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Angiogenesis and Lymphangiogenesis in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 18683

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Dr. Paola Chiodelli

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Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica, Brescia, Italy
Interests: angiogenesis; heparan sulfate proteoglycans; fgf/fgfrs; vegf/vegfrs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Angiogenesis, the process of the formation of new blood vessels, is orchestrated by proangiogenic and antiangiogenic factors. Angiogenesis is involved in various physiological and pathological processes, including cancer. The angiogenic switch is required to exit the dormient state of primary tumors and metastases at their initial phases of growth, and neovessel formation represents one of the hallmarks of cancer due to the requirement of a continuous supply of oxygen and nutrients by proliferating tumor cells and their capability of infiltrating blood vessels, leading to distant metastases. Another important player in cancer cell dissemination is represented by lymphangiogenesis, the formation of new lymphatic vessels. Lymphangiogenesis is at the basis of the formation of draining lymph node metastases that, in turn, may represent the source for further metastatic lesions via lymphatic and/or blood vessel routes. In this context, the modulation of angiogenesis and lymphangiogenesis is regarded as a logical approach to the treatment of various cancers. This Special Issue aims to provide, by reviews and original articles, an update on the molecular mechanisms of the angiogenic and lymphangiogenic processes, to point out possible future directions for the development of novel therapeutic approaches for the treatment of cancer patients.

Dr. Paola Chiodelli
Guest Editor

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Keywords

angiogenesis
lymphangiogenesis
endothelial cells
lymphatic endothelial cells
proangiogenic factors
antiangiogenic factors
hypoxia
cancer
metastasis
tumor vessel
tumor progression
antiangiogenic treatments

Published Papers (6 papers)

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Research

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34 pages, 7306 KiB

Open AccessArticle

The Role of Hyperthermia in Potentiation of Anti-Angiogenic Effect of Cisplatin and Resveratrol in Mice Bearing Solid Form of Ehrlich Ascites Tumour

by Darko Kučan, Nada Oršolić, Dyana Odeh, Snježana Ramić, Boris Jakopović, Jelena Knežević and Maja Jazvinšćak Jembrek

Int. J. Mol. Sci. 2023, 24(13), 11073; https://doi.org/10.3390/ijms241311073 - 04 Jul 2023

Cited by 2 | Viewed by 1092

Abstract

The aim of this study was to investigate the therapeutic potential of resveratrol in combination with cisplatin on the inhibition of tumour angiogenesis, growth, and macrophage polarization in mice bearing the solid form of an Ehrlich ascites tumour (EAT) that were exposed to whole-body hyperthermia treatment. In addition, we investigated whether a multimodal approach with hyperthermia and resveratrol could abolish cisplatin resistance in tumour cells through the modulation of histone deacetylase (HDAC) activity and levels of heat shock proteins (HSP70/HSP90) and contribute to the direct toxicity of cisplatin on tumour cells. The tumour was induced by injecting 1 × 10⁶ EAT cells subcutaneously (sc) into the thighs of Balb/c mice. The mice were treated with resveratrol per os for five consecutive days beginning on day 2 after tumour injection and/or by injecting cisplatin intraperitoneally (ip) at a dose of 2.5 mg/kg on days 10 and 12 and at a dose of 5 mg/kg on day 15. Immediately thereafter, the mice were exposed to systemic hyperthermia for 15 min at a temperature of 41 °C. The obtained results showed that the administration of resveratrol did not significantly contribute to the antitumour effect of cisplatin and hyperthermia, but it partially contributed to the immunomodulatory effect and to the reduction of cisplatin toxicity and to a slight increase in animal survival. This treatment schedule did not affect microvessel density, but it inhibited tumour growth and modulated macrophage polarization to the M1 phenotype. Furthermore, it abolished the resistance of tumour cells to cisplatin by modulating HDAC activity and the concentration of HSP70 and HSP90 chaperones, contributing to the increased lifespan of mice. However, the precise mechanism of the interaction between resveratrol, cisplatin, and hyperthermia needs to be investigated further. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Cancer)

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13 pages, 1258 KiB

Open AccessCommunication

Molecular Ultrasound Imaging Depicts the Modulation of Tumor Angiogenesis by Acetylsalicylic Acid

by Flurin Mueller-Diesing, Wiltrud Lederle, Anne Rix, Susanne Koletnik, Dennis Doleschel, Maximilian Snelting, Felix Gremse and Fabian Kiessling

