Publications by authors named "Roberto Tamma"

89 Publications

Correlation between circulating blood and microenvironment T lymphocytes in diffuse large B-cell lymphomas.

J Clin Pathol 2021 May 19. Epub 2021 May 19.

Hematology and Stem Cell Transplantation Unit, AOU Consorziale Policlinico, Bari, Italy

Aims: Diffuse large B-cell lymphoma (DLBCL) is characterised by marked clinical and biological heterogeneity, attributable to the tumour cells and their microenvironment.

Methods: In this study, we investigated circulating subsets of blood lymphocytes and monocytes and their relationship with T cells in the tumour microenvironment (TME) in chemoresistant and chemosensitive patients with DLBCL.

Results: The study showed that (1) absolute lymphocyte count (ALC) and CD3+ and CD4+ cells were reduced in chemoresistant patients compared with chemosensitive patients; (2) lymphocyte:monocyte ratio (LMR) showed a positive correlation with peripheral blood CD3+ and CD4+ cells; (3) ALC, LMR, peripheral blood CD3+ and CD4+ cells showed a positive correlation with T cells in the TME.

Conclusions: Overall, these data suggest that DLBCL with high TME T cells display a pre-existing antitumour immune response. In the rituximab-containing regimen, TME T cells are stimulated further to participate in the immune response against lymphoma cells. In contrast, DLBCL lymphomas with low T-cell infiltration reflect the absence of a pre-existing antitumour immunity and have a lower likelihood of obtaining an optimal response to therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2020-207048DOI Listing
May 2021

Different spatial distribution of inflammatory cells in the tumor microenvironment of ABC and GBC subgroups of diffuse large B cell lymphoma.

Clin Exp Med 2021 May 6. Epub 2021 May 6.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124, Bari, Italy.

Diffuse Large B-Cell Lymphoma (DLBCL) presents a high clinical and biological heterogeneity, and the tumor microenvironment chracteristics are important in its  progression. The aim of this study was to evaluate tumor T, B cells, macrophages and mast cells distribution in GBC and ABC DLBCL subgroups through a set of morphometric parameters allowing to provide a quantitative evaluation of the morphological features of the spatial patterns generated by these inflammatory cells.   Histological ABC and GCB samples were immunostained for CD4, CD8, CD68, CD 163, and tryptase in order to determine both percentage and position of positive cells in the tissue characterizing their spatial distribution. The results evidenced that cell patterns generated by CD4-, CD8-, CD68-, CD163- and tryptase-positive cell profiles exhibited a significantly higher uniformity index in ABC than in GCB subgroup. The positive-cell distributions appeared clustered in tissues from GCB, while in tissues from ABC such a feature was lower or absent. The combinations of spatial statistics-derived parameters can lead to better predictions of tumor cell infiltration than any classical morphometric method providing a more accurate description of the functional status of the tumor, useful for patient prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10238-021-00716-wDOI Listing
May 2021

Tumor Cell Microenvironment and Microvessel Density Analysis in MALT Type Lymphoma.

Anticancer Res 2021 Mar;41(3):1291-1297

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy.

Background/aim: MALT type lymphoma belongs to marginal zone lymphoma (MZL). MALT lymphomas' inflammatory microenvironment contributes to the pathogenesis of this cancer. In this study, we analyzed and quantified the tumor inflammatory microenvironment in MALT lymphoma samples and in healthy controls, and the microvessel content by immunohistochemistry and morphometric estimation.

Patients And Methods: Biopsy specimens from MALT type lymphoma patients and from non-metastatic axillary lymph nodes (CTRL) were analyzed by immunochemistry in order to quantify CD3, CD4, CD8, CD68, CD163, tryptase, CD34, and Ki67 positive cells.

Results: A substantial increase in the number of cells that were positive for the above markers and microvascular density (MVD) were observed in the MALT group. We also found a positive correlation between microvessels and CD8 cells and between CD8 cells and M2 type macrophages, while tryptase mast cells correlated with CD4 cells. The mitotic proliferation index Ki67 was higher in MALT samples.

Conclusion: The interactions between inflammatory cells in the tumor microenvironment and their correlation with angiogenesis is a useful tool in the development of new immunotherapy strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14886DOI Listing
March 2021

The role of mast cells in human skin cancers.

Clin Exp Med 2021 Feb 12. Epub 2021 Feb 12.

Department of Medicine, Section of Human Anatomy, University of Udine, Udine, Italy.

