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PubMed2005

Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases.

BACKGROUND: Two types of cells are cultured from the human peripheral blood, early endothelial progenitor cells (EPCs) and outgrowth endothelial cells (OECs), as previously reported. Here, we further characterize these cells, especially with respect to their different origins and functions both in vitro and in vivo. We also investigated whether the combination of these different cell types shows synergism during neovascularization. METHODS AND RESULTS: Early EPCs were heterogeneously made up of both CD14+ monocyte-derived cells, which secrete cytokines, and CD14(-)-derived cells, which contain high levels of (CD34+)KDR+ cells. OECs were cultured almost exclusively from CD14- cells, not CD14+ cells, and were distinct from mature endothelial cells in terms of proliferation potential, KDR+ expression level, and telomerase activity. A portion of cells from CD14- cells and early EPCs produced rapidly proliferating, capillary-forming cells in both the Matrigel plug and the ischemic hind limb similar to OECs. Early EPCs and OECs expressed receptors for vascular endothelial growth factor and interleukin-8, cytokines secreted by early EPCs. There was a differential increase in matrix metalloproteinases (MMPs): MMP-9 in early EPCs and MMP-2 in OECs. In vitro, the angiogenic capability of the 2 cell types was augmented by mutual interaction through cytokines and MMPs. Injection of a mixture of the 2 cells resulted in superior neovascularization in vivo to any single-cell-type transplantation. CONCLUSIONS: Distinct origins of the different types of EPCs exist that have different functions in neovascularization. Mixed transplantation of these cells results in synergistic neovascularization through cytokines and MMPs.

Animals↗
PubMed1998

Neurofibromatosis type 2: growth stimulation of mixed acoustic schwannoma by concurrent adjacent meningioma: possible role of growth factors. Case report.

The authors report the case of a young man suffering from neurofibromatosis type 2 (NF2) who harbored bilateral acoustic schwannomas and a parasellar meningioma. Neuroimaging studies performed during a 4-year follow-up period showed that the bilateral schwannomas had grown very little and at similar rates. However, after the meningioma had infiltrated the tentorium and approached the ipsilateral schwannoma at the incisura, both Schwann cell tumors started to grow rapidly, particularly the one adjacent to the meningioma, of which the percentage of annual growth rate increased by approximately a factor of 10(2). At the same time, magnetic resonance imaging showed that this tumor also changed its features. During surgery, the acoustic schwannoma was firmly adherent to both meningioma and tentorium. Histological examination revealed meningotheliomatous cells in the schwannoma adjacent to the meningioma. Antiphosphotyrosine immunoblotting of PC12 cells was compatible with the presence of an epidermal growth factor (EGF)-like molecule in the cerebrospinal fluid (CSF) of the patient. This factor was not detected in the CSF of five other NF2 patients, two of whom bore associated bilateral acoustic schwannomas and meningioma in remote locations. It is hypothesized that the meningotheliomatous cells infiltrating the schwannoma triggered an autocrine/paracrine growth-stimulatory mechanism that involved an EGF-like factor.

Adolescent↗
PubMed2007

beta-Nerve growth factor participates in an auto/paracrine pathway of regulation of the meiotic differentiation of rat spermatocytes.

NGF appears to be involved in spermatogenesis. However, mice lacking NGF or TrkA genes do not survive more than a few days whereas p75(NTR) knockout mice are viable and fertile. Therefore, we addressed the effect of betaNGF on spermatogenesis by using the systems of rat germ cell culture we established previously. betaNGF did not modify the number of Sertoli cells, pachytene spermatocytes, secondary spermatocytes nor the half-life of round spermatids, but increased the number of secondary meiotic metaphases and decreased the number of round spermatids formed in vitro. These effects of betaNGF were reversible and maximal at about 4 x 10(-11) M. Conversely, K252a, a Trk-specific kinase inhibitor, enhanced the number of round spermatids above that of control cultures. The presence of betaNGF and its receptors TrkA and p75(NTR) was investigated in testis sections, in Sertoli cell and germ cell fractions, and in germ cell and Sertoli cell co-cultures. betaNGF was detected only in germ cells from pachytene spermatocytes of stages VII up to spermatids of stages IX-X. TrkA and p75(NTR) were detected in Sertoli cells and in these germ cells. Taken together, these results indicate that betaNGF should participate in an auto/paracrine pathway of regulation of the second meiotic division of rat spermatocytes in vivo.

Animals↗
PubMed2003

Homeostasis of the extracellular matrix of normal and osteoarthritic human articular cartilage chondrocytes in vitro.

