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1.
Int J Mol Sci ; 25(10)2024 May 20.
Article in English | MEDLINE | ID: mdl-38791608

ABSTRACT

Due to its propensity to metastasize, cancer remains one of the leading causes of death worldwide. Thanks in part to their intrinsic low cytotoxicity, the effects of the flavonoid family in the prevention and treatment of various human cancers, both in vitro and in vivo, have received increasing attention in recent years. It is well documented that Apigenin (4',5,7-trihydroxyflavone), among other flavonoids, is able to modulate key signaling molecules involved in the initiation of cancer cell proliferation, invasion, and metastasis, including JAK/STAT, PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and Wnt/ß-catenin pathways, as well as the oncogenic non-coding RNA network. Based on these premises, the aim of this review is to emphasize some of the key events through which Apigenin suppresses cancer proliferation, focusing specifically on its ability to target key molecular pathways involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cells (CSCs), cell cycle arrest, and cancer cell death.


Subject(s)
Apigenin , Epithelial-Mesenchymal Transition , Neoplasms , Apigenin/pharmacology , Apigenin/therapeutic use , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Animals , Epithelial-Mesenchymal Transition/drug effects , Signal Transduction/drug effects , Cell Proliferation/drug effects , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism
2.
Int J Mol Sci ; 24(10)2023 May 16.
Article in English | MEDLINE | ID: mdl-37240168

ABSTRACT

Luteolin (3',4',5,7-tetrahydroxyflavone), a member of the flavonoid family derived from plants and fruits, shows a wide range of biomedical applications. In fact, due to its anti-inflammatory, antioxidant and immunomodulatory activities, Asian medicine has been using luteolin for centuries to treat several human diseases, including arthritis, rheumatism, hypertension, neurodegenerative disorders and various infections. Of note, luteolin displays many anti-cancer/anti-metastatic properties. Thus, the purpose of this review consists in highlighting the relevant mechanisms by which luteolin inhibits tumor progression in metastasis, i.e., affecting epithelial-mesenchymal transition (EMT), repressing angiogenesis and lysis of extracellular matrix (ECM), as well as inducing apoptosis.


Subject(s)
Luteolin , Neoplasms , Humans , Luteolin/pharmacology , Luteolin/therapeutic use , Epithelial-Mesenchymal Transition , Neoplasms/metabolism , Flavonoids/pharmacology , Apoptosis , Cell Line, Tumor
3.
Int J Mol Sci ; 24(3)2023 Jan 18.
Article in English | MEDLINE | ID: mdl-36768260

ABSTRACT

Redox homeostasis is determinant in the modulation of quiescence/self-renewal/differentiation of stem cell lines. The aim of this study consisted of defining the impact of redox modifications on cell fate in a human hepatic progenitor line. To achieve this, the HepaRG cell line, which shows oval ductular bipotent characteristics, was used. The impact of redox status on the balance between self-renewal and differentiation of HepaRG cells was investigated using different methodological approaches. A bioinformatic analysis initially proved that the trans-differentiation of HepaRG toward bipotent progenitors is associated with changes in redox metabolism. We then exposed confluent HepaRG (intermediate differentiation phase) to oxidized (H2O2) or reduced (N-acetylcysteine) extracellular environments, observing that oxidation promotes the acquisition of a mature HepaRG phenotype, while a reduced culture medium stimulates de-differentiation. These results were finally confirmed through pharmacological modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2), a principal modulator of the antioxidant response, in confluent HepaRG. NRF2 inhibition led to intracellular pro-oxidative status and HepaRG differentiation, while its activation was associated with low levels of reactive species and de-differentiation. In conclusion, this study shows that both intra- and extracellular redox balance are crucial in the determination of HepaRG fate. The impact of redox status in the differentiation potential of HepaRG cells is significant on the utilization of this cell line in pre-clinical studies.


Subject(s)
Hydrogen Peroxide , NF-E2-Related Factor 2 , Humans , NF-E2-Related Factor 2/metabolism , Hydrogen Peroxide/metabolism , Liver/metabolism , Cell Line , Stem Cells/metabolism , Cell Differentiation/physiology , Oxidation-Reduction , Hepatocytes/metabolism
4.
Int J Mol Sci ; 25(1)2023 Dec 28.
Article in English | MEDLINE | ID: mdl-38203581

ABSTRACT

Hepatic fibrosis is a complex process that develops in chronic liver diseases. Even though the initiation and progression of fibrosis rely on the underlying etiology, mutual mechanisms can be recognized and targeted for therapeutic purposes. Irrespective of the primary cause of liver disease, persistent damage to parenchymal cells triggers the overproduction of reactive species, with the consequent disruption of redox balance. Reactive species are important mediators for the homeostasis of both hepatocytes and non-parenchymal liver cells. Indeed, other than acting as cytotoxic agents, reactive species are able to modulate specific signaling pathways that may be relevant to hepatic fibrogenesis. After a brief introduction to redox biology and the mechanisms of fibrogenesis, this review aims to summarize the current evidence of the involvement of redox-dependent pathways in liver fibrosis and focuses on possible therapeutic targets.