Mast cells (MCs) are immune cells derived from myeloid lineage present in all classes of vertebrates and have emerged preceding much time the development of adaptive immunity. MCs are involved in inflammatory processes, allergic reactions, and host responses to parasites and bacteria infectious diseases. MCs are located at the host-environment interface, at many sites of initial antigen entry, including skin, lung and gastrointestinal tract, and have part of a protective mechanism. Skin has an important role in protecting the host from invasion both as physical barriers and by employing an intricate network of resident immune and non-immune cells include macrophages, T and B lymphocytes, MCs, neutrophils, eosinophils, and Langerhans cells. In this review we discussed the role of MCs in human skin cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10238-021-00688-xDOI Listing
February 2021

microRNAs Biogenesis, Functions and Role in Tumor Angiogenesis.

Front Oncol 2020 27;10:581007. Epub 2020 Nov 27.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.

microRNAs (miRNAs) are small non-coding RNA molecules, evolutionary conserved. They target more than one mRNAs, thus influencing multiple molecular pathways, but also mRNAs may bind to a variety of miRNAs, either simultaneously or in a context-dependent manner. miRNAs biogenesis, including miRNA transcription, processing by Drosha and Dicer, transportation, RISC biding, and miRNA decay, are finely controlled in space and time. miRNAs are critical regulators in various biological processes, such as differentiation, proliferation, apoptosis, and development in both health and disease. Their dysregulation is involved in tumor initiation and progression. In tumors, they can act as onco-miRNAs or oncosuppressor-miRNA participating in distinct cellular pathways, and the same miRNA can perform both activities depending on the context. In tumor progression, the angiogenic switch is fundamental. miRNAs derived from tumor cells, endothelial cells, and cells of the surrounding microenvironment regulate tumor angiogenesis, acting as pro-angiomiR or anti-angiomiR. In this review, we described miRNA biogenesis and function, and we update the non-classical aspects of them. The most recent role in the nucleus, as transcriptional gene regulators and the different mechanisms by which they could be dysregulated, in tumor initiation and progression, are treated. In particular, we describe the role of miRNAs in sprouting angiogenesis, vessel co-option, and vasculogenic mimicry. The role of miRNAs in lymphoma angiogenesis is also discussed despite the scarcity of data. The information presented in this review reveals the need to do much more to discover the complete miRNA network regulating angiogenesis, not only using high-throughput computational analysis approaches but also morphological ones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.581007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729128PMC
November 2020

The role of vascular niche and endothelial cells in organogenesis and regeneration.

Exp Cell Res 2021 01 30;398(1):112398. Epub 2020 Nov 30.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

The term vascular niche indicate the physical and biochemical microenvironment around blood vessel where endothelial cells, pericytes, and smooth muscle cells organize themselves to form blood vessels and release molecules involved in the recruitment of hematopoietic stem cells, endothelial progenitor cells and mesenchymal stem cells. The vascular niche creates a permissive environment that enables different cell types to realize their developmental or regenerative programs. In this context, the proximity between the endothelium and the new-forming cellular components of organs suggests an essential role of endothelial cells in the organs maturation. Dynamic interactions between specific organ endothelial cells and different cellular conponents are crucial for different organ morphogenesis and function. Conversely, organs provide cues shaping vascular network structure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexcr.2020.112398DOI Listing
January 2021

IL-6 Contributes to the TGF-β1-Mediated Epithelial to Mesenchymal Transition in Human Salivary Gland Epithelial Cells.

Arch Immunol Ther Exp (Warsz) 2020 Sep 10;68(5):27. Epub 2020 Sep 10.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs (SMBNOS), Section of Human Anatomy and Histology, University of Bari "Aldo Moro", piazza Giulio Cesare 1, 70124, Bari, Italy.

To determine the role of IL-6 in bringing about the EMT, in SGEC obtained from healthy subjects. Human salivary gland (SGs) epithelial cells (SGEC) from primary Sjögren's syndrome (pSS) are able to synthesize interleukin (IL)-6, which is a critical mediator of the SGs modifications in response to chronic inflammation. Recently, a hypothetical link between epithelial-mesenchymal transition (EMT)-dependent salivary gland fibrosis and chronic inflammatory conditions has been suggested for pSS; the present study was conducted to evaluate this link. Primary cultures of human SGEC from salivary mucoceles were stimulated with increasing concentrations of IL-6 for 24-72 h. Microscopy, RT-PCR, Real-time PCR, immunoblotting and flow cytometry were used to detect morphological changes, mRNA and protein expression of the EMT markers E-Cadherin, Vimentin and Collagen type I following IL-6 stimulation. The data collected demonstrate that IL-6 can induce SGEC to undergo a morphological and phenotypical transition to a mesenchymal phenotype, in a dose-dependent manner. Decreased mRNA levels of E-Cadherin accompanied by higher mRNA levels of Vimentin and Collagen type I were observed in the IL-6-treated cells compared to control cells (all p < 0.05). This was confirmed at the protein level, demonstrating the decreased E-Cadherin expression, while Vimentin and Collagen type I expression was increased in IL-6-treated SGEC compared to controls (all p < 0.05). The results obtained corroborate the hypothesis that dysregulated cytokines IL-6 may contribute to the EMT-dependent fibrosis, offering a more complete understanding of the role of the EMT during SGs fibrosis in pSS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00005-020-00591-5DOI Listing
September 2020

Mast cells and angiogenesis in multiple sclerosis.