OBJECTIVE: In normal articular cartilage cells, the IGFRI/insulin-like growth factor 1 (IGF-1) autocrine pathway was shown to overrule the catabolic effects of the IL-1/IL-1RI pathway by up-regulation of the IL-1RII decoy receptor. The activity of the IGF-1/IGFR1 and IL-1/IL-1R pathways, and of the IL-1RII control mechanism in the synthesis and turnover of the extracellular matrix (ECM) by chondrocytes from normal and osteoarthritic (OA) articular cartilage was compared in order to identify possible therapeutic targets of this disease. METHODS: Phenotypically stable human articular cartilage cells were obtained from normal and OA cartilage of the same knee showing focal OA. The cells were cultured in alginate beads over 1 week to re-establish the intracellular cytokine and growth factors, to reexpress the respective plasma membrane receptors and to reach equilibrium in accumulated cell-associated matrix (CAM) compounds. Following liberation of the cells from the alginate beads, the levels of cell-associated matrix (CAM) aggrecan, type II collagen and fibronectin, of intracellular IGF-1, IL-1alpha and beta and of their respective plasma membrane-bound receptors, IGFR1, IL-1RI and the decoy receptor IL-1RII, were assayed using flow cytometry. RESULTS: Coordinated production and accumulation of CAM aggrecan and type II collagen under the effect of the IGFR1/IGF-1 autocrine pathway-as documented for chondrocytes from healthy controls-was absent when the chondrocytes had been obtained from OA joints. When compared with cells obtained from normal tissues, chondrocytes from fibrillated OA cartilage expressed significantly higher intracellular IGF-1 levels and plasma membrane-bound IGFR1. At the same time, significantly higher intracellular IL-1alpha and beta levels and upregulated plasma membrane-bound IL-1RI were observed. Plasma membrane-bound IL-1RII decoy receptor was downregulated in OA chondrocytes. The levels of CAM aggrecan, type II collagen and fibronectin were significantly reduced in the chondrocytes obtained from pathological tissue. CONCLUSION: Paired analysis of normal and OA chondrocytes from the same knee joint has shown an enhanced capacity of chondrocytes from OA cartilage to produce ECM macromolecules. However, the same cells have increased catabolic signalling pathways. As a consequence of this increased IL-1 activity and the reduced amounts of IL-1RII decoy receptor, less of the produced ECM macromolecules may persist in the CAM of the OA chondrocytes.

Adult↗
PubMed2002

Autocrine/paracrine regulation of apoptosis in epithelial cells by prostaglandin E2.

This study was designed to investigate the effect of IL-1alpha-induced up-regulation of cyclooxygenase-2 (COX-2) on prostaglandin E(2) (PGE(2)) secretion and the subsequent phenotypic effects of PGE(2) on epithelial cells. The effect of IL-1alpha on COX-2 expression was investigated in the T24 bladder epithelial cell line following treatment with 0, 0.05, 0.5, 1 or 10 ng/ml IL-1alpha for 1, 2, 4 or 6 h. Quantitative PCR confirmed up-regulation of expression of COX-2 with maximal expression observed following treatment with 0.5 ng/ml IL-1alpha for 1 h. Co-treatment of the cells with 0.5 ng/ml IL-1alpha in the presence or absence of 100 ng/ml IL-1 receptor antagonist (RA) abolished the up-regulation in COX-2 expression confirming that the effect of IL-1alpha is mediated via its membrane-bound receptors. Treatment with 0.5 ng/ml IL-1alpha resulted in a time-dependent increase in PGE(2) secretion with maximal secretion detected at 24 and 48 h after stimulation with IL-1alpha. Co-treatment of the cells with IL-1alpha and IL-1RA or the COX-2 enzyme inhibitor NS398 abolished the IL-1alpha mediated secretion of PGE(2). Treatment of T24 cells with 100 nM PGE(2) resulted in a significant elevation in cAMP generation confirming the expression of functional PGE(2) receptors. Finally, the effect of exogenous treatment with PGE(2) on apoptosis of T24 cells was assessed using cell death detection ELISA. T24 cells were treated with camptothecin to induce apoptosis in the presence or absence of 50 or 100 nM PGE(2) or 10 microM forskolin. Treatment of T24 cells with increasing doses of camptothecin alone resulted in a significant increase in the induction of apoptosis (P<0.01). However, co-treatment of the cells with 50 or 100 nM PGE(2) or 10 microM forskolin resulted in the inhibition of induction of the apoptotic pathway by camptothecin. These data demonstrate that PGE(2) inhibits apoptosis of epithelial cells possibly via cAMP-dependent pathway.