Subject(s)
Cognition , Liver Cirrhosis , Humans , Oxidation-Reduction , Biology
5.
Int J Mol Sci ; 22(12)2021 Jun 20.
Article in English | MEDLINE | ID: mdl-34202966

ABSTRACT

Ginger (Zingiber officinale Roscoe, family: Zingiberaceae), originating in South-East Asia, is one of the most used spices and condiments for foods and beverages. It is also used in traditional medicine for many human disorders including fever, gastrointestinal complications, arthritis, rheumatism, hypertension, and various infectious diseases due to its anti-inflammatory, antioxidant, antimicrobial, and antiemetic properties. Intriguingly, many recent studies evidenced the potent chemopreventive characteristics of ginger extracts against different types of cancer. The aim of this work is to review the literature related to the use of ginger extracts as a chemotherapeutic agent and to structure the cellular and molecular mechanisms through which ginger acts in different cancer types. Data summarized from experiments (in vitro or in vivo) and clinical studies, evidenced in this review, show that ginger derivatives perpetrate its anti-tumor action through important mediators, involved in crucial cell processes, such as cell cycle arrest, induction of cancer cell death, misbalance of redox homeostasis, inhibition of cell proliferation, angiogenesis, migration, and dissemination of cancer cells.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Chemoprevention , Neoplasms/prevention & control , Plant Extracts/pharmacology , Zingiber officinale/chemistry , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Antioxidants/chemistry , Antioxidants/pharmacology , Antioxidants/therapeutic use , Cell Cycle Checkpoints/drug effects , Cell Death/drug effects , Chemoprevention/methods , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition/drug effects , Humans , Neoplasms/drug therapy , Neoplasms/etiology , Neoplasms/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Oxidation-Reduction/drug effects , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Reactive Oxygen Species/metabolism , Structure-Activity Relationship
6.
Br J Cancer ; 123(8): 1302-1314, 2020 10.
Article in English | MEDLINE | ID: mdl-32684626

ABSTRACT

BACKGROUND: Mutations of the tumour-suppressor gene TP53 are the most frequent somatic genomic alterations in head and neck squamous cell carcinoma (HNSCC). However, it is not yet clear whether specific TP53 mutations bear distinct clinical and pathophysiological significance in different HNSCC subgroups. METHODS: A systematic bioinformatics appraisal of TP53 mutations was performed on 415 HNSCC cases available on The Cancer Genome Atlas (TCGA). The following features were analysed and correlated with known clinicopathological variables: mutational profile of TP53, location (within secondary structure and predicted domains of p53 protein) and well-known hotspot mutations. Interactome-genome-transcriptome network analysis highlighted different gene networks. An algorithm was generated to develop a new prognostic classification system based on patients' overall survival. RESULTS: TP53 mutations in HNSCCs exhibited distinct differences in different anatomical sites. The mutational profile of TP53 was an independent prognostic factor in HNSCC. High risk of death mutations, identified by our novel classification algorithm, was an independent prognostic factor in TCGA HNSCC database. Finally, network analysis suggested that distinct p53 molecular pathways exist in a site- and mutation-specific manner. CONCLUSIONS: The mutational profile of TP53 may serve as an independent prognostic factor in HNSCC patients, and is associated with distinctive site-specific biological networks.


Subject(s)
Computational Biology/methods , Head and Neck Neoplasms/genetics , Mutation , Squamous Cell Carcinoma of Head and Neck/genetics , Tumor Suppressor Protein p53/genetics , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/virology , Humans , Papillomaviridae/isolation & purification , Prognosis , Squamous Cell Carcinoma of Head and Neck/mortality , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/virology
7.
Mol Biol Rep ; 47(3): 2279-2288, 2020 Mar.
Article in English | MEDLINE | ID: mdl-32040707

ABSTRACT

Liver fibrosis affects over 100 million people in the world; it represents a multifactorial, fibro-inflammatory disorder characterized by exacerbated production of extracellular matrix with consequent aberration of hepatic tissue. The aetiology of this disease is very complex and seems to involve a broad spectrum of factors including the lifestyle, environment factors, genes and epigenetic changes. More evidences indicate that angiogenesis, a process consisting in the formation of new blood vessels from pre-existing vessels, plays a crucial role in the progression of liver fibrosis. Central to the pathogenesis of liver fibrosis is the hepatic stellate cells (HSCs) which represent a crossroad among inflammation, fibrosis and angiogenesis. Quiescent HSCs can be stimulated by a host of growth factors, pro-inflammatory mediators produced by damaged resident liver cell types, as well as by hypoxia, contributing to neoangiogenesis, which in turn can be a bridge between acute and chronic inflammation. As matter of fact, studies demonstrated that neutralization of vascular endothelial growth factor as well as other proangiogenic agents can attenuate the progression of liver fibrosis. With this review, our intent is to discuss the cause and the role of angiogenesis in liver fibrosis focusing on the current knowledge about the impact of anti-angiogenetic therapies in this pathology.


