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Article ; Online: Mind the (guidance) signals! Translational relevance of semaphorins, plexins, and neuropilins in pancreatic cancer.

Fard, Damon / Giraudo, Enrico / Tamagnone, Luca

2023 Volume 29, Issue 10, Page(s) 817–829

Abstract: Pancreatic cancer is a major cause of demise worldwide. Although key associated genetic changes have been discovered, disease progression is sustained by pathogenic mechanisms that are poorly understood at the molecular level. In particular, the tissue ... ...

Abstract	Pancreatic cancer is a major cause of demise worldwide. Although key associated genetic changes have been discovered, disease progression is sustained by pathogenic mechanisms that are poorly understood at the molecular level. In particular, the tissue microenvironment of pancreatic adenocarcinoma (PDAC) is usually characterized by high stromal content, scarce recruitment of immune cells, and the presence of neuronal fibers. Semaphorins and their receptors, plexins and neuropilins, comprise a wide family of regulatory signals that control neurons, endothelial and immune cells, embryo development, and normal tissue homeostasis, as well as the microenvironment of human tumors. We focus on the role of these molecular signals in pancreatic cancer progression, as revealed by experimental research and clinical studies, including novel approaches for cancer treatment.
MeSH term(s)	Humans ; Pancreatic Neoplasms ; Neuropilins ; Semaphorins ; Adenocarcinoma ; Tumor Microenvironment ; Pancreatic Neoplasms
Chemical Substances	plexin ; Neuropilins ; Semaphorins
Language	English
Publishing date	2023-08-17
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2023.07.009
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Article ; Online: Semaphorins: Missing Signals in Age-dependent Alteration of Neuromuscular Junctions and Skeletal Muscle Regeneration.

Fard, Damon / Barbiera, Alessandra / Dobrowolny, Gabriella / Tamagnone, Luca / Scicchitano, Bianca Maria

Aging and disease

2024 Volume 15, Issue 2, Page(s) 517–534

Abstract: Skeletal muscle is characterized by a remarkable capacity to rearrange after physiological changes and efficiently regenerate. However, during aging, extensive injury, or pathological conditions, the complete regenerative program is severely affected, ... ...

Abstract	Skeletal muscle is characterized by a remarkable capacity to rearrange after physiological changes and efficiently regenerate. However, during aging, extensive injury, or pathological conditions, the complete regenerative program is severely affected, with a progressive loss of muscle mass and function, a condition known as sarcopenia. The compromised tissue repair program is attributable to the gradual depletion of stem cells and to altered regulatory signals. Defective muscle regeneration can severely affect re-innervation by motor axons, and neuromuscular junctions (NMJs) development, ultimately leading to skeletal muscle atrophy. Defects in NMJ formation and maintenance occur physiologically during aging and are responsible for the pathogenesis of several neuromuscular disorders. However, it is still largely unknown how neuromuscular connections are restored on regenerating fibers. It has been suggested that attractive and repelling signals used for axon guidance could be implicated in this process; in particular, guidance molecules called semaphorins play a key role. Semaphorins are a wide family of extracellular regulatory signals with a multifaceted role in cell-cell communication. Originally discovered as axon guidance factors, they have been implicated in cancer progression, embryonal organogenesis, skeletal muscle innervation, and other physiological and developmental functions in different tissues. In particular, in skeletal muscle, specific semaphorin molecules are involved in the restoration and remodeling of the nerve-muscle connections, thus emphasizing their plausible role to ensure the success of muscle regeneration. This review article aims to discuss the impact of aging on skeletal muscle regeneration and NMJs remodeling and will highlight the most recent insights about the role of semaphorins in this context.
MeSH term(s)	Humans ; Semaphorins ; Neuromuscular Junction/pathology ; Muscle, Skeletal/pathology ; Axons/pathology ; Sarcopenia/pathology
Chemical Substances	Semaphorins
Language	English
Publishing date	2024-04-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2625789-0
ISSN	2152-5250 ; 2152-5250
ISSN (online)	2152-5250
ISSN	2152-5250
DOI	10.14336/AD.2023.0801
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Article: Message in a Bottle: Endothelial Cell Regulation by Extracellular Vesicles.

Palazzo, Claudia / D'Alessio, Alessio / Tamagnone, Luca

Cancers

2022 Volume 14, Issue 8

Abstract: Intercellular communication is a key biological mechanism that is fundamental to maintain tissue homeostasis. Extracellular vesicles (EVs) have emerged as critical regulators of cell-cell communication in both physiological and pathological conditions, ... ...