Apoptosis↗
PubMed2000

Slow intercellular Ca(2+) signaling in wild-type and Cx43-null neonatal mouse cardiac myocytes.

Focal mechanical stimulation of single neonatal mouse cardiac myocytes in culture induced intercellular Ca(2+) waves that propagated with mean velocities of approximately 14 micrometer/s, reaching approximately 80% of the cells in the field. Deletion of connexin43 (Cx43), the main cardiac gap junction channel protein, did not prevent communication of mechanically induced Ca(2+) waves, although the velocity and number of cells communicated by the Ca(2+) signal were significantly reduced. Similar effects were observed in wild-type cardiac myocytes treated with heptanol, a gap junction channel blocker. Fewer cells were involved in intercellular Ca(2+) signaling in both wild-type and Cx43-null cultures in the presence of suramin, a P(2)-receptor blocker; blockage was more effective in Cx43-null than in wild-type cells. Thus gap junction channels provide the main pathway for communication of slow intercellular Ca(2+) signals in wild-type neonatal mouse cardiac myocytes. Activation of P(2)-receptors induced by ATP release contributes a secondary, extracellular pathway for transmission of Ca(2+) signals. The importance of such ATP-mediated Ca(2+) signaling would be expected to be enhanced under ischemic conditions, when release of ATP is increased and gap junction channels conductance is significantly reduced.

Adenosine Triphosphate↗
PubMed2000

Human bone cell hyperpolarization response to cyclical mechanical strain is mediated by an interleukin-1beta autocrine/paracrine loop.

Mechanical stimuli imparted by stretch, pressure, tension, fluid flow, and shear stress result in a variety of biochemical responses important in bone (re)modeling. The molecules involved in the recognition and transduction of mechanical stimuli that lead to modulation of bone cell function are not yet fully characterized. Cyclical pressure-induced strain (PIS) induces a rapid change in membrane potential of human bone cells (HBC) because of opening of membrane ion channels. This response is mediated via integrins and requires tyrosine kinase activity and an intact actin cytoskeleton. We have used this electrophysiological response to further study the signaling events occurring early after mechanical stimulation of HBC. Stimulation of HBC at 0.33 Hz PIS, but not 0.104 Hz PIS, results in the production of a transferable factor that induces membrane hyperpolarization of unstimulated HBC. The production of this factor is inhibited by antibodies to beta1-integrin. Interleukin-1beta (IL-1beta and prostaglandin E2 (PGE2) were identified as candidate molecules for the transferable factor as both were shown to induce HBC hyperpolarization by opening of small conductance calcium-activated potassium channels, the means by which 0.33 Hz PIS causes HBC hyperpolarization. Antibodies to IL-1beta, but not other cytokines studied, inhibit the hyperpolarization response of HBC to 0.33 Hz PIS. Comparison of the signaling pathways required for 0.33 Hz PIS and IL-1beta-induced membrane hyperpolarization shows that both involve the phospholipase C/inositol triphosphate pathway, protein kinase C (PKC), and prostaglandin synthesis. Unlike 0.33 Hz PIS-induced membrane hyperpolarization, IL-1beta-induced hyperpolarization does not require tyrosine kinase activity or an intact actin cytoskeleton. These studies suggest that 0.33 Hz PIS of HBC induces a rapid, integrin-mediated, release of IL-1beta with a subsequent autocrine/paracrine loop resulting in membrane hyperpolarization. IL-1beta production in response to mechanical stimuli is potentially of importance in regulation of bone (re)modeling.

Antibodies↗
PubMedDate not supplied

[Prolactin in the immunological system: synthesis and biological effects].

Prolactin (PRL) is a 23 kDa protein hormone that is produced and secreted by the pituitary lactotrophs. Although PRL was initially regarded as an exclusive pituitary hormone, many nonpituitary tissues were later found to contain and produce this hormone. The most established extrapituitary sites that produce PRL are the decidua, the immune system, brain and endometrium. In the immune system, PRL acts as a cytokine where it plays an important role in human immune responses, including in autoimmune diseases. Here, we will discuss the regulation of PRL gene expression in human lymphocytes and review the functions of PRL made by the immune cells, including its involvement in autoimmunity.

Animals↗
PubMed1999

Notochordal cells interact with nucleus pulposus cells: regulation of proteoglycan synthesis.

