Endometriotic disease: the role of peritoneal fluid.
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Peritoneal fluid and the intraovarian milieu are a specific microenvironment. Peritoneal fluid originates mainly as an ovarian exudation product caused by increased vascular permeability, with cyclic variation in volume and steroid hormones which are always higher than in plasma. It contains large amounts of macrophages and their secretion products, and has a large exchange area with plasma through the peritoneum, which is highly permeable for small molecules. Diffusion becomes virtually zero for molecules with a molecular weight of >100000 Da. In women with the luteinized unruptured follicle (LUF) syndrome, concentrations of oestrogens and progesterone are much lower in the luteal phase. Endometriosis is associated with sterile low-grade inflammation, increased concentrations of activated macrophages and many of their secretions, such as cytokines, growth factors and angiogenic factors. Concentrations of CA-125 and of glycodelins are also increased, secreted locally by the endometrial cells. Natural killer (NK) cell function declines, possibly mediated by glycodelins or local intercellular adhesion molecule (ICAM) -1 shedding. The ovary is also a specific microenvironment, with steroid hormone concentrations 1000-fold higher in follicles than in plasma. Endometrial and superficially implanted cells are influenced by peritoneal fluid concentrations so that local environment, rather than inherent cellular differences could explain differences between superficial endometriosis and eutopic endometrium. Differences between superficial implants and endometriotic disease, deep infiltrating or cystic ovarian endometriosis, may thus arise via different endocrine environments. Superficial endometrial implants are regulated by peritoneal fluid factors, whereas deep endometriosis and cystic ovarian endometriosis are influenced by blood or ovarian factors. The endometriotic disease theory considers superficial endometriotic implants and their remodelling as a physiological process in most women, and concentrates on the causes of severe endometriosis such as differences in the eutopic endometrium from women with and without endometriosis (which may indicate hereditary differences), the invasiveness of some endometriotic cells in vitro, focal 'shielding' of endometriotic foci by adhesions, and inhibition of NK activity by ICAM-1 and glycodelins. Endometriotic disease is thus seen as a benign tumour. The type of cellular lesion, hereditary and immunological environments and local hormone concentrations in the ovary and in peritoneal fluid, will decide expression as cystic ovarian endometriosis, deep endometriosis or adenomyosis externa, and whether the latter is associated with adhesions. (+info)
Stimulation of tumour growth by wound-derived growth factors.
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The goal of this work was to determine the molecular basis for the induction of tumour vascularization and progression by injury. Magnetic resonance imaging (MRI) studies demonstrated that administration of wound fluid derived from cutaneous injuries in pigs reduced the lag for vascularization and initiation of growth of C6 glioma spheroids, implanted in nude mice, and accelerated tumour doubling time. The former effect can be attributed to the angiogenic capacity of wound fluid as detected in vivo by MRI, and in vitro in promoting endothelial cell proliferation. The latter effect, namely the induced rate of tumour growth, is consistent with the angiogenic activity of wound fluid as well as with the finding that wound fluid was directly mitogenic to the tumour cells, and accelerated growth of C6 glioma in spheroid culture. Of the multiple growth factors present in wound fluid, two key factors, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and platelet-derived growth factor (PDGF), were identified as the dominant mitogens for C6 glioma, and inhibition of their activity using specific neutralizing antibodies suppressed the mitogenic effect of wound fluid on DNA synthesis in C6 glioma. This study suggests that the stimulatory effect of injury on tumour progression can possibly be attenuated by therapeutic targeting directed against a limited number of specific growth factors. (+info)
Hypoxia-induced up-regulation of angiogenin in human malignant melanoma.