Inflamm Res 2020 Nov 17;69(11):1103-1110. Epub 2020 Aug 17.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico, Piazza G. Cesare, 11, 70124, Bari, Italy.

Multiple sclerosis (MS) is an autoimmune disease, characterized by multiple demyelination of axons in both white and gray matter in the Central Nervous System (CNS). There is increasing evidence to support the notion that angiogenesis and chronic inflammation are mutually related. Different immune cells, including monocytes-macrophages, lymphocytes, neutrophils, mast cells (MCs) and dendritic cells are able to secrete an array of angiogenic cytokines, which promote growth, migration, and activation of endothelial cells. MCs play various roles in MS pathogenesis, influencing the innate immune response in peripheral tissues and in CNS. The aim of this review article is to discuss the role of MCs in MS pathogenesis with particular reference to the involvement of these inflammatory cells in the angiogenic processes occurring during MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00011-020-01394-2DOI Listing
November 2020

Inflammatory Cells in Diffuse Large B Cell Lymphoma.

J Clin Med 2020 Jul 28;9(8). Epub 2020 Jul 28.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.

Diffuse large B cell lymphoma (DLBCL), known as the most common non-Hodgkin lymphoma (NHL) subtype, is characterized by high clinical and biological heterogeneity. The tumor microenvironment (TME), in which the tumor cells reside, is crucial in the regulation of tumor initiation, progression, and metastasis, but it also has profound effects on therapeutic efficacy. The role of immune cells during DLBCL development is complex and involves reciprocal interactions between tumor cells, adaptive and innate immune cells, their soluble mediators and structural components present in the tumor microenvironment. Different immune cells are recruited into the tumor microenvironment and exert distinct effects on tumor progression and therapeutic outcomes. In this review, we focused on the role of macrophages, Neutrophils, T cells, natural killer cells and dendritic cells in the DLBCL microenvironment and their implication as target for DLBCL treatment. These new therapies, carried out by the induction of adaptive immunity through vaccination or passive of immunologic effectors delivery, enhance the ability of the immune system to react against the tumor antigens inducing the destruction of tumor cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9082418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463675PMC
July 2020

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology.

Cancers (Basel) 2020 Jul 11;12(7). Epub 2020 Jul 11.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for about 40% of all cases of NHL. Analysis of the tumor microenvironment is an important aspect of the assessment of the progression of DLBCL. In this review article, we analyzed the role of different cellular components of the tumor microenvironment, including mast cells, macrophages, and lymphocytes, in the tumor progression of DLBCL. We examined several approaches to confront the available pieces of evidence, whereby three key points emerged. DLBCL is a disease of malignant B cells spreading and accumulating both at nodal and at extranodal sites. In patients with both nodal and extranodal lesions, the subsequent induction of a cancer-friendly environment appears pivotal. The DLBCL cell interaction with mature stromal cells and vessels confers tumor protection and inhibition of immune response while delivering nutrients and oxygen supply. Single cells may also reside and survive in protected niches in the nodal and extranodal sites as a source for residual disease and relapse. This review aims to molecularly and functionally recapitulate the DLBCL-milieu crosstalk, to relate niche and pathological angiogenic constitution and interaction factors to DLBCL progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12071869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408689PMC
July 2020

The use of the chick embryo CAM assay in the study of angiogenic activiy of biomaterials.

Microvasc Res 2020 09 5;131:104026. Epub 2020 Jun 5.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

The chick embryo chorioallantoic membrane (CAM) is a highly vascularized extraembryonic membrane, which carries out several functions during embryonic development, including exchange of respiratory gases, calcium transport from the eggshell, acid-base homeostasis in the embryo, and ion and water reabsorption from the allantoic fluid. Due to its easy accessibility, affordability and given that it constitutes an immunodeficient environment, CAM has been used as an experimental model for >50 years and in particular it has been broadly used to study angiogenesis and anti-angiogenesis. This review article describes the use of the CAM assay as a valuable assay to test angiogenic activity of biomaterials in vivo before they are further investigated in animal models. In this context, the use of CAM has become an integral part of the biocompatibility testing process for developing potential biomaterials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mvr.2020.104026DOI Listing
September 2020

Epithelial-Mesenchymal Transition in Cancer: A Historical Overview.