The disappearance of notochordal cells is correlated with early degenerative changes in the intervertebral disc. With increased disc degeneration there is a marked decrease in proteoglycan synthesis, resulting in loss of mechanical function. One possible mechanism for the decrease in proteoglycan synthesis is the loss of notochordal cells from the tissue. In this study, nucleus pulposus cells cocultured with notochordal cells exhibit an increase in proteoglycan synthesis. Interestingly, purified notochordal cells synthesize little proteoglycan as observed by [35S]sulfate incorporation into proteoglycans. The observed increase in proteoglycan synthesis does not appear to be dependent on cell-cell contact; rather it is the result of soluble factor(s) produced by notochordal cells. Finally, no difference in chondroitin sulfate chain size in notochordal-stimulated nucleus pulposus cells was observed which is consistent with an up-regulation in aggrecan core protein synthesis. These results are consistent with canine breeds where notochordal cells persist into adult age and disc degeneration is not observed. This suggests notochordal cells play a vital role in maintaining disc integrity.

Aggrecans↗
PubMed2005

Macrophage conditioned medium induces the expression of C-reactive protein in human aortic endothelial cells: potential for paracrine/autocrine effects.

C-reactive protein (CRP) is a risk marker for cardiovascular events in apparently healthy persons. Cogent data show that, aside from the liver, CRP is produced in atherosclerotic lesions, kidney, neurons, and alveolar macrophages. Because several proatherogenic effects of CRP have been documented in endothelial cells, we examined human aortic endothelial cells (HAEC) for CRP production. We detected the presence of CRP mRNA by RT-PCR and in situ hybridization, intracellular protein by Western blot and secreted protein by ELISA. Coincubation with the cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor alone and in combination showed that the most potent agonist for CRP production from HAEC is the combination of IL-1 and IL-6 (P < 0.05). To mimic the in vivo situation, we examined whether vascular smooth muscle cell (VSMC) and/or macrophage conditioned media (MCM) could augment CRP production by HAEC. While VSMC-conditioned media had no effect, incubation with MCM resulted in a significant twofold increase in the synthesis of both intracellular and secreted CRP (P < 0.05). The effect of MCM could be reversed by inhibiting both IL-1 and IL-6. Thus, stimulated synthesis and secretion of CRP by cells in the atherosclerotic lesion by paracrine/autocrine loops could result in local concentrations of CRP far in excess of plasma concentrations and could contribute to proinflammatory, proatherogenic effects.

Aorta↗
PubMed1999

Synaptic-like microvesicles in mammalian pinealocytes.

The recent deciphering of the protein composition of the synaptic vesicle membrane has led to the unexpected identification of a compartment of electron-lucent microvesicles in neuroendocrine cells which resemble neuronal synaptic vesicles in terms of molecular structure and function. These vesicles are generally referred to as synaptic-like microvesicles (SLMVs) and have been most intensively studied in pancreatic beta-cells, chromaffin cells of the adrenal medulla, and pinealocytes of the pineal gland. This chapter focuses on the present knowledge of SLMVs as now well-established constituents of mammalian pinealocytes. I review the results of morphological, immunocytochemical, and biochemical studies that were important for the characterization of this novel population of secretory vesicles in the pineal organ. The emerging concept that SLMVs serve as a device for intercellular communication within the pineal gland is outlined, and unanswered questions such as those pertaining to the physiological function and regulation of pineal SLMVs are discussed.

Animals↗
PubMed2003

Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1.

Urotensin-II (UII), a cyclic dodecapeptide with potent cardiovascular effects, has recently been shown to be abundantly expressed in the human kidney and excreted in human urine. To investigate whether UII acts as an autocrine/paracrine growth factor for renal epithelial cells, we have studied the effects of human UII (hUII) on DNA synthesis, cytosolic free Ca(2+) concentration ([Ca(2+)](i)), ERK activation, and protooncogene (c-myc) expression in a porcine renal epithelial cell line (LLCPK1). hUII stimulated [(3)H]thymidine uptake into quiescent cells in a dose-dependent manner (10(-9) to 10(-7) M); this effect was inhibited by a protein kinase C inhibitor (GF109203X), a MAPK kinase inhibitor (PD98059), and a calcium channel blocker (nicardipine). Neither phosphatidyl inositol-3 kinase inhibitors (LY294002, wortmannin) nor p38 kinase inhibitor (SB203580) affected the hUII-induced DNA syntheses. hUII rapidly (within 5 min) and dose-dependently (10(-9) to 10(-7) M) increased [Ca(2+)](i) in fura-2-loaded cells. hUII also caused a rapid and transient activation of ERK1/2 and induction of c-myc. LLCPK1 cells expressed UII mRNA and its receptor GPR14 mRNA, as determined by RT-PCR, and released UII-like immunoreactivity into media. Neutralization of endogenous UII by anti-hUII antibody, but not nonimmune serum, significantly suppressed DNA synthesis. These data suggest that hUII is an autocrine/paracrine growth factor for renal epithelial cells via activation of both protein kinase C and ERK1/2 pathways as well as Ca(2+) influx via voltage-dependent Ca(2+) channels.

