Multiple myeloma plasma cells home and expand in the bone marrow where cause an unbalanced bone remodelling with increased bone resorption and low bone formation that represent the typical feature in the majority of patients. A clinically relevant aspect of the interactions of multiple myeloma plasma cells in the bone marrow microenvironment is neovascularization, a constant hallmark of disease progression. This process is only partially supported by factors such as vascular endothelial growth factor, fibroblast growth factor-2 and metalloproteinases, which are directly secreted by the tumor cells. In fact, the presence in the bone marrow microenvironment of cytokines, in particular interleukin-6, as a consequence of plasma cell-stromal cell interactions, induces the production and secretion of angiogenic factors by other cells present in the bone microenvironment, thus contributing to the angiogenic switch during the progression of the disease. Near angiogenesis vasculogenesis occur in the bone marrow of myeloma patients and contribute to the vascular three formation. In the bone marrow of myeloma patients haematopoietic stem cells are recruited and induced to differentiate into endothelial cells by the angiogenic cytokines present in the microenvironment. Myeloma plasma cells also induce angiogenesis indirectly via recruitment and activation of stromal inflammatory cells (i.e.: macrophages and mast cells) to secrete their own angiogenic factors. They are recruited and activated by tumor plasma cells through the secretion of fibroblast growth factor-2, interleukin-8, and other chemokines, such as ITAC, Mig, IP-10. When macrophages and mast cells are activated they secrete their angiogenic factors: fibroblast growth factor-2, vascular endothelial growth factor, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, which contribute to enhance the tumor neovascularization. Finally, myeloma macrophages when exposed to vascular endothelial growth factor and fibroblast growth factor-2 secreted by plasma cells shows vasculogenic ability and acquire endothelial cell markers and transform into cells functionally and phenotypically similar to paired bone marrow endothelial cells. So they participate to the formation of the bone marrow capillary network (vasculogenic mimicry).

Bone marrow angiogenesis and progression in multiple myeloma

Careful examination of relevant literature shows that many of the most cherished concepts of the blood-brain barrier are incorrect. These include an almost mythological belief in its immaturity that is unfortunately often equated with absence or at least leakiness in the embryo and fetus. The original concept of a blood-brain barrier is often attributed to Ehrlich; however, he did not accept that permeability of cerebral vessels was different from other organs. Goldmann is often credited with the first experiments showing dye (trypan blue) exclusion from the brain when injected systemically, but not when injected directly into it. Rarely cited are earlier experiments of Bouffard and of Franke who showed methylene blue and trypan red stained all tissues except the brain. The term “blood-brain barrier” “Blut-Hirnschranke” is often attributed to Lewandowsky, but it does not appear in his papers. The first person to use this term seems to be Stern in the early 1920s. Studies in embryos by Stern & colleagues, Weed and Wislocki showed results similar to those in adult animals. These were well-conducted experiments made a century ago, thus the persistence of a belief in barrier immaturity is puzzling. As discussed in this review, evidence for this belief, is of poor experimental quality, often misinterpreted and often not properly cited. The functional state of blood-brain barrier mechanisms in the fetus is an important biological phenomenon with implications for normal brain development. It is also important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all the evidence and assessing its quality, rather than selecting papers that supports a preconceived notion or intuitive belief. This review attempts to right the wrongs. Based on car

/pdf/the-rights-and-wrongs-of-blood-brain-barrier-permeability-4sxqg3lyb6.pdf

The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

The structural and functional development of the choroid plexuses, the site of the blood-cerebrospinal fluid (CSF) barrier, in an opossum (Monodelphis domestica) was studied. Marsupial species are extremely immature at birth compared with more conventional eutherian species. Choroid plexus tissue of each brain ventricle, from early stages of development, was collected for light and electron microscopy. During development, the choroidal epithelium changes from a pseudostratified to a cuboidal layer. Individual epithelial cells appear to go through a similar maturation process even though the timing is different between and within each plexus. The ultrastructural changes during development in the choroidal epithelial cells consist of an increase in the number of mitochondria and microvilli, and changes in structure of endoplasmic reticulum. There are also changes in the core of plexuses with age. In contrast, the structure of the tight junctions between epithelial cells does not appear to change with maturation. In addition, the route of penetration for lipid insoluble molecules from blood to CSF across the choroid plexuses was examined using a small biotin-dextran. This showed that the tight junctions already form a functional barrier in early development by preventing the paracellular movement of the tracer. Intracellular staining shows that there may be a transcellular route for these molecules through the epithelial cells from blood to CSF. Apart from lacking a glycogen-rich stage, cellular changes in the developing opossum plexus seem to be similar to those in other species, demonstrating that this is a good model for studies of mammalian choroid plexus development.