Subject(s)
Liver Cirrhosis/pathology , Neovascularization, Pathologic , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Animals , Disease Management , Disease Progression , Disease Susceptibility , Environmental Biomarkers , Humans , Liver Cirrhosis/drug therapy , Liver Cirrhosis/etiology , Liver Cirrhosis/metabolism , Molecular Targeted Therapy , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism
8.
Mol Biol Rep ; 46(5): 5617-5629, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31273611

ABSTRACT

Cancer is among the leading causes of death worldwide. Several pharmacological protocols have been developed in order to block tumor progression often showing partial efficacy and severe counterproductive effects. It is now conceived that a healthy lifestyle coupled with the consumption of certain phytochemicals can play a protective role against tumor development and progression. According to this vision, it has been introduced the concept of "chemoprevention". This term refers to natural agents with the capability to interfere with the tumorigenesis and metastasis, or at least, attenuate the cancer-related symptoms. Piperine (1-Piperoylpiperidine), a main extract of Piper longum and Piper nigrum, is an alkaloid with a long history of medicinal use. In fact, it exhibits a variety of biochemical and pharmaceutical properties, including chemopreventive activities without significant cytotoxic effects on normal cells, at least at doses < of 250 µg/ml. The aim of this review is to discuss the relevant molecular and cellular mechanisms underlying the chemopreventive action of this natural alkaloid.


Subject(s)
Alkaloids/metabolism , Alkaloids/pharmacology , Benzodioxoles/metabolism , Benzodioxoles/pharmacology , Neoplasms/drug therapy , Piperidines/metabolism , Piperidines/pharmacology , Polyunsaturated Alkamides/metabolism , Polyunsaturated Alkamides/pharmacology , Apoptosis , Cell Proliferation , Chemoprevention , Disease Progression , Humans , Neoplasm Metastasis , Neoplasms/genetics , Neoplasms/metabolism , Plant Extracts/pharmacology
9.
Arthritis Rheumatol ; 71(11): 1913-1922, 2019 11.
Article in English | MEDLINE | ID: mdl-31233292

ABSTRACT

OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by periaortic and periiliac fibroinflammatory tissue. The pathogenic mechanisms leading to tissue accumulation and activation of fibroblasts are unclear. This study was undertaken to explore the role of fibrocytes, circulating precursors of tissue fibroblasts, in patients with CP. METHODS: We studied 44 patients with newly diagnosed CP and 30 healthy controls. Circulating fibrocytes were identified as Col1+CD45+ cells using flow cytometry. Retroperitoneal tissue biopsy samples from 9 CP patients were stained with anti-type I procollagen, anti-CXCR4, and anti-CD45 antibodies and analyzed by confocal microscopy to detect tissue-infiltrating fibrocytes. Circulating levels and tissue expression of CXCL12, a CXCR4 ligand that promotes fibrocyte homing, were investigated using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. We also characterized T helper polarization in biopsy samples from CP patients and measured serum levels of a panel of cytokines that are hallmarks of T helper responses and capable of influencing fibrocyte differentiation. RESULTS: The frequency of circulating Col1+CD45+ fibrocytes was higher in patients than in controls (P = 0.0371). CD45+proCol1+ and CXCR4+proCol1+ cells were detected in all examined biopsy samples from CP patients. Serum levels of CXCL12 were also higher in CP patients than controls (P = 0.0056), and tissue-infiltrating inflammatory cells intensely expressed CXCL12. Increased serum levels of Th2 cytokines (e.g., interleukin-13 [IL-13] and IL-10) were found in patients, and immunohistochemistry revealed a dominant infiltration of GATA-3+ cells, also indicating Th2 polarization; Th2-skewed responses are known to promote fibrocyte differentiation. CONCLUSION: Our findings indicate that fibrocytes are enriched in the peripheral blood of CP patients and infiltrate target lesions. The accumulation of fibrocytes in the pathologic tissue might be driven by CXCL12, and Th2-skewed immune responses are likely to facilitate their differentiation.


