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14 pages, 6224 KiB

Open AccessArticle

Mapping Semaphorins and Netrins in the Pathogenesis of Human Thoracic Aortic Aneurysms

by Dornazsadat Alebrahim, Mangala Nayak, Alison Ward, Patricia Ursomanno, Rebecca Shams, Annanina Corsica, Rayan Sleiman, Kissinger Hyppolite Fils, Michele Silvestro, Ludovic Boytard, Tarik Hadi, Bruce Gelb and Bhama Ramkhelawon

Int. J. Mol. Sci. 2019, 20(9), 2100; https://doi.org/10.3390/ijms20092100 - 28 Apr 2019

Cited by 5 | Viewed by 3060

Abstract

Thoracic aortic aneurysm (TAA) is a complex life-threatening disease characterized by extensive extracellular matrix (ECM) fragmentation and persistent inflammation, culminating in a weakened aorta. Although evidence suggests defective canonical signaling pathways in TAA, the full spectrum of mechanisms contributing to TAA is poorly [...] Read more.

Thoracic aortic aneurysm (TAA) is a complex life-threatening disease characterized by extensive extracellular matrix (ECM) fragmentation and persistent inflammation, culminating in a weakened aorta. Although evidence suggests defective canonical signaling pathways in TAA, the full spectrum of mechanisms contributing to TAA is poorly understood, therefore limiting the scope of drug-based treatment. Here, we used a sensitive RNA sequencing approach to profile the transcriptomic atlas of human TAA. Pathway analysis revealed upregulation of key matrix-degrading enzymes and inflammation coincident with the axonal guidance pathway. We uncovered their novel association with TAA and focused on the expression of Semaphorins and Netrins. Comprehensive analysis of this pathway showed that several members were differentially expressed in TAA compared to controls. Immunohistochemistry revealed that Semaphorin4D and its receptor PlexinB1, similar to Netrin-1 proteins were highly expressed in damaged areas of TAA tissues but faintly detected in the vessel wall of non-diseased sections. It should be considered that the current study is limited by its sample size and the use of internal thoracic artery as control for TAA for the sequencing dataset. Our data determines important neuronal regulators of vascular inflammatory events and suggest Netrins and Semaphorins as potential key contributors of ECM degradation in TAA. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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Review

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14 pages, 2334 KiB

Open AccessReview

Multifaceted Functional Role of Semaphorins in Glioblastoma

by Cristiana Angelucci, Gina Lama and Gigliola Sica

Int. J. Mol. Sci. 2019, 20(9), 2144; https://doi.org/10.3390/ijms20092144 - 30 Apr 2019

Cited by 17 | Viewed by 4418

Abstract

Glioblastoma (GBM) is the most malignant tumor type affecting the adult central nervous system. Despite advances in therapy, the prognosis for patients with GBM remains poor, with a median survival of about 15 months. To date, few treatment options are available and recent [...] Read more.

Glioblastoma (GBM) is the most malignant tumor type affecting the adult central nervous system. Despite advances in therapy, the prognosis for patients with GBM remains poor, with a median survival of about 15 months. To date, few treatment options are available and recent trials based on the molecular targeting of some of the GBM hallmark pathways (e.g., angiogenesis) have not produced any significant improvement in overall survival. The urgent need to develop more efficacious targeted therapies has led to a better molecular characterization of GBM, revealing an emerging role of semaphorins in GBM progression. Semphorins are a wide group of membrane-bound and secreted proteins, originally identified as axon guidance cues, signaling through their receptors, neuropilins, and plexins. A number of semaphorin signals involved in the control of axonal growth and navigation during development have been found to furthermore participate in crosstalk with different dysfunctional GBM pathways, controlling tumor cell proliferation, migration, and invasion, as well as tumor angiogenesis or immune response. In this review, we summarize the regulatory activities mediated by semaphorins and their receptors on the oncogenic pathways implicated in GBM growth and invasive/metastatic progression. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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14 pages, 959 KiB

Open AccessReview

Neuropilins Controlling Cancer Therapy Responsiveness

by Virginia Napolitano and Luca Tamagnone

Int. J. Mol. Sci. 2019, 20(8), 2049; https://doi.org/10.3390/ijms20082049 - 25 Apr 2019

Cited by 27 | Viewed by 4935

Abstract

Neuropilins (NRPs) are cell surface glycoproteins, acting as co-receptors for secreted Semaphorins (SEMAs) and for members of the vascular endothelial growth factor (VEGF) family; they have been initially implicated in axon guidance and angiogenesis regulation, and more recently in cancer progression. In addition, [...] Read more.