Transl Oncol 2020 Jun 22;13(6):100773. Epub 2020 Apr 22.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

Epithelial-mesenchymal transitions (EMTs), the acquisition of mesenchymal features from epithelial cells, occur during some biological processes and are classified into three types: the first type occurs during embryonic development, the second type is associated with adult tissue regeneration, and the third type occurs in cancer progression. EMT occurring during embryonic development in gastrulation, renal development, and the origin and fate of the neural crest is a highly regulated process, while EMT occurring during tumor progression is highly deregulated. EMT allows the solid tumors to become more malignant, increasing their invasiveness and metastatic activity. Secondary tumors frequently maintain the typical histologic characteristics of the primary tumor. These histologic features connecting the secondary metastatic tumors to the primary is due to a process called mesenchymal-epithelial transition (MET). MET has been demonstrated in different mesenchymal tumors and is the expression of the reversibility of EMT. EMT modulation could constitute an approach to avoid metastasis. Some of the targeted small molecules utilized as antiproliferative agents have revealed to inhibit EMT initiation or maintenance because EMT is regulated through signaling pathways for which these molecules have been designed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tranon.2020.100773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182759PMC
June 2020

Combined Replenishment of miR-34a and let-7b by Targeted Nanoparticles Inhibits Tumor Growth in Neuroblastoma Preclinical Models.

Small 2020 05 22;16(20):e1906426. Epub 2020 Apr 22.

Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, Genoa, 16147, Italy.

Neuroblastoma (NB) tumor substantially contributes to childhood cancer mortality. The design of novel drugs targeted to specific molecular alterations becomes mandatory, especially for high-risk patients burdened by chemoresistant relapse. The dysregulated expression of MYCN, ALK, and LIN28B and the diminished levels of miR-34a and let-7b are oncogenic in NB. Due to the ability of miRNA-mimics to recover the tumor suppression functions of miRNAs underexpressed into cancer cells, safe and efficient nanocarriers selectively targeted to NB cells and tested in clinically relevant mouse models are developed. The technology exploits the nucleic acids negative charges to build coated-cationic liposomes, then functionalized with antibodies against GD receptor. The replenishment of miR-34a and let-7b by NB-targeted nanoparticles, individually and more powerfully in combination, significantly reduces cell division, proliferation, neoangiogenesis, tumor growth and burden, and induces apoptosis in orthotopic xenografts and improves mice survival in pseudometastatic models. These functional effects highlight a cooperative down-modulation of MYCN and its down-stream targets, ALK and LIN28B, exerted by miR-34a and let-7b that reactivate regulatory networks leading to a favorable therapeutic response. These findings demonstrate a promising therapeutic efficacy of miR-34a and let-7b combined replacement and support its clinical application as adjuvant therapy for high-risk NB patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.201906426DOI Listing
May 2020

Inflammatory Infiltrate and Angiogenesis in Mantle Cell Lymphoma.

Transl Oncol 2020 Mar 29;13(3):100744. Epub 2020 Feb 29.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, Italy. Electronic address:

Mantle cell lymphoma (MCL) is an aggressive and rare B-cell non-Hodgkin lymphoma classified in two clinicopathological subtypes according to SOX11 expression and mutation state of immunoglobulin variable region heavy chain (IgVH) gene. The transcription factor SOX11, overexpressed in 78%-93% of MCL patients, plays a central role in modulating tumor microenvironment prosurvival signals and angiogenic genes. In this work, we have explored the lymph node microenvironment of three subgroups of MCL patients classified according to SOX11 expression as negative, light, and strong. CD34 microvessels, CD4 and CD8 T-lymphocytes, CD68 and CD163 macrophages, and the oncogene p53 expression were evaluated by immunohistochemistry. Moreover, STAT3 mRNA expression was analyzed by RNA-scope assay. Our results confirmed increased angiogenesis in the sample of patients positive to SOX11 compared to the negative ones and demonstrated that angiogenesis and SOX11 expression positively correlate to a higher T-lymphocytes inflammatory infiltrate. On the contrary, angiogenesis and SOX11 expression negatively correlate with macrophage's inflammatory infiltrate and p53 expression. STAT3 mRNA expression level was not relevant concerning angiogenesis or SOX11 expression. Overall, our data indicate that, in MCL, SOX11 expression is associated with increased angiogenesis and a high CD4 and CD8 T-cell infiltration, which are not sustained by CD163 macrophages infiltrate and p53 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tranon.2020.100744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052512PMC
March 2020

HB-EGF-EGFR Signaling in Bone Marrow Endothelial Cells Mediates Angiogenesis Associated with Multiple Myeloma.

