Yu, Yang Pan, Takeshi Iwata, Veluchamy Amutha Barathi, Yeo Sia Wey, Sai Bo Bo Tun, Beiying Qiu, Alison Tan, Xiaomeng Wang, Chui Ming Gemmy Cheung, Tien Yin Wong and Yasuo Yanagi
Int. J. Mol. Sci. 2022, 23(18), 10206; https://doi.org/10.3390/ijms231810206 - 6 Sep 2022
Cited by 5 | Viewed by 2353
Abstract
High-temperature requirement A1 (HtrA1) has been identified as a disease-susceptibility gene for age-related macular degeneration (AMD) including polypoidal choroidal neovasculopathy (PCV). We characterized the underlying phenotypic changes of transgenic (Tg) mice expressing ubiquitous CAG promoter (CAG-HtrA1 Tg). In vivo imaging modalities and histopathology [...] Read more.
High-temperature requirement A1 (HtrA1) has been identified as a disease-susceptibility gene for age-related macular degeneration (AMD) including polypoidal choroidal neovasculopathy (PCV). We characterized the underlying phenotypic changes of transgenic (Tg) mice expressing ubiquitous CAG promoter (CAG-HtrA1 Tg). In vivo imaging modalities and histopathology were performed to investigate the possible neovascularization, drusen formation, and infiltration of macrophages. Subretinal white material deposition and scattered white-yellowish retinal foci were detected on CFP [(Tg—33% (20/60) and wild-type (WT)—7% (1/15), p < 0.05]. In 40% (4/10) of the CAG-HtrA1 Tg retina, ICGA showed punctate hyperfluorescent spots. There was no leakage on FFA and OCTA failed to confirm vascular flow signals from the subretinal materials. Increased macrophages and RPE cell migrations were noted from histopathological sections. Monocyte subpopulations were increased in peripheral blood in the CAG-HtrA1 Tg mice (p < 0.05). Laser induced CNV in the CAG-HtrA1 Tg mice and showed increased leakage from CNV compared to WT mice (p < 0.05). Finally, choroidal explants of the old CAG-HtrA1 Tg mice demonstrated an increased area of sprouting (p < 0.05). Signs of subclinical inflammation was observed in CAG-HtrA1 Tg mice. Such subclinical inflammation may have resulted in increased RPE cell activation and angiogenic potential. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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8 pages, 1215 KiB  
Article
Proliferating Lymphatic Endothelial Cells as a Prognostic Marker in Head and Neck Squamous Cell Carcinoma
by Cristina Stefania Dumitru, Amalia Raluca Ceausu, Nela Pusa Gaje, Cristian Silviu Suciu and Marius Raica
Int. J. Mol. Sci. 2022, 23(17), 9793; https://doi.org/10.3390/ijms23179793 - 29 Aug 2022
Cited by 2 | Viewed by 1370
Abstract
Podoplanin and Ki-67 are two important markers of cancer progression. The aim of this study is to evaluate double immunostaining for Ki-67 and podoplanin in head and neck squamous cell carcinoma (HNSCC), and to observe the involvement of lymphagiogenesis in tumoral and peritumoral [...] Read more.
Podoplanin and Ki-67 are two important markers of cancer progression. The aim of this study is to evaluate double immunostaining for Ki-67 and podoplanin in head and neck squamous cell carcinoma (HNSCC), and to observe the involvement of lymphagiogenesis in tumoral and peritumoral areas, as well as the density of tumor proliferation correlated with histopathological grading. A total of 50 patients with HNSCC were included in this study. We carried out a morphological evaluation of tissue samples, after that, cases were selected for double Ki-67 and podoplanin immunostaining. Podoplanin expression was significantly correlated with histopathological grade (p < 0.05; p = 0.037) and expression of Ki-67 (p < 0.05; p = 0.050). A high expression of podoplanin, as well as of the proliferation factor Ki-67, was observed in histopathological grade G3 and the correlation between these (p < 0.05; p = 0.028), and implication of LMVD and LVI was not significant (LMVD p = 0.577; LVI p = 0.976). This study demonstrated the importance of double immunolabeling in assessing lymphagiogenesis and tumor proliferation in correlation with histopathological grades in HNSCC. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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Review

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26 pages, 932 KiB  
Review
Diagnostic, Prognostic, and Therapeutic Role for Angiogenesis Markers in Head and Neck Squamous Cell Carcinoma: A Narrative Review
by Lara Alessandrini, Laura Astolfi, Antonio Daloiso, Marta Sbaraglia, Tiziana Mondello, Elisabetta Zanoletti, Leonardo Franz and Gino Marioni
Int. J. Mol. Sci. 2023, 24(13), 10733; https://doi.org/10.3390/ijms241310733 - 27 Jun 2023
Cited by 2 | Viewed by 1359
Abstract
Despite refinements to diagnostic and therapeutic approaches over the last two decades, the outcome of patients with head and neck squamous cell carcinoma (HNSCC) has not shown substantial improvements, especially regarding those with advanced-stage disease. Angiogenesis is believed to be a turning point [...] Read more.