Structural characteristics and barrier properties of the choroid plexuses in developing brain of the opossum (Monodelphis Domestica).

We examined the role of hypoxia and HIF factors in embryonic angiogenesis and correlated the degree of hypoxia with the level of HIF and VEGF expression and blood vessel formation. Quail eggs were incubated in normoxic and hypoxic (16% O(2)) conditions. Tissue hypoxia marker, pimonidazol hydrochloride, was applied in vivo for 1 hr and detected in sections with Hypoxyprobe-1 Ab. VEGF and HIF expression was detected by in situ hybridization. HIF-1alpha protein was detected in sections and by Western blot. Endothelial cells were visualized with QH-1 antibody. Hypoxic regions were detected even in normoxic control embryos, mainly in brain, neural tube, branchial arches, limb primordia, and mesonephros. The expression patterns of HIF-1alpha and HIF-1beta factors followed, in general, the Hypoxyprobe-1 marked regions. HIF-2alpha was predominantly expressed in endothelial cells. Diffuse VEGF expression was detected in hypoxic areas of neural tube, myocardium, digestive tube, and most prominently in mesonephros. Growing capillaries were directed to areas of VEGF positivity. Hypoxic regions in hypoxic embryos were larger and stained more intensely. VEGF and HIF-1 factors were proportionately elevated in Hypoxyprobe-1 marked regions without being expressed at new sites and were followed by increased angiogenesis. Our results demonstrate that normal embryonic vascular development involves the HIF-VEGF regulatory cascade. Experimentally increasing the level of hypoxia to a moderate level resulted in over-expression of HIF-1 factors and VEGF followed by an increase in the density of developing vessels. These data indicate that embryonic angiogenesis is responsive to environmental oxygen tension and, therefore, is not entirely genetically controlled.

/pdf/experimental-hypoxia-and-embryonic-angiogenesis-33c1xolv2s.pdf

Experimental hypoxia and embryonic angiogenesis.

To determine the effect of chronic hypoxia on myocardial capillarity, we exposed pregnant ewes to an altitude of 3,820 m from day 30 today 139 of gestation and compared the fetus to low-altitude (∼...

Effects of long-term, high-altitude hypoxia on the capillarity of the ovine fetal heart

The consequences of long-term O2 deprivation on heart development were analyzed morphometrically and ultrastructurally, utilizing the hearts of chicken embryos developed under hypoxia from the 3rd to the 18th incubation day. The results indicate that embryos kept under low O2 blood tension do not show disturbances in heart morphohistogenesis, but are characterized by a thicker epicardium and a thinner myocardium than the controls; moreover, both the number and calibre of the heart microvessels are increased. The thickening of the epicardium is due to hyperplasia of the mesothelial cells, increment in calibre of the submesothelial vessels, and to conspicuous perivascular infiltration of blood-derived cells. The thinning of the cardiac muscle seems to be dependent on myocardiocyte hypotrophy and myofibril reduction. The increase in the volume density of myocardium vessels, due to their dilatation and proliferation, may be considered expression of a vascular adaptive reaction to low oxygen tissue concentration.

The effects of long-term hypoxia on epicardium and myocardium in developing chick embryo hearts.

The development of the blood-cerebrospinal fluid (CSF) and cerebrospinal fluid-blood barriers, and the differentiation of the choroidal vessel wall, have been ultrastructurally investigated in the choroidal plexuses of the lateral ventricles of 10, 15, 18 and 21 day chicken embryos, fixed in normal conditions and also after intracardial and intraventricular injection of horseradish peroxidase. In all the analyzed developmental stages the choroidal epithelial cells seem able to endocytose and degradate, in their lysosomal apparatus, the tracer molecules reaching their ventricular and basolateral sides. The intravascularly injected horseradish peroxidase can enter the ventricular cavity by interepithelial route only at 10th incubation day, when the tight intercellular junctions are not formed everywhere, while a transepithelial transport is always hindered. The marker injected into the ventricular cavity reaches the subepithelial compartment and the blood stream, at 10th incubation day by interepithelial as well as transepithelial route and, successively, by transepithelial vesicular transport alone. The differentiation processes undergone by the choroidal blood vessels consist in a progressive thinning of the endothelial cells, appearance of pores, already numerous at 15th incubation day, and formation of the endothelial basement lamina, the final event in vessel wall maturation.

The barrier systems in the choroidal plexuses of the chick embryo studied by means of horseradish peroxidase

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The effects of long-term hypoxia on epicardium and myocardium in developing chick embryo hearts.

The barrier systems in the choroidal plexuses of the chick embryo studied by means of horseradish peroxidase