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

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.

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

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.

Dp71 Expression in Human Glioblastoma.

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).

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

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.

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

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.

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

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.

Surface markers: An identity card of endothelial cells.

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.

Limitations of Anti-Angiogenic Treatment of Tumors.

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.

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

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.

Inflammatory cells infiltrate and angiogenesis in locally advanced and metastatic cholangiocarcinoma.

Background: Cholangiocarcinoma (CCA) is the second most common subtype of primary hepatobiliary cancer and one of the most aggressive characterized by an extremely poor prognosis with limited treatment options. Inflammatory cells in tumour microenvironment support tumour growth in term of progression, angiogenesis and metastatic capacity. A link between inflammation and biliary carcinogenesis has been previously observed but the mechanisms involved remain to be determined.

Microvascular density, macrophages, and mast cells in human clear cell renal carcinoma with and without bevacizumab treatment.

Background: Clear cell renal cell carcinoma (ccRCC) represents a highly vascularized aggressive kidney cancer. Due to ccRCC chemotherapy resistance, antiangiogenesis is one of the most innovative targeted therapies for this tumor. The tumor microenvironment exerts important roles in tumor growth, angiogenesis, and metastatic escape.

α-Methyl-prednisolone normalizes the PKC mediated brain angiogenesis in dystrophic mdx mice.

A fraction of patients affected by Duchenne Muscular Dystrophy (DMD) shows mental disability as a consequence of neuronal and metabolic alteration. In this study, we evaluated the effect of α-methyl-prednisolone (PDN) on the expression of the angiogenic marker HIF1α, VEGFA and VEGFR-2 (FLK1) in correlation with PKC expression in the brain of mdx mouse, an experimental model of DMD. We demonstrated that HIF1α, VEGFA and FLK1 are overexpressed in the brain of dystrophic mdx mice in parallel with an increase of PKC expression and reduction of the tight junctions Occludin leading to altered angiogenesis.

DP71 and SERCA2 alteration in human neurons of a Duchenne muscular dystrophy patient.

Cognitive deficit has been identified in one third of patients affected by Duchenne Muscular Dystrophy, primarily attributed to loss of the short Dp71 dystrophin, the major brain dystrophin isoform. In this study, we investigated for the first time the Dp71 and Dp71-associated proteins cellular localization and expression in human neurons obtained by differentiation from induced pluripotent stem cell line of a patient affected by cognitive impairment. We found structural and molecular alterations in both pluripotent stem cell and derived neurons, reduced Dp71 expression, and a Ca cytoplasmic overload in neurons coupled with increased expression of the SERCA2 pump in the dystrophic neurons.

STAT-3 RNAscope Determination in Human Diffuse Large B-Cell Lymphoma.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription with many important functions, including regulation of cell proliferation, differentiation, survival, angiogenesis, and immune response.

Materials And Methods: In this study, we have compared by means of RNAscope technology STAT3 RNA expression in human DLBCL in a selected group of activated B-cell-like DLBCL (ABC-DLBCL) patients with another group of germinal center B-cell-like DLBCL (GBC-DLBCL) patients.

Erythropoietin in tumor angiogenesis.

Erythropoietin (EPO) is a moonlighting protein since is ability to work as hormone, cytokine and growth factor. Its cardinal function is to regulate erythropoiesis in the bone marrow. However, EPO with his receptor EPOR are expressed also in non-hematopoietic tissues such as endothelium where they exert a protective function.

Mast cells and primary systemic vasculitides.

Vasculitides are characterized by inflammation and necrosis of blood vessels leading to vessel occlusion and ischemic damages of tissues. Among the inflammatory cells involved in vasculitides, neutrophils, T cells, and macrophages have been identified as the predominant cell type. This review article is focused on the role of mast cells in these chronic inflammatory processes.

Bcl6/p53 expression, macrophages/mast cells infiltration and microvascular density in invasive breast carcinoma.

To better understand the breast cancer progression and therapeutic resistance is crucial deepen the molecular mechanisms related to regulation of cells behavior in the tumor microenvironment. Inappropriate expression or activation of transcription factors in tumor breast microenvironment can lead to the malignant behavior of breast cancer cells. Bcl6 is a transcriptional factor that may play a role in the pathogenesis of breast cancer.

VEGFA and VEGFR2 RNAscope determination in gastric cancer.

Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death worldwide. Several studies on angiogenic blocking agents in gastric cancer revealing promising results by the use of monoclonal antibodies against VEGFA or its receptor VEGFR2 or against VEGFA activating pathway. The validation of biomarkers useful to better organize the clinical trials involving anti-angiogenic therapies is crucial.

Rhu-Epo down-regulates pro-tumorigenic activity of cancer-associated fibroblasts in multiple myeloma.

We have previously demonstrated that recombinant human erythropoietin (rHuEpo) is involved in the regulation of the angiogenic response in multiple myeloma (MM) through a direct effect on macrophages and endothelial cells isolated from the bone marrow of patients with MM. The aim of the present study was designed to determine the effects of rHuEpo on cancer-associated fibroblasts (CAFs) from monoclonal gammopathy of undetermined significance (MGUS) and MM patients by means of in vitro and in vivo assays. rHuEpo treatment reduces the expression of mRNA levels of fibroblast activation markers, namely alpha smooth actin (αSMA) and fibroblast activation protein (FAP) in MGUS and MM CAFs, and of pro-inflammatory and pro-angiogenic cytokines, including interleukin (IL)-6 and IL-8, vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF) in MM CAFs.

Reduced myofilament component in primary Sjögren's syndrome salivary gland myoepithelial cells.

Primary Sjögren's syndrome (pSS) is a solitary poorly understood autoimmune inflammatory disease by involvement of the salivary and lacrimal glands resulting in dry mouth and dry eyes. Myoepithelial cells (MECs) are cells knowing for its hybrid epithelial and mesenchymal phenotype that are important components of the salivary gland (SGs) structure aiding the expulsion of saliva from acinar lobules. In this study we investigate possible alteration in the myofilament component of MECs in SGs specimens obtained from pSS patients in comparison with healthy subjects, to evaluate MECs hypothetical involvement in the pathogenesis of pSS.

Fibroblast growth factor modulates mast cell recruitment in a murine model of prostate cancer.

Mast cells are important modifiers of prostate tumor microenvironment. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system plays a non-redundant autocrine/paracrine role in the growth, vascularization and progression of prostate tumors. Accordingly, the FGF antagonist long pentraxin-3 (PTX3) and the PTX3-derived small molecule FGF-trap NSC12 have been shown to inhibit the growth and vascularization of different FGF-dependent tumor types, including prostate cancer.

Spatial distribution of mast cells and macrophages around tumor glands in human breast ductal carcinoma.

Macrophages and mast cells are usually present in the tumor microenvironment and play an important role as regulators of inflammation, immunological response and angiogenesis in the tumor microenvironment. In this study, we have evaluated macrophage, mast cell, and microvessel density in a selected group of different grade of invasive breast carcinoma tumor specimens. Furthermore, we have investigated the pattern of distribution of CD68-positive macrophages and tryptase-positive mast cells around tumor glands.

Abnormal distribution of AQP4 in minor salivary glands of primary Sjögren's syndrome patients.

A decreased saliva production occurs in primary Sjögren's syndrome (pSS), an autoimmune disease characterized by oral and ocular dryness due to dysfunction of the lacrimal and salivary glands (SGs). Since water movement is involved in saliva secretion, the expression, localization, and function of the water channels aquaporins (AQPs) have been extensively studied in SGs. To date, the presence of AQP4 remains controversial and ambiguous in human SGs.

Mast cells in breast cancer angiogenesis.

Mast cells, accumulate in the stroma surrounding certain tumors and take part to the inflammatory reaction occurring at the periphery of the tumor. Mast cell-secreted angiogenic cytokines facilitate tumor vascularization not only by a direct effect but also by stimulating other inflammatory cells of the tumor microenvironment to release other angiogenic mediators. An increased number of mast cells have been demonstrated in angiogenesis associated with solid tumors, including breast cancer.

Stat3-positive tumor cells contribute to vessels neoformation in primary central nervous system lymphoma.

With the aim of elucidating the relationship between Stat3 expression and tumor vessels abnormalities in the PCNLs, in this study we evaluated Stat3 and pStat3 expression by Real-time PCR and by immunohistochemistry in biopsy sections from PCNSL patients. Correlations of the expression levels with the presence of aberrant vessels were analyzed by confocal laser microscopy analysis, using FVIII as endothelial cell marker, CD133 and nestin as cancer stem cell (CSC) marker, CD20 as tumor cell marker, and Stat3. In addition, we investigated Stat3 mutations in lymphoma cells to clarify the role of the constitutive expression of Stat3 and of its phosphorylated forms.