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Angiogenesis is essential for tumor progression and metastasis, however, the angiogenesis regulators that are biologically relevant for human melanoma are still unknown. In this study, we analyzed the expression of the potent angiogenic factor angiogenin (ANG) in human melanoma in vitro and in vivo. Four different human melanoma cell lines and two normal melanocytes were kept either under normoxic or hypoxic conditions. After 24 h of hypoxic culture conditions, ANG was up-regulated in the melanoma cell lines but not in normal melanocytes. Induction levels correlated with the metastatic potential of the cell lines. These data were confirmed by Northern blot analysis. In contrast, induction of vascular endothelial growth factor by hypoxia was equally strong in the examined highly aggressive melanoma cell lines and in one nonaggressive cell line. Other angiogenic factors tested as well as the melanoma growth stimulatory activity (Gro-alpha) showed no up-regulation. Thus, in the present study, hypoxia-induced up-regulation in melanoma cells was only observed for ANG and vascular endothelial growth factor. Immunohistochemical studies showed that 8 of 10 melanomas and all 15 metastases were positive for ANG, particularly in the vicinity of small vessels, whereas all benign nevi were negative. Reverse transcription-PCR detected only weak ANG mRNA in nevi but strong signals in primary melanomas and metastases. In conclusion, we demonstrate for the first time enhanced expression of ANG in highly metastatic cell lines as well as in melanomas and metastases in vivo, suggesting that ANG expression is associated with the metastatic potential. (+info)
Effect of NO, vasodilator prostaglandins, and adenosine on skeletal muscle angiogenic growth factor gene expression.
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Exercise training results in several muscle adaptations, one of which is angiogenesis. Acutely, exercise leads to release of nitric oxide, prostacyclin (PGI2), and adenosine (A) in the skeletal muscles. In this paper, we asked whether any of these locally released vasodilators, as well as other known dilator prostaglandins (PGE1 and PGE2), have the potential to increase angiogenic growth factor gene expression in resting skeletal muscle. Seven groups of 5-7 female Wistar rats (age 8-12 wk, weight 250 +/- 10 g) were anesthetized and instrumented for carotid artery pressure and electromagnetic femoral artery blood flow measurement. One group acted as control while the other groups each received one of the following six agents by constant arterial infusion (dose in microg/min): A (200), nitroprusside (NP, 4.2), acetylcholine (100), PGE1 (1.9), PGE2 (1.7), and PGI2 (1.7). Each agent reduced peripheral vascular resistance to a similar extent (at least twofold). Densitometric mRNA/18S levels for vascular endothelial growth factor (VEGF) were increased 50% by NP and acetylcholine, were unaffected by PGE1 and PGE2, and were reduced 40% by PGI2. For basic fibroblast growth factor, only PGI2 had any effect, reducing mRNA/18S approximately 25%. For transforming growth factor-beta1, A, NP, and PGE1 led to reduced mRNA/18S, whereas PGE2 slightly increased mRNA/18S. For the principal putative angiogenic growth factor, VEGF, these data suggest that naturally secreted vasodilators in contracting skeletal muscle could be involved in regulation of gene expression, namely, nitric oxide in a positive and PGI2 in a negative direction. (+info)
Vascular endothelial growth factor is bound in amniotic fluid and maternal serum.
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To study vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) concentrations and their possible binders, serum from 22 non-pregnant and 55 pregnant women (15 at weeks 10-13; 40 at term), umbilical vein (n = 24) and artery (n = 13) and amniotic fluid (a pool of 50 at weeks 15-17; 11 at term) were assessed for VEGF and PlGF by an enzyme-linked immunosorbent assay. In amniotic fluid and maternal serum VEGF concentrations were <16 ng/ml and added VEGF was not recovered. VEGF was detected in serum from mothers post-partum (137 +/- 142 ng/l, mean +/- SD), umbilical artery (421 +/- 288 ng/l) and vein (502 +/- 339 ng/l) and non-pregnant controls (182 +/- 147 ng/l), and added VEGF was fully recovered. PlGF was detected in pregnancy serum (52 +/- 23 ng/l early pregnancy; 439 +/- 217 ng/l term pregnancy) and in amniotic fluid (early pregnancy 56 ng/l; term pregnancy 30 +/- 18 ng/l). PlGF was fully recovered in all samples. Gel filtration and isoelectric focusing revealed that in maternal serum and amniotic fluid [125I]VEGF was bound to a protein with an Mr of 400-700 kDa and an isoelectric point of approximately 8. This protein was not identical with alpha-2-macroglobulin (by an immunofluorometric assay), pregnancy zone protein or pregnancy associated plasma protein-A (by immunodiffusion). In conclusion, VEGF-binding activity is present in amniotic fluid and maternal blood. It disappears after delivery and is not detectable in fetal or non-pregnant serum. (+info)
Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients.