Neuropilins (NRPs) are cell surface glycoproteins, acting as co-receptors for secreted Semaphorins (SEMAs) and for members of the vascular endothelial growth factor (VEGF) family; they have been initially implicated in axon guidance and angiogenesis regulation, and more recently in cancer progression. In addition, NRPs have been shown to control many other fundamental signaling pathways, especially mediated by tyrosine kinase receptors (RTKs) of growth factors, such as HGF (hepatocyte growth factor), PDGF (platelet derived growth factor) and EGF (epidermal growth factor). This enables NRPs to control a range of pivotal mechanisms in the cancer context, from tumor cell proliferation and metastatic dissemination, to tumor angiogenesis and immune escape. Moreover, cancer treatment failures due to resistance to innovative oncogene-targeted drugs is typically associated with the activity of alternative RTK-dependent pathways; and neuropilins’ capacity to control oncogenic signaling cascades supports the hypothesis that they could elicit such mechanisms in cancer cells, in order to escape cytotoxic stress and therapeutic attacks. Intriguingly, several studies have recently assayed the impact of NRPs inhibition in combination with diverse anti-cancer drugs. In this minireview, we will discuss the state-of-art about the relevance of NRPs as potential predictive biomarkers of drug response, and the rationale to target these proteins in combination with other anticancer therapies. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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22 pages, 1967 KiB

Open AccessReview

Semaphorin 3C as a Therapeutic Target in Prostate and Other Cancers

by Daniel H.F. Hui, Kevin J. Tam, Ivy Z.F. Jiao and Christopher J. Ong

Int. J. Mol. Sci. 2019, 20(3), 774; https://doi.org/10.3390/ijms20030774 - 12 Feb 2019

Cited by 19 | Viewed by 5577

Abstract

The semaphorins represent a large family of signaling molecules with crucial roles in neuronal and cardiac development. While normal semaphorin function pertains largely to development, their involvement in malignancy is becoming increasingly evident. One member, Semaphorin 3C (SEMA3C), has been shown to drive [...] Read more.

The semaphorins represent a large family of signaling molecules with crucial roles in neuronal and cardiac development. While normal semaphorin function pertains largely to development, their involvement in malignancy is becoming increasingly evident. One member, Semaphorin 3C (SEMA3C), has been shown to drive a number of oncogenic programs, correlate inversely with cancer prognosis, and promote the progression of multiple different cancer types. This report surveys the body of knowledge surrounding SEMA3C as a therapeutic target in cancer. In particular, we summarize SEMA3C’s role as an autocrine andromedin in prostate cancer growth and survival and provide an overview of other cancer types that SEMA3C has been implicated in including pancreas, brain, breast, and stomach. We also propose molecular strategies that could potentially be deployed against SEMA3C as anticancer agents such as biologics, small molecules, monoclonal antibodies and antisense oligonucleotides. Finally, we discuss important considerations for the inhibition of SEMA3C as a cancer therapeutic agent. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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44 pages, 1515 KiB

Open AccessReview

Neuropilins in the Context of Tumor Vasculature

by Stephan Niland and Johannes A. Eble

Int. J. Mol. Sci. 2019, 20(3), 639; https://doi.org/10.3390/ijms20030639 - 01 Feb 2019

Cited by 58 | Viewed by 8135

Abstract

Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, [...] Read more.

Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. This review highlights the diverse neuropilin ligands and interacting partners on endothelial cells, which are relevant in the context of the tumor vasculature and the tumor microenvironment. In addition to tumor cells, the latter contains cancer-associated fibroblasts, immune cells, and endothelial cells. Based on the prevalent neuropilin-mediated interactions, the suitability of various neuropilin-targeted substances for influencing tumor angiogenesis as a possible building block of a tumor therapy is discussed. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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20 pages, 974 KiB

Open AccessReview

Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression

by Shira Toledano, Inbal Nir-Zvi, Rotem Engelman, Ofra Kessler and Gera Neufeld

Int. J. Mol. Sci. 2019, 20(3), 556; https://doi.org/10.3390/ijms20030556 - 28 Jan 2019

Cited by 61 | Viewed by 5895

Abstract

Semaphorins are the products of a large gene family containing 28 genes of which 21 are found in vertebrates. Class-3 semaphorins constitute a subfamily of seven vertebrate semaphorins which differ from the other vertebrate semaphorins in that they are the only secreted semaphorins [...] Read more.

Semaphorins are the products of a large gene family containing 28 genes of which 21 are found in vertebrates. Class-3 semaphorins constitute a subfamily of seven vertebrate semaphorins which differ from the other vertebrate semaphorins in that they are the only secreted semaphorins and are distinguished from other semaphorins by the presence of a basic domain at their C termini. Class-3 semaphorins were initially characterized as axon guidance factors, but have subsequently been found to regulate immune responses, angiogenesis, lymphangiogenesis, and a variety of additional physiological and developmental functions. Most class-3 semaphorins transduce their signals by binding to receptors belonging to the neuropilin family which subsequently associate with receptors of the plexin family to form functional class-3 semaphorin receptors. Recent evidence suggests that class-3 semaphorins also fulfill important regulatory roles in multiple forms of cancer. Several class-3 semaphorins function as endogenous inhibitors of tumor angiogenesis. Others were found to inhibit tumor metastasis by inhibition of tumor lymphangiogenesis, by direct effects on the behavior of tumor cells, or by modulation of immune responses. Notably, some semaphorins such as sema3C and sema3E have also been found to potentiate tumor progression using various mechanisms. This review focuses on the roles of the different class-3 semaphorins in tumor progression. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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12 pages, 428 KiB