Subject(s)
Fibroblasts/metabolism , Retroperitoneal Fibrosis/metabolism , Th2 Cells/metabolism , Case-Control Studies , Cell Differentiation , Chemokine CXCL12/metabolism , Collagen Type I/metabolism , Cytokines/immunology , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Fibroblasts/cytology , Fibroblasts/immunology , Fibrosis , Flow Cytometry , Humans , Immunohistochemistry , Inflammation , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-13/immunology , Interleukin-13/metabolism , Leukocyte Common Antigens/metabolism , Male , Microscopy, Confocal , Middle Aged , Receptors, CXCR4/metabolism , Retroperitoneal Fibrosis/immunology , Retroperitoneal Fibrosis/pathology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Th2 Cells/immunology
10.
FASEB J ; 33(3): 3112-3128, 2019 03.
Article in English | MEDLINE | ID: mdl-30550356

ABSTRACT

The chondroitin sulfate proteoglycan 4 ( CSPG4) gene encodes a transmembrane proteoglycan (PG) constituting the largest and most structurally complex macromolecule of the human surfaceome. Its transcript shows an extensive evolutionary conservation and, due to the elaborated intracellular processing of the translated protein, it generates an array of glycoforms with the potential to exert variant-specific functions. CSPG4-mediated molecular events are articulated through the interaction with more than 40 putative ligands and the concurrent involvement of the ectodomain and cytoplasmic tail. Alternating inside-out and outside-in signal transductions may thereby be elicited through a tight functional connection of the PG with the cytoskeleton and its regulators. The potential of CSPG4 to influence both types of signaling mechanisms is also asserted by its lateral mobility along the plasma membrane and its intersection with microdomain-restricted internalization and endocytic trafficking. Owing to the multitude of molecular interplays that CSPG4 may engage, and thanks to a differential phosphorylation of its intracellular domain accounted by crosstalking signaling pathways, the PG stands out for its unique capability to affect numerous cellular phenomena, including those purporting pathologic conditions. We discuss here the progresses made in advancing our understanding about the structural-functional bases for the ability of CSPG4 to widely impact on cell behavior, such as to highlight how its multivalency may be exploited to interfere with disease progression.-Tamburini, E., Dallatomasina, A., Quartararo, J., Cortelazzi, B., Mangieri, D., Lazzaretti, M., Perris, R. Structural deciphering of the NG2/CSPG4 proteoglycan multifunctionality.


Subject(s)
Antigens/chemistry , Proteoglycans/chemistry , Amino Acid Sequence , Animals , Antigens/genetics , Antigens/metabolism , Cell Membrane/metabolism , Chondroitin Sulfate Proteoglycans/chemistry , Chondroitin Sulfate Proteoglycans/genetics , Chondroitin Sulfate Proteoglycans/metabolism , Evolution, Molecular , Humans , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Models, Molecular , Nerve Regeneration/physiology , Neurites/metabolism , Phylogeny , Protein Interaction Domains and Motifs , Proteoglycans/genetics , Proteoglycans/metabolism
11.
Fluids Barriers CNS ; 15(1): 28, 2018 Oct 05.
Article in English | MEDLINE | ID: mdl-30290761

ABSTRACT

BACKGROUND: Nanotubular structures, denoted tunneling nanotubes (TNTs) have been described in recent times as involved in cell-to-cell communication between distant cells. Nevertheless, TNT-like, long filopodial processes had already been described in the last century as connecting facing, growing microvessels during the process of cerebral cortex vascularization and collateralization. Here we have investigated the possible presence and the cellular origin of TNTs during normal brain vascularization and also in highly vascularized brain tumors. METHODS: We searched for TNTs by high-resolution immunofluorescence confocal microscopy, applied to the analysis of 20-µm, thick sections from lightly fixed, unembedded samples of both developing cerebral cortex and human glioblastoma (GB), immunolabeled for endothelial, pericyte, and astrocyte markers, and vessel basal lamina molecules. RESULTS: The results revealed the existence of pericyte-derived TNTs, labeled by proteoglycan NG2/CSPG4 and CD146. In agreement with the described heterogeneity of these nanostructures, ultra-long (> 300 µm) and very thin (< 0.8 µm) TNTs were observed to bridge the gap between the wall of distant vessels, or were detected as short (< 300 µm) bridging cables connecting a vessel sprout with its facing vessel or two apposed vessel sprouts. The pericyte origin of TNTs ex vivo in fetal cortex and GB was confirmed by in vitro analysis of brain pericytes, which were able to form and remained connected by typical TNT structures. CONCLUSIONS: None of the multiple roles described for TNTs can be excluded from a possible involvement during the processes of both normal and pathological vessel growth. A possible function, suggested by the pioneering studies made during cerebral cortex vascularization, is in cell searching and cell-to-cell recognition during the processes of vessel collateralization and vascular network formation. According to our results, it is definitely the pericyte-derived TNTs that seem to actively explore the surrounding microenvironment, searching for (site-to-site recognition), and connecting with (pericyte-to-pericyte and/or pericyte-to-endothelial cell communication), the targeted vessels. This idea implies that TNTs may have a primary role in the very early phases of both physiological and tumor angiogenesis in the brain.