Cancers (Basel) 2020 Jan 10;12(1). Epub 2020 Jan 10.

Department of Biomedical Sciences and Human Oncology, Guido Baccelli Unit of Internal Medicine, University of Bari Medical School, 70124 Bari, Italy.

Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF-EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF-EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF-EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12010173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017291PMC
January 2020

Epigenetic control of tumor angiogenesis.

Microcirculation 2020 04 8;27(3):e12602. Epub 2020 Jan 8.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

The term "epigenetic" is used to refer to heritable alterations in chromatin that are not due to changes in DNA sequence. Different growth factors and vascular genes mediate the angiogenic process, which is regulated by epigenetic states of genes. The aim of this article is to analyze the role of epigenetic mechanisms in the control and regulation of tumor angiogenetic processes. The reversibility of epigenetic events in contrast to genetic aberrations makes them potentially suitable for therapeutic intervention. In this context, DNA methyltransferase (DNMT) and HDAC inhibitors indirectly-via the tumor cells-exhibit angiostatic effects in vivo, and inhibition of miRNAs can contribute to the development of novel anti-angiogenesis therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/micc.12602DOI Listing
April 2020

RNAscope dual ISH-IHC technology to study angiogenesis in diffuse large B-cell lymphomas.

Histochem Cell Biol 2020 Mar 13;153(3):185-192. Epub 2019 Dec 13.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11 Policlinico, 70124, Bari, Italy.

Diffuse large B-cell lymphomas (DLBCLs) are the most common types of Non-Hodgkin's lymphomas and are highly heterogeneous in terms of phenotype and treatment response. The natural course of DLBCLs tumor progression is featured by a flow of events leading to the enhancement of proliferative and invasive capabilities and, therefore, towards the establishment of a more aggressive phenotype. Angiogenesis is a constant hallmark of DLBCLs progression, has prognostic potential and promote DLBCLs dissemination. The study of DLBCLs angiogenesis mechanisms, and the tumor endothelium characterization, will allow us to identify new prognostic/predictive biomarkers to proper patient selection to antiangiogenic treatment. In our previous work, by RNAscope technology, we have demonstrated that Janus kinase (Jak) and signal transducer activator of transcription pathway (STAT) is one of the proangiogenic pathways activated in DLBCLs and it drives neoangiogenesis occurred by vasculogenesis mechanism. Here, we describe a detailed protocol to perform RNAscope technology alone and in combination with immunohistochemistry (called dual RNAscope ISH-IHC) in DLBCLs formalin-fixed, paraffin-embedded sections. We propose dual ISH-IHC as an extremely powerful method to study angiogenesis in DLBCLs, because it allows one to answer important biological questions that are difficult to address using other single methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00418-019-01834-zDOI Listing
March 2020

Oxytocin regulates body composition.

Proc Natl Acad Sci U S A 2019 Dec 16. Epub 2019 Dec 16.

The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

The primitive neurohypophyseal nonapeptide oxytocin (OXT) has established functions in parturition, lactation, appetite, and social behavior. We have shown that OXT has direct actions on the mammalian skeleton, stimulating bone formation by osteoblasts and modulating the genesis and function of bone-resorbing osteoclasts. We deleted OXT receptors (OXTRs) selectively in osteoblasts and osteoclasts using and mice, respectively. Both male and female : mice recapitulate the low-bone mass phenotype of mice, suggesting that OXT has a prominent osteoblastic action in vivo. Furthermore, abolishment of the anabolic effect of estrogen in : mice suggests that osteoblastic OXTRs are necessary for estrogen action. In addition, the high bone mass in : mice indicates a prominent action of OXT in stimulating osteoclastogenesis. In contrast, we found that in pregnant and lactating : mice, elevated OXT inhibits bone resorption and rescues the bone loss otherwise noted during pregnancy and lactation. However, OXT does not contribute to ovariectomy-induced bone loss. Finally, we show that OXT acts directly on OXTRs on adipocytes to suppress the white-to-beige transition gene program. Despite this direct antibeiging action, injected OXT reduces total body fat, likely through an action on OXT-ergic neurons. Consistent with an antiobesity action of OXT, and mice display increased total body fat. Overall, the actions of OXT on bone mass and body composition provide the framework for future therapies for osteoporosis and obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1913611116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936484PMC
December 2019

Vascular Wall as Source of Stem Cells Able to Differentiate into Endothelial Cells.