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We have compared the platelet number and the serum concentration of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We have also measured the mitogenic effect of patient sera on endothelial cells in vitro in order to estimate the biological activity of serum VEGF. Serum VEGF concentration correlated with platelet number (r = 0.61; P < 10(-4)). Serum IL-6 levels correlated with platelet count (r = 0.36; P < 10(-3)), with serum VEGF levels (r = 0.55; P < 10(-4)) and with the calculated load of VEGF per platelet (r = 0.4; P = 3 x 10(-4)). Patients with thrombocytosis had a median VEGF serum concentration which was 3.2 times higher (P < 10(-4)) and a median IL-6 serum level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF did not show an association with any of the other parameters. Patient sera with high VEGF and bFGF content stimulated endothelial cell proliferation significantly more than other sera (P = 4 x 10(-3)). These results support the role of platelets in the storage of biologically active VEGF. Platelets seem to prevent circulating VEGF from inducing the development of new blood vessels except at sites where coagulation takes place. IL-6, besides its thrombopoietic effect, also seems to affect the amount of VEGF stored in the platelets. This is in accordance with the indirect angiogenic action of IL-6 reported previously. The interaction of IL-6 with the angiogenic pathways in cancer might explain the stimulation of tumour growth occasionally observed during IL-6 administration. It also conforms to the worse outcome associated with high IL-6 levels and with thrombocytosis in several tumour types and benign angiogenic diseases. (+info)
Inducible expression of the cell surface heparan sulfate proteoglycan syndecan-2 (fibroglycan) on human activated macrophages can regulate fibroblast growth factor action.
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Monocyte/macrophages play important roles in regulating tissue growth and angiogenesis through the controlled release of heparin-binding growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor, and heparin binding epidermal growth factor. The action of these potent growth mediators is known to be regulated by adsorption to heparan sulfate proteoglycans (HSPGs) on the surface and within the extracellular matrix of other neighboring cells, which respectively promote or restrict interactions with their signal-transducing receptors on target cells. Here we report on the nature of HSPGs inducibly expressed on the surface of macrophages that confer these cells with the capacity to regulate endogenous growth factor activity. We reveal that activated human macrophages express only a single major 48-kDa cell surface HSPG, syndecan-2 (fibroglycan) as the result of de novo RNA and protein synthesis. In addition, we demonstrate this macrophage HSPG selectively binds the macrophage-derived growth factors FGF-2, vascular endothelial growth factor and heparin binding EGF and can present FGF-2 in a form that transactivates receptor-bearing BaF32 cells. These results define a novel and unique proteoglycan profile for macrophages and imply a key role for syndecan-2 in the delivery of sequestered growth factors by inflammatory macrophages for productive binding to their appropriate target cells in vivo. (+info)
Aberrant cutaneous expression of the angiogenic factor midkine is associated with neurofibromatosis type-1.
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Neurofibromatosis type 1 is a common autosomal dominant disorder (incidence 1:3500) characterized by lesions that include neural crest derivatives such as Schwann cells and melanocytes. A critical event in the pathogenesis of neurofibromatosis type 1 is the heterozygous germ-line loss of the tumor suppressor gene NF1. Additional genetic and/or epigenetic events have been posited, including various alterations in growth factor expression. By in situ hybridization and immunohistochemistry, we demonstrate aberrant expression of the angiogenic and tumorigenic growth factor midkine in the skin of patients with neurofibromatosis type 1, but not normal individuals. We demonstrate that midkine expression is independent of the presence of neurofibromas, and thus appears to be associated with mutations in the NF1 gene. Furthermore, midkine-containing culture media is shown to stimulate the growth of human endothelial and neurofibroma-derived cells. In conclusion, we introduce the skin as a source of dysregulated growth factors in neurofibromatosis type 1, and suggest the further study of the angiogenic factor midkine in neurofibromatosis type 1 pathogenesis. (+info)