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

An image analysis of the spatial distribution of perivascular mast cells in human melanoma

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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)

"Sprouting angiogenesis", a reappraisal

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Stromal cell organisation in the mouse lymph node. A light and electron microscopic investigation using the zinc iodide-osmium technique

The organisation of the stromal cell compartment in the mouse lymph node was studied by light and electron microscopy after tissue impregnation by the zinc iodide-osmium (ZIO) method. Fibroblastic reticular cells (FRCs) represented the main stromal cell population. These cells were located both in the cortical region and in the medulla and exhibited various configurations. In the cortex, FRCs were fusiform in shape and came into close proximity with the floor of the subcapsular sinus. In the medulla, the FRCs were shaped like irregular dendritic cells which formed a complex 3-dimensional network. The FRCs surrounded vascular structures such as capillaries and/or high endothelial venules; in these instances they were organised in a discontinuous sheath-like fashion around the vessel wall. By light and electron microscopy, FRCs have been observed to come in close spatial relationship with a number of cells in the lymph node, including sinus endothelial cells, the endothelium of high endothelial venules and capillaries, various types of lymphocytes, follicular dendritic cells and interdigitating cells. These microanatomical features are consistent with the proposal that FRCs may be involved in the communicative networks between the different lymph node compartments. In particular, the FRCs may be involved in the transport of molecules from the sinus compartment to the high endothelial venules or to the distinct cell populations in the lymphoid parenchyma