Adv Exp Med Biol 2020 ;1237:29-36

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

The traditional view of the vascular biology is changed by the discovery of vascular progenitor cells in bone marrow or peripheral blood Further complexity is due to the findings that the vessel walls harbor progenitor and stem cells, called vascular wall-resident vascular stem cells (VW-VSCs), able to differentiate to mature vascular wall cells. These immature stem/progenitor cell populations and multipotent mesenchymal lineage participate in postnatal neovascularization and vascular wall remodeling. Further studies are necessary to deepen the knowledge on characterization and biology of VW-VSCs, in particular of endothelial progenitor cells (EPCs) in order to improve their use in clinical settings for regenerative approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/5584_2019_421DOI Listing
February 2020

Scleral ossicles: angiogenic scaffolds, a novel biomaterial for regenerative medicine applications.

Biomater Sci 2019 Dec;8(1):413-425

Department of Biomedical, Metabolic Science and Neuroscience, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Given the current prolonged life expectancy, various pathologies affect increasingly the aging subjects. Regarding the musculoskeletal apparatus, bone fragility induces more susceptibility to fractures, often not accompanied by good ability of self-repairing, in particular when critical-size defects (CSD) occur. Currently orthopedic surgery makes use of allografting and autografting which, however, have limitations due to the scarce amount of tissue that can be taken from the donor, the possibility of disease transmission and donor site morbidity. The need to develop new solutions has pushed the field of tissue engineering (TE) research to study new scaffolds to be functionalized in order to obtain constructs capable of promoting tissue regeneration and achieve stable bone recovery over time. This investigation focuses on the most important aspect related to bone tissue regeneration: the angiogenic properties of the scaffold to be used. As an innovative solution, scleral ossicles (SOs), previously characterized as natural, biocompatible and spontaneously decellularized scaffolds used for bone repair, were tested for angiogenic potential and biocompatibility. To reach this purpose, in ovo Chorioallantoic Membrane Assay (CAM) was firstly used to test the angiogenic potential; secondly, in vivo subcutaneous implantation of SOs (in a rat model) was performed in order to assess the biocompatibility and the inflammatory response. Finally, thanks to the analysis of mass spectrometry (LCMSQE), the putative proteins responsible for the SO angiogenic properties were identified. Thus, a novel natural biomaterial is proposed, which is (i) able to induce an angiogenic response in vivo by subcutaneous implantation in a non-immunodeficient animal model, (ii) which does not induce any inflammatory response, and (iii) is useful for regenerative medicine application for the healing of bone CSD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9bm01234fDOI Listing
December 2019

The chick embryo chorioallantoic membrane as an in vivo experimental model to study multiple myeloma.

Enzymes 2019 18;46:23-35. Epub 2019 Oct 18.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.

The chick embryo chorioallantoic membrane (CAM) has long been used as an in vivo assay for the study of tumor angiogenesis because when tumor grafts are placed at day 6-10 days of incubation the chick's immunocompetent system is not fully developed and the conditions for rejection have not been yet established. All studies for mammalian neoplasms, including multiple myeloma, have utilized tumor cell lines, tumor bioptic specimens, cell suspensions derived from tumors, mouse tumor xenografts bioptic specimens. CAM can also be used to study the effects of anti-angiogenic molecules on tumor cell suspensions of tumor bioptic specimens. This review article summarizes and discussed our experience concerning the use of the CAM to study multiple myeloma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.enz.2019.08.006DOI Listing
November 2019

Dp71 Expression in Human Glioblastoma.

Int J Mol Sci 2019 Oct 31;20(21). Epub 2019 Oct 31.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.

Background: Dp71 is the most abundant dystrophin () gene product in the nervous system. Mutation in the Dp71 coding region is associated with cognitive disturbances in Duchenne muscular dystrophy (DMD) patients, but the function of dystrophin Dp71 in tumor progression remains to be established. This study investigated Dp71 expression in glioblastoma, the most common and aggressive primary tumor of the central nervous system (CNS).

Methods: Dp71 expression was analyzed by immunofluorescence, immunohistochemistry, RT-PCR, and immunoblotting in glioblastoma cell lines and cells isolated from human glioblastoma multiforme (GBM) bioptic specimens.

Results: Dp71 isoform was expressed in normal human astrocytes (NHA) cell lines and decreased in glioblastoma cell lines and cells isolated from human glioblastoma multiforme bioptic specimens. Moreover, Dp71 was localized in the nucleus in normal cells, while it was localized into the cytoplasm of glioblastoma cells organized in clusters. We have shown, by double labeling, that Dp71 colocalizes with lamin B in normal astrocytes cells, confirming the roles of Dp71 and lamin B in maintaining nuclear architecture. Finally, we demonstrated that decreased Dp71 protein in cells isolated from human bioptic specimens was inversely correlated with the Ki-67 tumor proliferative index.