Subject(s)
Brain Neoplasms/physiopathology , Cerebral Cortex/physiopathology , Endothelial Cells/physiology , Glioblastoma/physiopathology , Nanotubes , Neovascularization, Pathologic , Neovascularization, Physiologic , Pericytes/physiology , Adult , Brain Neoplasms/blood supply , Brain Neoplasms/pathology , Cell Communication , Cells, Cultured , Cerebral Cortex/blood supply , Cerebral Cortex/cytology , Endothelial Cells/cytology , Female , Glioblastoma/blood supply , Glioblastoma/pathology , Humans , Male , Middle Aged , Pericytes/cytology
12.
Tumour Biol ; 39(6): 1010428317705757, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28621232

ABSTRACT

Although usually referred to as a structural actin-binding protein, LIM and SH3 domain-containing protein may actually be dynamically involved in the control of a wide spectrum of cellular processes, by virtue of its interaction with several molecular partners. Alongside being ubiquitously expressed in physiological conditions, LIM and SH3 domain-containing protein is overexpressed in a growing number of human cancers, in which it may actively contribute to their aggressiveness by promoting cell proliferation and migration. In view of the recent findings, implicating the protein in cancer progression, we discuss here the most relevant discoveries highlighting the role of this versatile protein in various human tumors. The correlation between LIM and SH3 domain-containing protein expression levels in cancer and the poor outcome and metastatic behavior of tumors denotes the clinical significance of this protein and hints its potential value as a new cancer prognostic or even diagnostic biomarker. This may be decisive not only to optimize existing pharmacological regimes but also to delineate novel, more efficacious therapeutic and/or preventive approaches.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Biomarkers, Tumor/genetics , Carcinogenesis/genetics , Cytoskeletal Proteins/genetics , LIM Domain Proteins/genetics , Neoplasms/genetics , Adaptor Proteins, Signal Transducing/biosynthesis , Biomarkers, Tumor/biosynthesis , Cell Proliferation/genetics , Cytoskeletal Proteins/biosynthesis , Gene Expression Regulation, Neoplastic , Humans , LIM Domain Proteins/biosynthesis , Neoplasms/pathology , Prognosis
13.
J Cell Mol Med ; 19(9): 2098-107, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26010680

ABSTRACT

Gynaecological leiomyosarcoma (gLMS) represent a heterogeneous group of soft tissue sarcoma, characterized by rare incidence, high aggressiveness and propensity to infiltrate secondary organs, poor prognosis and lethality, because of the lack of biological mechanisms that underlying their progression and effective pharmaceutical treatments. This study was focused on some of the aspects of progression and dissemination of a subtype of gLMS namely vulvar LMS (vLMS). We therefore used a vulvar LMS-derived cell line namely SK-LMS-1, coupled with in vitro and in vivo assays. We observed that SK-LMS-1 cells have a strong invasive capacity in vitro, through the activity of matrix metalloproteinases 2 and 9, while in vivo these cells induce a strong angiogenic response and disseminate to the chick embryo liver. Therefore, we postulate that metalloproteinases are involved in the spreading behaviour of SK-LMS-1. Further investigations are necessary to better understand the molecular and cellular machinery involved in the progression of this malignancy.


Subject(s)
Leiomyosarcoma/blood supply , Leiomyosarcoma/enzymology , Matrix Metalloproteinases/metabolism , Neovascularization, Pathologic/enzymology , Vulvar Neoplasms/blood supply , Vulvar Neoplasms/enzymology , Angiogenesis Inducing Agents/metabolism , Animals , Cell Line, Tumor , Chickens , Chorioallantoic Membrane/metabolism , Collagen/metabolism , Drug Combinations , Enzyme Activation , Female , Humans , Laminin/metabolism , Leiomyosarcoma/pathology , Neoplasm Invasiveness , Neoplasm Metastasis , Proteoglycans/metabolism , Vulvar Neoplasms/pathology
14.
Histol Histopathol ; 30(1): 69-76, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25046102

ABSTRACT

The role of angiogenesis as a hallmark of tumor progression has been poorly explored in leiomyosarcoma, a rare but aggressive mesenchymal malignancy. We aimed to characterize microvessel distribution and morphology - including pericyte coverage - in a retrospective series of leyomiosarcomas of the soft tissues and the uterus. 41 whole-block tumor slides from formalin-fixed paraffin-embedded tissues were immunostained for endothelial-specific marker CD31 and microvessel density was quantified by assigning a grade to the frequency of CD31 positive microvessels. Vessel morphology and pericyte coverage were investigated by double-labeling for CD31 and either PDGFRß, αSMA, desmin, CD90, or CD146. We found that microvessel density correlated with tumor grade in leiomyosarcoma of soft tissues, in analogy with what has been established in several types of carcinoma. This did not apply to uterine leiomyosarcoma, possibly due to the abundant myometrial vascularization. The evaluation of perivascular cell markers related to vessel stability revealed immature microvascular networks with aberrant pericyte coverage, irrespective of tumor origin or grade. Our observations substantiate the role of angiogenesis in the progression of soft tissue leiomyosarcoma. A multiple-marker approach to the assessment of pericyte coverage can identify different profiles of vessel immaturity correlated with tumor grade.