Despite refinements to diagnostic and therapeutic approaches over the last two decades, the outcome of patients with head and neck squamous cell carcinoma (HNSCC) has not shown substantial improvements, especially regarding those with advanced-stage disease. Angiogenesis is believed to be a turning point in the development of solid tumors, being a premise for mass growth and potential distant dissemination. Cancer-induced angiogenesis is a result of increased expression of angiogenic factors, decreased expression of anti-angiogenic factors, or a combination of both. The assessment of angiogenesis has also emerged as a potentially useful biological prognostic and predictive factor in HNSCC. The aim of this review is to assess the level of current knowledge on the neo-angiogenesis markers involved in the biology, behavior, and prognosis of HNSCC. A search (between 1 January 2012 and 10 October 2022) was run in PubMed, Scopus, and Web of Science electronic databases. After full-text screening and application of inclusion/exclusion criteria, 84 articles are included. The current knowledge and debate on angiogenesis in HNSCC presented in the eligible articles are stratified as follows: (i) diagnostic markers; (ii) prognostic markers; (iii) predictive markers; and (iv) markers with a potential therapeutic role. Angiogenesis is a biological and pathological indicator of malignancies progression and has negative implications in prognosis of some solid tumors; several signals capable of tripping the “angiogenic switch” have also been identified in HNSCC. Although several studies suggested that antiangiogenic agents might be a valuable adjunct to conventional chemo-radiation of HNSCC, their long-term therapeutic value remains uncertain. Further investigations are required on combinations of antiangiogenic agents with conventional chemotherapeutic ones, immunotherapeutic and molecularly targeted agents in HNSCC. Additional data are necessary to pinpoint which patients could benefit most from these treatments. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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19 pages, 9163 KiB  
Review
Therapeutic Lymphangiogenesis Is a Promising Strategy for Secondary Lymphedema
by Yuuki Shimizu, Yiyang Che and Toyoaki Murohara
Int. J. Mol. Sci. 2023, 24(9), 7774; https://doi.org/10.3390/ijms24097774 - 24 Apr 2023
Cited by 2 | Viewed by 2441
Abstract
Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following lymph node dissection during the surgical treatment or radiation therapy of breast or pelvic cancer. The clinical problems associated with lymphedema are reduced quality of life in terms of appearance and function, [...] Read more.
Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following lymph node dissection during the surgical treatment or radiation therapy of breast or pelvic cancer. The clinical problems associated with lymphedema are reduced quality of life in terms of appearance and function, as well as the development of skin ulcers, recurrent pain, and infection. Currently, countermeasures against lymphedema are mainly physical therapy such as lymphatic massage, elastic stockings, and skin care, and there is no effective and fundamental treatment with a highly recommended grade. Therefore, there is a need for the development of a fundamental novel treatment for intractable lymphedema. Therapeutic lymphangiogenesis, which has been attracting attention in recent years, is a treatment concept that reconstructs the fragmented lymphatic network to recover lymphatic vessel function and is revolutionary to be a fundamental cure. This review focuses on the translational research of therapeutic lymphangiogenesis for lymphedema and outlines the current status and prospects in the development of therapeutic applications. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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26 pages, 778 KiB  
Review
Tumor Microenvironment in Sporadic Vestibular Schwannoma: A Systematic, Narrative Review
by Diego Cazzador, Laura Astolfi, Antonio Daloiso, Giulia Tealdo, Edi Simoni, Antonio Mazzoni, Elisabetta Zanoletti and Gino Marioni
Int. J. Mol. Sci. 2023, 24(7), 6522; https://doi.org/10.3390/ijms24076522 - 30 Mar 2023
Cited by 3 | Viewed by 1647
Abstract
Although diagnosis and treatment of vestibular schwannomas (VSs) improved in recent years, no factors have yet been identified as being capable of predicting tumor growth. Molecular rearrangements occur in neoplasms before any macroscopic morphological changes become visible, and the former are the underlying [...] Read more.
Although diagnosis and treatment of vestibular schwannomas (VSs) improved in recent years, no factors have yet been identified as being capable of predicting tumor growth. Molecular rearrangements occur in neoplasms before any macroscopic morphological changes become visible, and the former are the underlying cause of disease behavior. Tumor microenvironment (TME) encompasses cellular and non-cellular elements interacting together, resulting in a complex and dynamic key of tumorigenesis, drug response, and treatment outcome. The aim of this systematic, narrative review was to assess the level of knowledge on TME implicated in the biology, behavior, and prognosis of sporadic VSs. A search (updated to November 2022) was run in Scopus, PubMed, and Web of Science electronic databases according to the PRISMA guidelines, retrieving 624 titles. After full-text evaluation and application of inclusion/exclusion criteria, 37 articles were included. VS microenvironment is determined by the interplay of a dynamic ecosystem of stromal and immune cells which produce and remodel extracellular matrix, vascular networks, and promote tumor growth. However, evidence is still conflicting. Further studies will enhance our understanding of VS biology by investigating TME-related biomarkers able to predict tumor growth and recognize immunological and molecular factors that could be potential therapeutic targets for medical treatment. Full article
(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis: From Molecular Regulation to Therapeutic Application)
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