Conclusion: A decreased Dp71 expression is associated with cancer proliferation and poor prognosis in glioblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20215429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862465PMC
October 2019

Morphometric analysis of the branching of the vascular tree in the chick embryo area vasculosa.

Microvasc Res 2020 03 23;128:103935. Epub 2019 Oct 23.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy. Electronic address:

The chick embryo includes the area vasculosa is subdivided into 2 concentric zones, the inner transparent area pellucida vasculosa and the surrounding less transparent area opaca vasculosa, peripherally limited by the sinus terminalis. In this study, we have analyzed by a modern morphometric approach the total length of the vascular network, the number of vascular branches, of the branching points density, the modality of vessel ramification, and spatial arrangement of the vascular network in four consecutive stages of development of the area vasculosa. The results have shown that there is a significant 15% increase in the total length of the vascular network associated with a progressive increase of the number of vascular branches and of the branching points density. Moreover, the results indicated that vascular spatial disorder significantly decreased during development in area vasculosa, suggesting a more uniform occupancy of the tissue by the vascular pattern. Finally, a more regular pattern of branching was observed, as indicated by the significant decrease of topological disorder of the vascular tree.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mvr.2019.103935DOI Listing
March 2020

STAT3, tumor microenvironment, and microvessel density in diffuse large B cell lymphomas.

Leuk Lymphoma 2020 03 17;61(3):567-574. Epub 2019 Oct 17.

Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, University of Bari Medical School, Bari, Italy.

Constitutively activated STAT3 is correlated with more advanced clinical stage and overall poor survival of diffuse large B-cell lymphoma (DLBCL). The aim of this study was to evaluate STAT3 and Ki67 tumor cell expression, inflammatory cell infiltration, microvascular density in DLBCL bioptic specimens. RNA-scope showed that activated B cell (ABC) tissue samples contained a significant higher number of STAT3+ cells as compared to germinal center B (GCB) tissue samples. Immunohistochemical analysis showed a significant increased levels of CD3, CD8, CD68, CD163, CD34, and Ki67 positive cells in ABC patients. A positive correlation between STAT3 and CD3, CD8, CD68, and CD163 was evidenced in ABC group. In ABC group, we found also a positive correlation between CD8 and CD34 and a positive correlation between Ki67 and, CD68, and CD163. These data indicate that in ABC-as compared to GCB-DLBCL, a higher STAT3 expression is associated with a higher CD163+ TAM and CD8+ cell infiltration which induces a strong angiogenic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2019.1678154DOI Listing
March 2020

Polyacrylate/polyacrylate-PEG biomaterials obtained by high internal phase emulsions (HIPEs) with tailorable drug release and effective mechanical and biological properties.

Mater Sci Eng C Mater Biol Appl 2019 Dec 8;105:110060. Epub 2019 Aug 8.

Department of Drug Sciences, University of Pavia, Viale Taramelli 12-14, Pavia 27100, Italy. Electronic address:

The paper focuses on the preparation of polyacrylate based biomaterials designed as patches for dermal/transdermal drug delivery using materials obtained by the high internal phase emulsion (HIPE) technique. In particular, butyl acrylate and glycidyl methacrylate were selected, respectively, as backbone and functional monomer while two different crosslinkers, bifunctional or trifunctional, were used to form the covalent network. The influence of PEG on the main properties of the materials was also investigated. The obtained materials show a characteristic and interconnected internal structure as confirmed by SEM studies. By an industrial point of view, an interesting feature of this system is that it can be shaped as needed, in any form and thickness. The physiochemically characterized materials showed a tailorable curcumin (model of hydrophobic drugs) drug release, effective mechanical properties and cell viability and resulted neither pro nor anti-angiogenic as demonstrated in vivo by the chick embryo choriallantoic membrane (CAM) assay. Based on these results, the obtained polyHIPEs could be proposed as devices for dermal/transdermal drug delivery and/or for the direct application on wounded skin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msec.2019.110060DOI Listing
December 2019

PTX3 Modulates Neovascularization and Immune Inflammatory Infiltrate in a Murine Model of Fibrosarcoma.

Int J Mol Sci 2019 Sep 17;20(18). Epub 2019 Sep 17.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, P.zza Giulio Cesare 11, 70124 Bari, Italy.