Subject(s)
Biomarkers, Tumor/metabolism , Leiomyosarcoma/metabolism , Neovascularization, Pathologic/metabolism , Soft Tissue Neoplasms/metabolism , Uterine Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Antigens, CD/metabolism , Female , Humans , Male , Microcirculation , Middle Aged , Neovascularization, Pathologic/pathology , Pericytes/metabolism , Pericytes/pathology , Prognosis , Retrospective Studies , Soft Tissue Neoplasms/pathology , Uterine Neoplasms/pathology
15.
Biosci Rep ; 34(6): e00147, 2014 Nov 04.
Article in English | MEDLINE | ID: mdl-25236925

ABSTRACT

STS (soft tissue sarcomas) are rare malignant tumours deriving from cells of mesenchymal origin and represent only 1% of all malignant neoplasms. It has been extensively demonstrated that angiogenesis has an important role in cancer malignancy. Particularly, a lot of studies demonstrate the importance of angiogenesis in the development of carcinomas, whereas little is known about the role of angiogenesis in sarcomas and especially in STS. This review aims at summarizing the new discoveries about the nature and the importance of angiogenesis in STS and the new possible therapeutic strategies involved. Only a few studies concerning STS focus on tumour neovascularization and proangiogenic factors and look for a correlation with the patients prognosis/survival. These studies demonstrate that intratumoural MVD (microvessels density) may not accurately represent the angiogenic capacity of STS. Nevertheless, this does not exclude the possibility that angiogenesis could be important in STS. The importance of neoangiogenesis in soft tissue tumours is confirmed by the arising number of publications comparing angiogenesis mediators with clinical features of patients with STS. The efficacy of anti-angiogenic therapies in other types of cancer is well documented. The understanding of the involvement of the angiogenic process in STS, together with the necessity to improve the therapy for this often mortal condition, prompted the exploration of anti-tumour compounds targeting this pathway. In conclusion, this review emphasizes the importance to better understand the mechanisms of angiogenesis in STS in order to subsequently design-specific target therapies for this group of poorly responding tumours.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Neovascularization, Pathologic/prevention & control , Sarcoma/blood supply , Sarcoma/drug therapy , Fibroblast Growth Factor 2/antagonists & inhibitors , Fibroblast Growth Factor 2/metabolism , Humans , Matrix Metalloproteinases/metabolism , Models, Biological , Neovascularization, Pathologic/metabolism , Placenta Growth Factor , Pregnancy Proteins/antagonists & inhibitors , Pregnancy Proteins/metabolism , Sarcoma/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism
16.
Nephrol Dial Transplant ; 27(10): 3875-84, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23114905

ABSTRACT

BACKGROUND: Idiopathic retroperitoneal fibrosis (IRF) is a rare fibro-inflammatory disorder characterized by a periaortic tissue which often encases the ureters causing acute renal failure. IRF histology shows fibrosis and a chronic inflammatory infiltrate with frequent tissue eosinophilia. We assessed a panel of molecules promoting eosinophilia and fibrosis in IRF patients and performed an immunogenetic study. METHODS: Serum levels of eotaxin/CCL11, regulated and normal T-cell expressed and secreted (RANTES), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-5, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) were measured using a multiplex assay in 24 newly diagnosed, untreated IRF patients and 14 healthy controls. Retroperitoneal biopsies (available in 8/24 patients) were histologically evaluated to assess eosinophil infiltration, whereas mast cells (MCs) were identified by immunohistochemical analysis for human tryptase. Immunohistochemistry for eotaxin/CCL11 and its receptor CCR3 was also performed. Six single nucleotide polymorphisms (SNPs) within the CCL11 gene (rs6505403, rs1860184, rs4795896, rs17735961, rs16969415 and rs17809012) were investigated in 142 IRF patients and 214 healthy controls. RESULTS: Serum levels of eotaxin/CCL11 were higher in IRF patients than in controls (P = 0.009). Eotaxin/CCL11 drives tissue infiltration of eosinophils and MCs, which can promote fibrosis. Eosinophilic infiltration was prominent (>5 cells/hpf) in five (62.5%) cases, and abundant tryptase-positive MCs were found in all cases; notably, MCs were in a degranulating state. Immunohistochemistry showed that CCL11 was highly produced by infiltrating mononuclear cells and that its receptor CCR3 was expressed by infiltrating eosinophils, MCs, lymphocytes and fibroblasts. None of the tested CCL11 SNPs showed disease association, but the TTCCAT haplotype was significantly associated with IRF (P = 0.0005). CONCLUSIONS: These findings suggest that the eotaxin/CCL11-CCR3 axis is active in IRF and may contribute to its pathogenesis; the TTCCAT haplotype within the CCL11 gene is significantly associated with IRF.