Int. J. Mol. Sci. 2023, 24(8), 7060; https://doi.org/10.3390/ijms24087060 - 11 Apr 2023

Viewed by 1210

Abstract

Acetylsalicylic acid (ASA) is a well-established drug for heart attack and stroke prophylaxis. Furthermore, numerous studies have reported an anti-carcinogenic effect, but its exact mechanism is still unknown. Here, we applied VEGFR-2-targeted molecular ultrasound to explore a potential inhibitory effect of ASA on tumor angiogenesis in vivo. Daily ASA or placebo therapy was performed in a 4T1 tumor mouse model. During therapy, ultrasound scans were performed using nonspecific microbubbles (CEUS) to determine the relative intratumoral blood volume (rBV) and VEGFR-2-targeted microbubbles to assess angiogenesis. Finally, vessel density and VEGFR-2 expression were assessed histologically. CEUS indicated a decreasing rBV in both groups over time. VEGFR-2 expression increased in both groups up to Day 7. Towards Day 11, the binding of VEGFR-2-specific microbubbles further increased in controls, but significantly (p = 0.0015) decreased under ASA therapy (2.24 ± 0.46 au vs. 0.54 ± 0.55 au). Immunofluorescence showed a tendency towards lower vessel density under ASA and confirmed the result of molecular ultrasound. Molecular US demonstrated an inhibitory effect of ASA on VEGFR-2 expression accompanied by a tendency towards lower vessel density. Thus, this study suggests the inhibition of angiogenesis via VEGFR-2 downregulation as one of the anti-tumor effects of ASA. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Cancer)

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21 pages, 5128 KiB

Open AccessArticle

Synthesis and Anticancer Evaluation of New Indole-Based Tyrphostin Derivatives and Their (p-Cymene)dichloridoruthenium(II) Complexes

by Natalie Oberhuber, Hindole Ghosh, Bianca Nitzsche, Prasad Dandawate, Michael Höpfner, Rainer Schobert and Bernhard Biersack

Int. J. Mol. Sci. 2023, 24(1), 854; https://doi.org/10.3390/ijms24010854 - 03 Jan 2023

Cited by 6 | Viewed by 1901

Abstract

New N-alkylindole-substituted 2-(pyrid-3-yl)-acrylonitriles with putative kinase inhibitory activity and their (p-cymene)Ru(II) piano-stool complexes were prepared and tested for their antiproliferative efficacy in various cancer models. Some of the indole-based derivatives inhibited tumor cell proliferation at (sub-)micromolar concentrations with IC₅₀ values below those of the clinically relevant multikinase inhibitors gefitinib and sorafenib, which served as positive controls. A focus was set on the investigation of drug mechanisms in HCT-116 p53-knockout colon cancer cells in order to evaluate the dependence of the test compounds on p53. Colony formation assays as well as experiments with tumor spheroids confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic caspase-3/7 activity and ROS formation, as well as anti-angiogenic properties. Docking calculations with EGFR and VEGFR-2 identified the two 3-aryl-2-(pyrid-3-yl)acrylonitrile derivatives 2a and 2b as potential kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in cancer treatment. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Cancer)

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36 pages, 4094 KiB

Open AccessArticle

Transcriptomic and Functional Evidence for Differential Effects of MCF-7 Breast Cancer Cell-Secretome on Vascular and Lymphatic Endothelial Cell Growth

by Giovanna Azzarito, Michele Visentin, Brigitte Leeners and Raghvendra K. Dubey

Int. J. Mol. Sci. 2022, 23(13), 7192; https://doi.org/10.3390/ijms23137192 - 28 Jun 2022