Fibrosarcoma is an aggressive subtype of soft tissue sarcoma categorized in infantile/congenital-type and adult-type. Fibrosarcoma cells and its surrounding immune inflammatory infiltrates overexpress or induce the expression of fibroblast growth factor-2 (FGF-2) that have a crucial role in tumor progression and angiogenesis. The inflammation-associated long pentraxin 3 (PTX3) was found to reduce FGF-2-mediated angiogenesis, but its role on fibrosarcoma immune inflammatory infiltrate is still unknown. In this study, we have evaluated the PTX3 activity on immune infiltrating mast cells, macrophages and T-lymphocytes by immunohistochemistry on murine MC-TGS17-51 fibrosarcoma cells and on transgenic TgN(Tie2-hPTX3) mouse. In these fibrosarcoma models we found a reduced neovascularization and a significant decrease of inflammatory infiltrate. Indeed, we show that PTX3 reduces the level of complement 3 (C3) deposition reducing fibrosarcoma progression. In conclusion, we hypothesize that targeting fibrosarcoma microenvironment by FGF/FGFR inhibitors may improve treatment outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20184599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770794PMC
September 2019

Surface markers: An identity card of endothelial cells.

Microcirculation 2020 01 12;27(1):e12587. Epub 2019 Sep 12.

Department of Medicine, Section of Human Anatomy, University of Udine, Udine, Italy.

All endothelial cells have the common characteristic that they line the vessels of the blood circulatory system. However, endothelial cells display a large degree of heterogeneity in the function of their location in the vascular tree. In this article, we have summarized the expression patterns of a number of well-accepted endothelial surface markers present in normal microvascular endothelial cells, arterial and venous endothelial cells, lymphatic endothelial cells, tumor endothelial cells, and endothelial precursor cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/micc.12587DOI Listing
January 2020

The morphological basis of the development of the chick embryo immune system.

Exp Cell Res 2019 08 26;381(2):323-329. Epub 2019 May 26.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.

The chick immune system is a fundamental model in basic immunology. In birds, the bone marrow derived pluripotent stem cells after entering the circulation, migrate to bursa of Fabricius to benefit from a microenvironment which supports the differentiation and maturation of B lymphocytes by the help of its resident cells and tissues. Delivering sufficient functional B cells is required to maintain their peripheral population and normal peripheral humoral responses. Additionally, bursa acts as an active site for the generation of antibody diversity through gene conversion. Being consisted of 98% B lymphocytes, the organ is occupied by other cell types including T cells, macrophages, eosinophils and mast cells. Thymus, which is an epithelial organ is the main site of T cell development where positive and negative selections contribute to the development of functional and not autoreactive T cell repertoire. Bursectomy and thymectomy are surgical exercises through which the involvement of cells of specific immunity including B cells and T cells can be determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexcr.2019.05.027DOI Listing
August 2019

Limitations of Anti-Angiogenic Treatment of Tumors.

Transl Oncol 2019 Jul 20;12(7):981-986. Epub 2019 May 20.

Department of Medicine, Section of Human Anatomy, University of Udine, Italy.

Clinical trials using anti-vascular endothelial growth factor /(VEGF) molecules induce a modest improvement in overall survival, measurable in weeks to just a few months, and tumors respond differently to these agents. In this review article, we have exposed some tumor characteristics and processes that may impair the effectiveness of anti-angiogenic approaches, including genotypic changes on endothelial cells, the vascular normalization phenomenon, and the vasculogenic mimicry. The usage of anti-angiogenic molecules leads to hypoxic tumor microenvironment which enhances tumor invasiveness. The role of tumor-infiltrating cells, including tumor associated macrophages and fibroblasts (TAMs and TAFs) in the therapeutic response to anti-angiogenic settings was also highlighted. Finally, among the new therapeutic approaches to target tumor vasculature, anti-PD-1 or anti-PD-L1 therapy sensitizing and prolonging the efficacy of anti-angiogenic therapy, have been discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tranon.2019.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529826PMC
July 2019

Angiogenesis in Pancreatic Cancer: Pre-Clinical and Clinical Studies.

Cancers (Basel) 2019 Mar 18;11(3). Epub 2019 Mar 18.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, 70124 Bari, Italy.

Angiogenesis is a crucial event in tumor development and progression, occurring by different mechanisms and it is driven by pro- and anti-angiogenic molecules. Pancreatic cancer vascularization is characterized by a high microvascular density, impaired microvessel integrity and poor perfused vessels with heterogeneous distribution. In this review article, after a brief introduction on pancreatic cancer classification and on angiogenesis mechanisms involved in its progression, the pre-clinical and clinical trials conducted in pancreatic cancer treatment using anti-angiogenic inhibitors will be described. Finally, we will discuss the anti-angiogenic therapy paradox between the advantage to abolish vessel supply to block tumor growth and the disadvantage due to reduction of drug delivery at the same time. The purpose is to identify new anti-angiogenic molecules that may enhance treatment regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11030381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468440PMC
March 2019