Open AccessReview

VEGF/Neuropilin Signaling in Cancer Stem Cells

by Arthur M. Mercurio

Int. J. Mol. Sci. 2019, 20(3), 490; https://doi.org/10.3390/ijms20030490 - 23 Jan 2019

Cited by 77 | Viewed by 6350

Abstract

The function of vascular endothelial growth factor (VEGF) in cancer extends beyond angiogenesis and vascular permeability. Specifically, VEGF-mediated signaling occurs in tumor cells and this signaling contributes to key aspects of tumorigenesis including the self-renewal and survival of cancer stem cells (CSCs). In [...] Read more.

The function of vascular endothelial growth factor (VEGF) in cancer extends beyond angiogenesis and vascular permeability. Specifically, VEGF-mediated signaling occurs in tumor cells and this signaling contributes to key aspects of tumorigenesis including the self-renewal and survival of cancer stem cells (CSCs). In addition to VEGF receptor tyrosine kinases, the neuropilins (NRPs) are critical for mediating the effects of VEGF on CSCs, primarily because of their ability to impact the function of growth factor receptors and integrins. VEGF/NRP signaling can regulate the expression and function of key molecules that have been implicated in CSC function including Rho family guanosine triphosphatases (GTPases) and transcription factors. The VEGF/NRP signaling axis is a prime target for therapy because it can confer resistance to standard chemotherapy, which is ineffective against most CSCs. Indeed, several studies have shown that targeting either NRP1 or NRP2 can inhibit tumor initiation and decrease resistance to other therapies. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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9 pages, 611 KiB

Open AccessReview

Semaphorin Signaling in Cancer-Associated Inflammation

by Giulia Franzolin and Luca Tamagnone

Int. J. Mol. Sci. 2019, 20(2), 377; https://doi.org/10.3390/ijms20020377 - 17 Jan 2019

Cited by 29 | Viewed by 4694

Abstract

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, [...] Read more.

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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12 pages, 828 KiB

Open AccessReview

Role of Semaphorins in Immunopathologies and Rheumatic Diseases

by Samuel Garcia

Int. J. Mol. Sci. 2019, 20(2), 374; https://doi.org/10.3390/ijms20020374 - 16 Jan 2019

Cited by 21 | Viewed by 4773

Abstract

Rheumatic diseases are disorders characterized by joint inflammation, in which other organs are also affected. There are more than two hundred rheumatic diseases, the most studied so far are rheumatoid arthritis, osteoarthritis, spondyloarthritis, systemic lupus erythematosus, and systemic sclerosis. The semaphorin family is [...] Read more.

Rheumatic diseases are disorders characterized by joint inflammation, in which other organs are also affected. There are more than two hundred rheumatic diseases, the most studied so far are rheumatoid arthritis, osteoarthritis, spondyloarthritis, systemic lupus erythematosus, and systemic sclerosis. The semaphorin family is a large group of proteins initially described as axon guidance molecules involved in nervous system development. Studies have demonstrated that semaphorins play a role in other processes such as the regulation of immunity, angiogenesis, bone remodeling, apoptosis, and cell migration and invasion. Moreover, semaphorins have been related to the pathogenesis of multiple sclerosis, asthma, Alzheimer, myocarditis, atherosclerosis, fibrotic diseases, osteopetrosis, and cancer. The aim of this review is to summarize current knowledge regarding the role of semaphorins in rheumatic diseases, and discuss their potential applications as therapeutic targets to treat these disorders. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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14 pages, 2444 KiB

Open AccessReview

Neuroimmune Semaphorin 4A in Cancer Angiogenesis and Inflammation: A Promoter or a Suppressor?

by Apoorva S. Iyer and Svetlana P. Chapoval

Int. J. Mol. Sci. 2019, 20(1), 124; https://doi.org/10.3390/ijms20010124 - 30 Dec 2018

Cited by 15 | Viewed by 4638

Abstract

Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the [...] Read more.

Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the immune system, Sema4A regulates immune cell activation and function, instructing a fine tuning of the immune response. Recent studies have shown a dysregulation of Sema4A expression in several types of cancer such as hepatocellular carcinoma, colorectal, and breast cancers. Cancers have been associated with abnormal angiogenesis. The function of Sema4A in angiogenesis and cancer is not defined. Recent studies have demonstrated Sema4A expression and function in endothelial cells. However, the results of these studies are controversial as they report either pro- or anti-angiogenic Sema4A effects depending on the experimental settings. In this mini-review, we discuss these findings as well as our data on Sema4A regulation of inflammation and angiogenesis, which both are important pathologic processes underlining tumorigenesis and tumor metastasis. Understanding the role of Sema4A in those processes may guide the development of improved therapeutic treatments for cancer. Full article

(This article belongs to the Special Issue Semaphorins, Plexins, and Neuropilin Functions in the Tumor Microenvironment)

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