Animals↗
PubMed2004

A type I IFN-dependent pathway induced by Schistosoma mansoni eggs in mouse myeloid dendritic cells generates an inflammatory signature.

Schistosomes are helminth parasites that display a dual impact on the immune system of their hosts. Although the larval stage, also known as schistosomulum, appears to subvert the host defenses, the egg stage induces strong inflammatory reactions. Given the pivotal role of dendritic cells (DC) in initiating and regulating immune responses, we compared the distinct transcriptional programs induced in immature mouse DC by S. mansoni eggs or schistosomula. Although SLA abrogated the transcription of many genes implicated in DC functions, eggs caused myeloid DC to produce IFN-beta. Autocrine/paracrine signaling through the type I IFN receptor in response to eggs was necessary for the induction of known IFN-responsive genes and enhanced the synthesis of key inflammatory products. Taken as a whole, our data provide molecular insights into the immune evasion mechanism of schistosomula and suggest an unexpected role for type I IFN in the innate response to helminth eggs.

Animals↗
PubMed1999

Insulin-like growth factor-II/mannose 6 phosphate receptors facilitate the matrix effects of latent transforming growth factor-beta1 released from genetically modified keratinocytes in a fibroblast/keratinocyte co-culture system.

This study was conducted to explore the mechanism of activation of transforming growth factor-beta1 (TGF-beta1) which is critical to its role in many physiological and pathological conditions. To date, almost all reports concerning TGF-beta1 activation delineated that release of mature TGF-beta1 from latency associated protein (LAP) is required for its activation. We report that latent TGF-beta1 (LTGF-beta1) released from TGF-beta1 genetically modified keratinocytes grown in the top chamber of a co-culture system functions as a fibrogenic factor through interaction with insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptors of human dermal fibroblasts grown in the lower chamber of this system. Following successful transduction, the pLin-LTGF-beta1 vector was amplified in PA31 7 packaging cells which possess viral structural proteins for vector in the presence of neomycin. Conditioned medium derived from packaging cells containing competent viral particles was then used to transduce either keratinocytes or fibroblasts grown in the upper chamber of a co-culture system, in which a 0.4 microm porous membrane separates the two chambers. In this way, LTGF-beta1 produced by transduced cells in the upper chamber is released and diffuses into the lower chambers where dermal fibroblasts are grown. Conditioned medium from the lower chamber was removed 3 days later and used to evaluate the latency and bioactivity of TGF-beta1 using enzyme-linked immunosorbent assay (ELISA) and mink lung (Mv1 Lu) epithelial growth inhibition assay. Cells were also harvested and used for RNA extraction. The results of these experiments showed that 1) the TGF-beta1-LAP complex, which was latent in traditionally used mink lung growth inhibition assay, directly modulated the expression of collagenase, type I, and type III collagen mRNA by dermal fibroblasts; 2) this stimulation was inhibited by M6P in a dose-dependent manner; 3) the TGF-beta1-LAP inhibits Mv1Lu epithelial cells only when this complex was incubated with cell membranes isolated from dermal fibroblasts; and 4) LTGF-beta1 activation seems to occur through a conformational alteration rather than by release of the mature TGF-beta1 from LAP in our co-cultured system. This conformational alteration seems to occur through the interaction of the TGF-beta1-LAP complex with the IGF-II/M6P receptors. Thus, the quantity of IGF-II/M6P receptors is important in cellular response to LTGF-beta1 in any physiological and pathological conditions.

Autocrine Communication↗
PubMed2003

Para/autocrine regulation of estrogen receptors in hippocampal neurons.

