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. In this study, we show that recombinant FGF2 is able to cause mast cell recruitment in vivo in the Matrigel plug assay. Conversely, PTX3 overexpression in transgenic mice or treatment with the FGF inhibitor NSC12 result in a significant inhibition of the growth and vascularization of TRAMP-C2 tumor grafts, a murine model of prostate cancer, that were paralleled by a decrease of mast cell infiltrate into the lesion. These data confirm and extend previous observations about the capacity of mast cells to respond chemotactically to FGF2 stimulation and provide evidence about a relationship among mast cell recruitment, angiogenesis, and tumor growth in human prostate adenocarcinom

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. 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

Proteolytic Activity of Human Lymphoid Tumor Cells. Correlation with Tumor Progression

Matrix metalloproteinase (MMP) expression and production are associated with advanced-stage tumor and contribute to tumor progression, invasion and metastases. The current study was designed to determine the expression and production of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) by human lymphoid tumor cells. Changes in expression and production were also investigated during tumor progression of multiple myeloma and mycosis fungoides. In situ hybridization analysis revealed that lymphoblastic leukemia B cells (SB cell line), multiple myeloma (MM) cells (U266 cell line) and lymphoblastic leukemia T cells (CEM and Jurkat cell lines) express constitutively the mRNA for MMP-2 and/or MMP-9. We demonstrated by gelatin-zymography of cell culture medium that both enzymes were secreted in their cleaved (activated) form. In situ hybridization of bone marrow plasma cells and gelatin- zymography of the medium showed that patients with active MM (diagnosis, relapse, leukemic progression) express higher levels of MMP-2 mRNA and protein than patients with non-active MM (complete/objective response, plateau) and with monoclonal gammopathies of undetermined significance (MGUS). MMP-9 expression and secretion was similar in all patient groups. In patients with mycosis fungoides (MF), the expression of MMP-2 and MMP-9 mRNAs was significantly upregulated with advancing stage, in terms of lesions both positive for one of two mRNAs and with the greatest intensity of expression. Besides MF cells, the MMP-2 and/or MMP-9 mRNAs were expressed by some stromal cell populations (microvascular endothelial cells, fibroblasts, macrophages), suggesting that these cells cooperate in the process of tumor invasion. Our studies identify MMPs as an important class of proteinases involved in the extracellular matrix (ECM) degradation by human lymphoid tumors, and suggest that MMPs inhibitors may lead to important new treatment for their control

New insights in Diffuse Large B Cell Lymphoma Pathobiology

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

Inflammatory Cells in Diffuse Large B Cell Lymphoma

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

Role of erythropoietin in the angiogenic activity of bone marrow endothelial cells of MGUS and multiple myeloma patients

Increasing evidences suggest several biological roles for erythropoietin and its receptor (Epo and EpoR), unrelated to erythropoiesis, including angiogenesis. Here, we detected the expression of EpoR in bone marrow-derived endothelial cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients (MGECs and MMECs, respectively) and assessed whether Epo plays a role in MGECs- and MMECs-mediated angiogenesis. We show that EpoR is expressed by both MGECs and MMECs even though at a higher level in the first ones. Both EC types respond to rHuEpo in terms of cell proliferation, whereas other responses, including activation of JAK2/STAT5 and PI3K/Akt pathways, cell migration and capillarogenesis are enhanced by Epo in MGECs, but not in MMECs. In addition, the conditioned media of both Epo-treated cells induce a strong angiogenic response in vivo in the chorioallantoic membrane assay, comparable to that of vascular endothelial growth factor (VEGF). Overall, these data highlight the effect of Epo on MGECs- and MMECs-mediated angiogenesis: MGECs are more responsive to Epo treatment than MMECs, probably because over-angiogenic phenotype of MMECs is already activated by their autocrine/paracrine loops occurring in the "angiogenic switch" from MGUS

Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma

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Prednisolone restores blood brain barrier damages in dystrophic MDX mouse

Although the glucocorticoids delay the progression of Duchenne muscular dystrophy (DMD) their mechanism of action is unknown. In our previous studies we demonstrated that in the mdx mice, an animal model of DMD, besides the muscle degeneration, serious damages of the blood-brain barrier (BBB) occur taking to enhanced vessels permeability and brain edema (1). Moreover, we observed that the mdx mice after α–methyl-prednisolone (PDN) treatment ameloriated the histopathological profiles and the excitation-contraction of the myofibers (2). In this study, we evaluated the effects of the PDN on the BBB of the mdx mice, by estimating the immunocytochemical and biochemical expression of endothelial ZO-1 and occludin, pericyte desmin, and glial GFAP and short dystrophin isoform Dp 71 proteins, used as BBB markers. In addition, we analyzed the expression of dystrophin associate proteins (DAPs) aquaporin-4 (AQP4) and α-β dystroglycan in parallel in both brain and muscles of PDN treated mdx as well as in control mice. Results showed in mdx PDN treated mice a significant increase of the mRNA and protein content of all the glial, pericyte and endothelial proteins as compared to untreated mdx. Moreover, by immunoprecipitation we demonstrated that the BBB alteration in the mdx mice were coupled with enhanced occludin and AQP4 phosphorylation degree which, instead, was reduced after PDN treatment. Finally we observed that AQP4 and α-β dystroglycan complex increases its mRNA and protein content in both PDN mdx brain and muscle fibers, compared with mdx mice where the perivascular glial membranes and the myofibers showed a light staining after immunofluorescence analysis . These data indicate that the PDN restores the BBB damages in the mdx mice by inducing in the glial cell the expression of GFAP, AQP4 and Dp71 proteins and in the pericytes and endothelial cells, of the desmin and ZO-1 proteins, which are deficient in the distrophic mice. Moreover, the reduction in the AQP4 and occludin phosphorylation degree coupled with their ankoring to glial and endothelial membranes in the PDN mdx mice suggests that the glial and endothelial cells may be a cellular target of the drug. Finally, the enhanced expression of DAPs AQP4 and α-β dystroglycan in both brain and myofibers of PDN treated mdx mice compared to untreated mdx ones suggest the PDN might ameliorate the brain vessels and muscles functions of the dystrophic mice by a restoring a correct links between DAPs proteins and the extracellular matrix. 1. Nico B et al. Glia, 42: 235-251. (2003). 2. Cozzoli A. et al., Neuropathol. Appl. Neurobiol. 37, 243-256 (2011)