Subject(s)
Chemokine CCL11/metabolism , Retroperitoneal Fibrosis/immunology , Becaplermin , Case-Control Studies , Chemokine CCL11/blood , Chemokine CCL11/genetics , Chemokine CCL5/blood , Eosinophils/pathology , Female , Fibroblast Growth Factor 2/blood , Genetic Association Studies , Granulocyte Colony-Stimulating Factor/blood , Haplotypes , Humans , Immunogenetic Phenomena , Interleukin-5/blood , Male , Mast Cells/pathology , Middle Aged , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-sis/blood , Receptors, CCR3/metabolism , Retroperitoneal Fibrosis/genetics , Retroperitoneal Fibrosis/pathology
17.
J Cardiovasc Electrophysiol ; 23(3): 271-9, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21954878

ABSTRACT

INTRODUCTION: Atrial fibrillation (AF) in mitral regurgitation (MR) is a complex disease where multiple factors may induce left-atrial structural remodeling (SR). We explored the differential SR of the left-atrial posterior wall (LAPW) of patients affected by MR with or without persistent AF, and the expression of key proteins involved in its pathogenesis. METHODS AND RESULTS: Light microscopy of LAPW samples from 27 patients with MR and persistent AF (group 1), 33 with MR in sinus rhythm (group 2), and 15 autopsy controls (group 3) was used to measure myocyte diameter, percentage of myocytolytic myocytes, interstitial fibrosis, and capillary density; RT-PCR and Western blotting were used to assess the mRNA and protein levels of SOD-1, SOD-2, HO-1, calpain, MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF; immunofluorescence was used to locate these proteins. Myocyte diameter was similar in groups 1 and 2, but larger than controls. Compared to group 2, group 1 had more myocytolytic myocytes (20.8 ± 5.6% vs 14.7 ± 4.5%; P < 0.0001), increased interstitial fibrosis (10.4 ± 5.1% vs 7.5 ± 4.2%; P < 0.05), and decreased capillary density (923 ± 107 No/mm(2) vs 1,040 ± 100 No/mm(2); P < 0.0001). All of the proteins were more expressed in groups 1 and 2 than in controls. The protein and mRNA levels of SOD-1, SOD-2, MMP-2, and MMP-9 were higher in group 1 than in group 2. CONCLUSIONS: The LAPW of MR patients with or without AF shows considerable SR. The former has more severe histopathological changes and higher levels of proteins involved in SR, thereby reaching a threshold beyond which the sinus impulse cannot normally activate atrial myocardium.


Subject(s)
Atrial Fibrillation/metabolism , Atrial Fibrillation/pathology , Heart Atria/metabolism , Heart Atria/pathology , Mitral Valve Insufficiency/metabolism , Mitral Valve Insufficiency/pathology , Adult , Aged , Aged, 80 and over , Arrhythmia, Sinus/physiopathology , Atrial Fibrillation/complications , Autopsy , Blotting, Western , Calpain/metabolism , DNA, Complementary/biosynthesis , DNA, Complementary/isolation & purification , Female , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Male , Matrix Metalloproteinase 2/metabolism , Microscopy, Confocal , Middle Aged , Mitral Valve Insufficiency/complications , Myocytes, Cardiac/pathology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , RNA/biosynthesis , RNA/isolation & purification , Real-Time Polymerase Chain Reaction , Superoxide Dismutase/genetics , Superoxide Dismutase-1 , Vascular Endothelial Growth Factor A/metabolism
18.
Lab Invest ; 90(11): 1645-60, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20714324

ABSTRACT

In this study, we investigated the involvement of dystrophin-associated proteins (DAPs) and their relationship with the perivascular basement membrane in the brains of mdx mice and controls at the age of 2 months. We analyzed (1) the expression of glial DAPs α-ß-dystroglycan (DG), α-syntrophin, aquaporin-4 (AQP4) water channel, Kir 4.1 and dystrophin isoform (Dp71) by immunocytochemistry, laser confocal microscopy, immunogold electron microscopy, immunoblotting and RT-PCR; (2) the ultrastructure of the basement membrane and expression of laminin and agrin; and (3) the dual immunofluorescence colocalization of AQP4/α-ß-DG, and of Kir 4.1/agrin. The following results were observed in mdx brain as compared with controls: (1) a significant reduction in protein content and mRNA expression of DAPs; (2) ultrastructurally, a thickened and discontinuous appearance of the basement membrane and a significant reduction in laminin and agrin; and (3) a molecular rearrangment of α-ß-DG, coupled with a parallel loss of agrin and Kir 4.1 on basement membrane and glial endfeet. These data indicate that in mdx brain the deficiency in dystrophin and dystrophin isoform (Dp71) is coupled with a reduction of DAP components, coupled with an altered anchoring to the basement membrane.