Previous studies have shown that estrogens, originating from ovaries, have a wide variety of estrogen receptor (ER)-mediated effects in the hippocampus. In the present study, we have investigated whether estrogens, which are synthesized in the hippocampus, could induce these effects as well. As a parameter, we used ER expression in response to estrogen synthesis, because estrogen receptors are ligand-inducible transcription factors. The experiments were carried out with cultures of isolated adult rat hippocampal cells, which contained about 95% neurons and about 5% oligodendrocytes in serum-free and steroid-free medium. Hippocampal neurons express both estrogen receptor isoforms (ERalpha and ERbeta), as shown by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. The release of estrogens by hippocampal neurons was quantified by radioimmunoassay (RIA). The ER isoforms (alpha and beta) were studied by semiquantitative immunocytochemical image analysis. Hippocampal cells precultured for 4 days were found to synthesize 17beta-estradiol for the next 8 days. This synthesis was completely inhibited by letrozol, an aromatase inhibitor. Inhibition of estrogen synthesis by letrozol induced a significant decrease in ERalpha expression, but an increase in ERbeta. As a control, supplementation of the medium with 17beta-estradiol resulted in a significant increase of ERalpha expression, whereas ERbeta was downregulated. Our findings provide evidence for a de novo synthesis of estrogens in the hippocampus, differential regulation of estrogen receptor isoforms by estrogen and consequently for a para/autocrine loop of estrogen action in the hippocampus.

Animals↗
PubMed2005

The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics.

The human intestinal Caco-2 cell line has been extensively used over the last twenty years as a model of the intestinal barrier. The parental cell line, originally obtained from a human colon adenocarcinoma, undergoes in culture a process of spontaneous differentiation that leads to the formation of a monolayer of cells, expressing several morphological and functional characteristics of the mature enterocyte. Culture-related conditions were shown to influence the expression of these characteristics, in part due to the intrinsic heterogeneity of the parental cell line, leading to selection of sub-populations of cells becoming prominent in the culture. In addition, several clonal cell lines have been isolated from the parental line, exhibiting in general a more homogeneous expression of differentiation traits, while not always expressing all characteristics of the parental line. Culture-related conditions, as well as the different Caco-2 cell lines utilized in different laboratories, often make it extremely difficult to compare results in the literature. This review is aimed at summarizing recent, or previously unreviewed, data from the literature on the effects of culture-related factors and the influence of line sub-types (parental vs. different clonal lines) on the expression of differentiation traits important for the use of Caco-2 cells as a model of the absorptive and defensive properties of the intestinal mucosa. Since the use of Caco-2 cells has grown exponentially in recent years, it is particularly important to highlight these methodological aspects in order to promote the standardization and optimisation of this intestinal model.

Autocrine Communication↗
PubMed2005

Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.

Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.

Actins↗
PubMed1998

Marked elevation of brain natriuretic peptide levels in pericardial fluid is closely associated with left ventricular dysfunction.

OBJECTIVES: The purpose of this study was to investigate whether atrial and brain natriuretic peptides (ANP and BNP, respectively) represent autocrine/paracrine factors and are accumulated in pericardial fluid. BACKGROUND: ANP and BNP, systemic hormones produced by the heart, have elevated circulating levels in patients with heart failure. Recent evidence suggests that the heart itself is one of the target organs for these peptides. METHODS: With an immunoreactive radiometric assay, we measured the concentrations of these peptides in plasma and pericardial fluid simultaneously in 28 patients during coronary artery bypass graft surgery. RESULTS: The pericardial levels of BNP were markedly elevated in patients with impaired left ventricular function. We investigated the correlation of ANP and BNP levels in plasma or pericardial fluid with left ventricular hemodynamic variables. None of the hemodynamic variables correlated with ANP levels in plasma or pericardial fluid. Both plasma and pericardial fluid levels of BNP were significantly related to left ventricular end-diastolic and systolic volume indexes (LVEDVI and LVESVI, respectively). In addition, BNP pericardial fluid levels had closer relations with LVEDVI (r = 0.679, p < 0.0001) and LVESVI (r = 0.686, p < 0.0001) than did BNP plasma levels (LVEDVI: r = 0.567, p = 0.0017; LVESVI: r = 0.607, p = 0.0010). BNP levels in pericardial fluid but not in plasma correlated with left ventricular end-diastolic pressure (r = 0.495, p = 0.0074). CONCLUSIONS: BNP levels in pericardial fluid served as more sensitive and accurate indicators of left ventricular dysfunction than did BNP levels in plasma. Thus, BNP may be secreted from the heart into the pericardial space in response to left ventricular dysfunction, and it may have a pathophysiologic role in heart failure as an autocrine/paracrine factor.

Aged↗