Cited by 4 | Viewed by 2452

Abstract

Vascular and lymphatic vessels drive breast cancer (BC) growth and metastasis. We assessed the cell growth (proliferation, migration, and capillary formation), gene-, and protein-expression profiles of Vascular Endothelial Cells (VECs) and Lymphatic Endothelial Cells (LECs) exposed to a conditioned medium (CM) from estrogen receptor-positive BC cells (MCF-7) in the presence or absence of Estradiol. We demonstrated that MCF-7-CM stimulated growth and capillary formation in VECs but inhibited LEC growth. Consistently, MCF-7-CM induced ERK1/2 and Akt phosphorylation in VECs and inhibited them in LECs. Gene expression analysis revealed that the LECs were overall (≈10-fold) more sensitive to MCF-7-CM exposure than VECs. Growth/angiogenesis and cell cycle pathways were upregulated in VECs but downregulated in LECs. An angiogenesis proteome array confirmed the upregulation of 23 pro-angiogenesis proteins in VECs. In LECs, the expression of genes related to ATP synthesis and the ATP content were reduced by MCF-7-CM, whereas MTHFD2 gene, involved in folate metabolism and immune evasion, was upregulated. The contrasting effect of MCF-7-CM on the growth of VECs and LECs was reversed by inhibiting the TGF-β signaling pathway. The effect of MCF-7-CM on VEC growth was also reversed by inhibiting the VEGF signaling pathway. In conclusion, BC secretome may facilitate cancer cell survival and tumor growth by simultaneously promoting vascular angiogenesis and inhibiting lymphatic growth. The differential effects of BC secretome on LECs and VECs may be of pathophysiological relevance in BC. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Cancer)

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Review

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14 pages, 1180 KiB

Open AccessReview

The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy

by Peace Mabeta and Vanessa Steenkamp

Int. J. Mol. Sci. 2022, 23(24), 15585; https://doi.org/10.3390/ijms232415585 - 09 Dec 2022

Cited by 34 | Viewed by 4090

Abstract

The vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) axis is indispensable in the process of angiogenesis and has been implicated as a key driver of tumor vascularization. Consequently, several strategies that target VEGF and its cognate receptors, VEGFR-1 and VEGFR-2, have been designed to treat cancer. While therapies targeting full-length VEGF have resulted in an improvement in both overall survival and progression-free survival in various cancers, these benefits have been modest. In addition, the inhibition of VEGFRs is associated with undesirable off-target effects. Moreover, VEGF splice variants that modulate sprouting and non-sprouting angiogenesis have been identified in recent years. Cues within the tumor microenvironment determine the expression patterns of these variants. Noteworthy is that the mechanisms of action of these variants challenge the established norm of VEGF signaling. Furthermore, the aberrant expression of some of these variants has been observed in several cancers. Herein, developments in the understanding of the VEGF/VEGFR axis and the splice products of these molecules, as well as the environmental cues that regulate these variants are reviewed. Furthermore, strategies that incorporate the targeting of VEGF variants to enhance the effectiveness of antiangiogenic therapies in the clinical setting are discussed. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Cancer)

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26 pages, 1351 KiB

Open AccessReview

Novel Drugs with High Efficacy against Tumor Angiogenesis

by Shiyu Qi, Shoulong Deng, Zhengxing Lian and Kun Yu

Int. J. Mol. Sci. 2022, 23(13), 6934; https://doi.org/10.3390/ijms23136934 - 22 Jun 2022

Cited by 36 | Viewed by 7246

Abstract

Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and metastasis. Therefore, there is great interest in developing antiangiogenic strategies. Hypoxia is the basic initiating factor of tumor angiogenesis, which leads to the increase of vascular endothelial growth factor (VEGF), angiopoietin (Ang), hypoxia-inducible factor (HIF-1), etc. in hypoxic cells. The pathways of VEGF and Ang are considered to be critical steps in tumor angiogenesis. A number of antiangiogenic drugs targeting VEGF/VEGFR (VEGF receptor) or ANG/Tie2, or both, are currently being used for cancer treatment, or are still in various stages of clinical development or preclinical evaluation. This article aims to review the mechanisms of angiogenesis and tumor angiogenesis and to focus on new drugs and strategies for the treatment of antiangiogenesis. However, antitumor angiogenic drugs alone may not be sufficient to eradicate tumors. The molecular chaperone heat shock protein 90 (HSP90) is considered a promising molecular target. The VEGFR system and its downstream signaling molecules depend on the function of HSP90. This article also briefly introduces the role of HSP90 in angiogenesis and some HSP90 inhibitors. Full article

(This article belongs to the Special Issue Angiogenesis and Lymphangiogenesis in Cancer)

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