Subject(s)
Agrin/analysis , Brain/metabolism , Dystrophin-Associated Proteins/analysis , Laminin/analysis , Muscular Dystrophy, Duchenne/metabolism , Animals , Aquaporin 4/analysis , Blotting, Western , Calcium-Binding Proteins/analysis , Disease Models, Animal , Down-Regulation , Dystroglycans/analysis , Fluorescent Antibody Technique , Membrane Proteins/analysis , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Microscopy, Confocal , Microscopy, Electron , Muscle Proteins/analysis , Muscular Dystrophy, Duchenne/pathology , Potassium Channels, Inwardly Rectifying/analysis
19.
Eur J Cancer ; 45(18): 3315-25, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19836227

ABSTRACT

Brain tumour oedema is coupled with blood-brain barrier damage and alteration in water flow. Aquaporin-4 (AQP4) is involved in the development and resolution of brain oedema, and it is strongly upregulated in glioblastoma multiforme (GBM). Here, we evaluated AQP4 expression and content in GBM and correlated with VEGF-VEGFR-2 expression. In the relapse after chemotherapy and radiotherapy, AQP4 content reduced in parallel with VEGF-VEGFR-2, as compared with primary tumours, and in the peripheral areas of relapsed tumours AQP4 mimicked normal findings of perivascular rearrangement. After immunogold electron microscopy, gold particles were attached on the glial membrane facing the perivascular side, likewise AQP4 gold labelling of the vessels of the control areas. In primary tumours the peripheral vessels appeared faintly marked by AQP4, while the perivascular tumour cells showed a strong expression. The vasculature of the inner tumour areas was unlabelled by AQP4, while tumour cells were labelled, in both primary and relapsing tumours. Relapsed tumours after radiotherapy alone showed slight AQP4 reduction and perivascular restoring in the peripheral areas of the tumour. These data indicate that in GBM chemotherapy and radiotherapy induce a down-regulation in AQP4 expression restoring its perivascular rearrangement suggesting its potential role in the resolution of brain oedema.


Subject(s)
Aquaporin 4/metabolism , Blood-Brain Barrier/metabolism , Brain Edema/metabolism , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Aquaporin 4/drug effects , Aquaporin 4/radiation effects , Blood-Brain Barrier/pathology , Body Water/metabolism , Brain Edema/pathology , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Capillary Permeability , Cerebrovascular Circulation , Combined Modality Therapy , Down-Regulation/drug effects , Down-Regulation/radiation effects , Glioblastoma/pathology , Glioblastoma/therapy , Humans , Up-Regulation , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vascular Endothelial Growth Factors/metabolism
20.
Cancer Lett ; 277(2): 199-204, 2009 May 18.
Article in English | MEDLINE | ID: mdl-19150583

ABSTRACT

In this study we purposed an alternative method to study the angiogenic and invasive potential of neuroblastoma cell suspensions implanted on the chick embryo chorioallantoic membrane (CAM) surface. Neuroblastoma cells were seeded in Matrigel and thereafter the suspension was pipetted onto the CAM surface at day 8 of incubation inside a silicon ring previously loaded onto the CAM surface. Four days after implantation, the silicon ring was removed and the angiogenic and invasive response were studied morphologically at macroscopic and microscopic levels and by reverse transcriptase-polymerase chain reaction (RT-PCR) by using human and chicken primers for several angiogenic cytokines, namely vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), angiopoietin-1 (ANG-1), hypoxia inducible factor-2alpha (HIF-2alpha), and for an endogenous angiostatic molecule, namely endostatin. Results showed that: (1) Neuroblastoma cells induced an angiogenic response in the CAM assay comparable to that induced by FGF-2; (2) neuroblastoma cells are packed inside Matrigel or are recognizable in the CAM mesenchyme; (3) Angiogenic activity of neuroblastoma cells is associated to an high expression of the transcripts of human VEGF-A, FGF-2, ANG-1 and HIF-2alpha and to a low expression in the transcript of a human endostatin while in the control specimens there is no expression of both angiogenic and angiostatic molecules; and (4) the expression of the transcripts of the same chicken angiogenesis stimulators and inhibitor is unmodified in treated and control specimens. Overall, these data indicate that neuroblastoma cells growth on the chick CAM express characteristics of the human disease. This experimental model could be employed for further research on human tumor progression and anti-angiogenic molecules screening.


Subject(s)
Chorioallantoic Membrane/blood supply , Neovascularization, Pathologic , Neuroblastoma/blood supply , Angiopoietin-1/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Chick Embryo , Chorioallantoic Membrane/pathology , Endostatins/metabolism , Fibroblast Growth Factor 2/metabolism , Humans , Neoplasm Invasiveness , Neuroblastoma/metabolism , Neuroblastoma/pathology , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/metabolism
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