Abstract	Intercellular communication is a key biological mechanism that is fundamental to maintain tissue homeostasis. Extracellular vesicles (EVs) have emerged as critical regulators of cell-cell communication in both physiological and pathological conditions, due to their ability to shuttle a variety of cell constituents, such as DNA, RNA, lipids, active metabolites, cytosolic, and cell surface proteins. In particular, endothelial cells (ECs) are prominently regulated by EVs released by neighboring cell types. The discovery that cancer cell-derived EVs can control the functions of ECs has prompted the investigation of their roles in tumor angiogenesis and cancer progression. In particular, here, we discuss evidence that supports the roles of exosomes in EC regulation within the tumor microenvironment and in vascular dysfunction leading to atherosclerosis. Moreover, we survey the molecular mechanisms and exosomal cargoes that have been implicated in explanations of these regulatory effects.
Language	English
Publishing date	2022-04-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14081969
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Article: Endothelial Cell Metabolism in Vascular Functions.

Filippini, Antonio / Tamagnone, Luca / D'Alessio, Alessio

Cancers

2022 Volume 14, Issue 8

Abstract: The endothelium is the innermost layer of all blood and lymphatic vessels composed of a monolayer of specialized endothelial cells (ECs). It is regarded as a dynamic and multifunctional endocrine organ that takes part in essential processes, such as the ... ...

Abstract	The endothelium is the innermost layer of all blood and lymphatic vessels composed of a monolayer of specialized endothelial cells (ECs). It is regarded as a dynamic and multifunctional endocrine organ that takes part in essential processes, such as the control of blood fluidity, the modulation of vascular tone, the regulation of immune response and leukocyte trafficking into perivascular tissues, and angiogenesis. The inability of ECs to perform their normal biological functions, known as endothelial dysfunction, is multi-factorial; for instance, it implicates the failure of ECs to support the normal antithrombotic and anti-inflammatory status, resulting in the onset of unfavorable cardiovascular conditions such as atherosclerosis, coronary artery disease, hypertension, heart problems, and other vascular pathologies. Notably, it is emerging that the ability of ECs to adapt their metabolic status to persistent changes of the tissue microenvironment could be vital for the maintenance of vascular functions and to prevent adverse vascular events. The main purpose of the present article is to shed light on the unique metabolic plasticity of ECs as a prospective therapeutic target; this may lead to the development of novel strategies for cardiovascular diseases and cancer.
Language	English
Publishing date	2022-04-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14081929
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Article ; Online: Semaphorins in health and disease.

Fard, Damon / Tamagnone, Luca

Cytokine & growth factor reviews

2020 Volume 57, Page(s) 55–63

Abstract: Cell-cell communication is pivotal to guide embryo development, as well as to maintain adult tissues homeostasis and control immune response. Among extracellular factors responsible for this function, are the Semaphorins, a broad family of around 20 ... ...

Abstract	Cell-cell communication is pivotal to guide embryo development, as well as to maintain adult tissues homeostasis and control immune response. Among extracellular factors responsible for this function, are the Semaphorins, a broad family of around 20 different molecular cues conserved in evolution and widely expressed in all tissues. The signaling cascades initiated by semaphorins depend on a family of conserved receptors, called Plexins, and on several additional molecules found in the receptor complexes. Moreover, multiple intracellular pathways have been described to act downstream of semaphorins, highlighting significant diversity in the signaling cascades controlled by this family. Notably, semaphorin expression is altered in many human diseases, such as immunopathologies, neurodegenerative diseases and cancer. This underscores the importance of semaphorins as regulatory factors in the tissue microenvironment and has prompted growing interest for assessing their potential relevance in medicine. This review article surveys the main contexts in which semaphorins have been found to regulate developing and healthy adult tissues, and the signaling cascades implicated in these functions. Vis a vis, we will highlight the main pathological processes in which semaphorins are thought to have a role thereof.
MeSH term(s)	Cell Communication ; Cell Membrane ; Humans ; Neoplasms ; Semaphorins/metabolism ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Semaphorins
Language	English
Publishing date	2020-09-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1330534-7
ISSN	1879-0305 ; 1359-6101
ISSN (online)	1879-0305
ISSN	1359-6101
DOI	10.1016/j.cytogfr.2020.05.006
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Article ; Online: Neuropilins Controlling Cancer Therapy Responsiveness.

Napolitano, Virginia / Tamagnone, Luca

International journal of molecular sciences

2019 Volume 20, Issue 8

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 ... ...

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, 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.
MeSH term(s)	Animals ; Humans ; Molecular Targeted Therapy ; Neoplasms/therapy ; Neuropilins/chemistry ; Neuropilins/metabolism ; Tumor Microenvironment
Chemical Substances	Neuropilins
Language	English
Publishing date	2019-04-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20082049
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Article ; Online: Semaphorins as emerging clinical biomarkers and therapeutic targets in cancer.

Mastrantonio, Roberta / You, Hua / Tamagnone, Luca

Theranostics

2021 Volume 11, Issue 7, Page(s) 3262–3277

Abstract: Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, ... ...

Abstract	Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, inflammatory and anti-cancer immune responses. Semaphorins comprise secreted and cell surface-exposed molecules and their receptors are mainly found in the Plexin and Neuropilin families, which are further implicated in a signaling network controlling the tumor microenvironment. Accumulating evidence indicates that semaphorins may be considered as novel clinical biomarkers for cancer, especially for the prediction of patient survival and responsiveness to therapy. Moreover, preclinical experimental studies have demonstrated that targeting semaphorin signaling can interfere with tumor growth and/or metastatic dissemination, suggesting their relevance as novel therapeutic targets in cancer; this has also prompted the development of semaphorin-interfering molecules for application in the clinic. Here we will survey, in diverse human cancers, the current knowledge about the relevance of semaphorin family members, and conceptualize potential lines of future research development in this field.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/agonists ; Biomarkers, Tumor/antagonists & inhibitors ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Cell Communication/drug effects ; Cell Movement/drug effects ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Metastasis ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/mortality ; Neoplasms/pathology ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/mortality ; Neovascularization, Pathologic/pathology ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neuropilins/genetics ; Neuropilins/metabolism ; Prognosis ; Semaphorins/agonists ; Semaphorins/antagonists & inhibitors ; Semaphorins/genetics ; Semaphorins/metabolism ; Signal Transduction ; Survival Analysis ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/genetics
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Cell Adhesion Molecules ; Nerve Tissue Proteins ; Neuropilins ; Semaphorins ; plexin
Language	English
Publishing date	2021-01-15
Publishing country	Australia
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.54023
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Article ; Online: Semaphorin Signaling in Cancer-Associated Inflammation.

Franzolin, Giulia / Tamagnone, Luca

International journal of molecular sciences

2019 Volume 20, Issue 2

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 ... ...

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, 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.
MeSH term(s)	Adaptive Immunity ; Animals ; Gene Expression Regulation ; Humans ; Immunity, Innate ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Multigene Family ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Semaphorins/genetics ; Semaphorins/metabolism ; Signal Transduction ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology
Chemical Substances	Semaphorins
Language	English
Publishing date	2019-01-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20020377
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Article ; Online: Semaphorins as Regulators of Phenotypic Plasticity and Functional Reprogramming of Cancer Cells.

Gurrapu, Sreeharsha / Tamagnone, Luca

Trends in molecular medicine

2019 Volume 25, Issue 4, Page(s) 303–314

Abstract: Semaphorins, initially found as neuronal guidance cues in embryo development, are now appreciated as major regulators of tissue morphogenesis and homeostasis, as well as of cancer progression. In fact, semaphorin signals have a profound impact on cell ... ...

Abstract	Semaphorins, initially found as neuronal guidance cues in embryo development, are now appreciated as major regulators of tissue morphogenesis and homeostasis, as well as of cancer progression. In fact, semaphorin signals have a profound impact on cell morphology, which has been commonly associated with the ability to regulate monomeric GTPases, cell-substrate adhesion, and cytoskeletal dynamics. Recently, however, several reports have indicated a novel and additional function of diverse semaphorins in the regulation of gene expression and cell phenotype plasticity. In this review article, we discuss these novel findings, focusing on the role of semaphorin signals in the regulation of bi-directional epithelial-mesenchymal transitions, stem cell properties, and drug resistance, which greatly contribute to the pathogenesis of cancer.
MeSH term(s)	Adaptation, Physiological ; Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cellular Reprogramming/genetics ; Drug Resistance, Neoplasm/genetics ; Epithelial-Mesenchymal Transition/genetics ; Humans ; Neoplasms/drug therapy ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Semaphorins/genetics ; Semaphorins/metabolism ; Signal Transduction
Chemical Substances	Antineoplastic Agents ; Semaphorins
Language	English
Publishing date	2019-02-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2019.01.010
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Article ; Online: Targeting Semaphorin 4D in Cancer: A Look from Different Perspectives.

Tamagnone, Luca / Franzolin, Giulia

Cancer research

2019 Volume 79, Issue 20, Page(s) 5146–5148

Abstract: Semaphorin 4D (Sema4D) plays a role in various cell types including B lymphocytes, differentiating neurons, endothelial cells, and cancer cells. Preclinical ... ...

Abstract	Semaphorin 4D (Sema4D) plays a role in various cell types including B lymphocytes, differentiating neurons, endothelial cells, and cancer cells. Preclinical and
MeSH term(s)	Antigens, CD ; Endothelial Cells ; Semaphorins ; Signal Transduction
Chemical Substances	Antigens, CD ; CD100 antigen ; Semaphorins
Language	English
Publishing date	2019-10-01
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-19-2387
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