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Results for “Paracrine Communication”

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PubMed2006

Probing the microenvironment of mammary tumors using multiphoton microscopy.

Advances in optical imaging technologies that allow the subcellular resolution of undissected tissue have begun to offer new clues into the biology of development and disease. For cancer, such advances mean that the primary tumor is no longer a black box and that the disease can be studied throughout the metastatic cascade and not just as an endpoint. In this review we examine the advances in multiphoton imaging technology that have been used to define the microenvironment and its role in delineating the invasion and intravasation steps of metastasis inside living mammary tumors. Results show that the tumor microenvironment is a dynamic place where interactions between tumor cells, macrophages, blood vessels, and extracellular matrix fibers define the metastatic phenotype.

Animals↗
PubMed2006

Alveolar and lactogenic differentiation.

The mouse mammary gland is a complex tissue that proliferates and differentiates under the control of systemic hormones during puberty, pregnancy and lactation. Once a highly branched milk duct system has been established, during mid/late pregnancy, alveoli, little saccular outpouchings, sprout all over the ductal system and differentiate to become the sites of milk secretion. Here, we review the emerging network of the signaling pathways that connects hormonal stimuli with locally produced signaling molecules and the components of intracellular pathways that regulate alveologenesis and lactation. The powerful tools of mouse genetics have been instrumental in uncovering many of the signaling components involved in controlling alveolar and lactogenic differentiation.

Animals↗
PubMed2002

Intrapericardial therapy and diagnosis.

Diagnosis and treatment for the heart and virtually all its structures is becoming available via the pericardium. With or without pericardial effusion (formerly necessary for safe access), instruments that can enter the noneffusive pericardium are available and thoroughly tested experimentally, with human trials currently under way. Successful therapy includes antiarrhythmic, vasodilatory, angiogenic, and other gene-related modalities and agents that stimulate the pericardial mesothelium to exceed the normal production of many active substances.

Animals↗
PubMed1989

Cytokine networks in the uteroplacental unit: macrophages as pivotal regulatory cells.

A rich array of potent regulatory molecules has been identified in the uteroplacental unit. Most recently uncovered are the cytokines, families of polypeptides that establish intercellular communications, a paracrine effect, and often bind to synthetic cells in autocrine regulatory loops. Nearly all of the disparate maternal and fetal cell types in the uteroplacental unit are integrated into the cytokine network. The highly versatile macrophage, abundant in uteroplacental tissues, has emerged as a potentially pivotal cell type because of its unique ability to send and receive cytokine signals. Elevated levels of cytokines, possibly secreted when uteroplacental macrophages are activated by either bacterial endotoxins or receptor-bound cytokines, may compromise pregnancy. In particular, cytokines have been implicated in the induction of pre-term labor associated with infections. Intensive research is required to delineate the temporal patterns of cytokine synthesis that characterize pregnancy, to evaluate the events leading to normal and premature pregnancy termination and to establish protocols for therapeutic interventions in cases of infection.

Animals↗
PubMed1994

Different cells and cell lines produce factors that modulate Sertoli cell function.

Peritubular myoid cells derived from immature rat testes produce factors that modulate Sertoli cell function (P-Mod-S). The secretion of these factors is controlled in part by androgens. Cultured prostatic stromal cells strongly resemble peritubular myoid cells and produce mediators with similar activity. Here we investigated whether myoid cell lines can be used as a source of P-Mod-S-like factors. Rat kidney fibroblast (NRK) and mouse fibroblast (3T3) cell lines were used as non-myoid controls. Surprisingly, serum-free media conditioned by all cell lines studied modulated Sertoli cell function in a similar fashion as media conditioned by peritubular cells (PTCM) or stromal cells (STCM). Using Sertoli cell transferrin secretion as an endpoint for P-Mod-S-like activity, the nature of the active principles involved was further explored. The observed activity could not be explained by residual contamination with fetal calf serum. Moreover, the effects of the conditioned media could not be mimicked by classical growth factors (IGF-I, bFGF, EGF, TGF-beta, NGF, PDGF-BB) added singly or in combination with submaximally effective concentrations of PTCM. Finally, the possibility that conditioned media might indirectly enhance Sertoli cell function by promoting the production or deposition of extracellular matrix elements was made unlikely by the demonstration that the observed effects were not mimicked by Matrigel and were unaffected when Sertoli cells were seeded on Matrigel. Superdex 75 chromatography after analytical reversed-phase chromatography indicates that the factors from different origin have a similar size (45-50 kDa). It is concluded that mediators with P-Mod-S-like activity are produced by various cells and cell lines both with and without smooth muscle cell characteristics. Whether the active principles involved are really identical requires further investigation.

Animals↗
PubMed2006

Contact paracrine inhibitory networks within human gestational tissues.

We have determined the effects of separating chorion from decidua on the production of cytokines and prostaglandins. Chorionic production always exceeded that of decidua. Production rates were significantly greater in separated explants compared with intact choriodecidua, which suggests a potential contact paracrine inhibitory network.

Chorion↗
PubMed2005

Vascular endothelial growth factor receptor upregulation in response to cell-based angiogenic gene therapy.

BACKGROUND: We have previously reported that transplantation of vascular endothelial growth factor transfected cells into myocardial scar enhances angiogenesis. We evaluated the effect of transplanted cell type, time, and region of the heart on expression of the vascular endothelial growth factor receptors fms-like tyrosine kinase-1 (flt-1) and fetal liver kinase-1 (flk-1). METHODS: Lewis rats underwent myocardial cryoinjury 3 weeks before transplantation with heart cells (a mixed culture of cardiomyocytes, smooth muscle cells, endothelial cells, and fibroblasts), vascular endothelial growth factor transfected heart cells, skeletal myoblasts, vascular endothelial growth factor transfected skeletal myoblasts, or medium (controls) (N = 13 each). Flt-1 and flk-1 expression in the scar, border zone, and normal myocardium were evaluated at 3 days and 1, 2, and 4 weeks by quantitative polymerase chain reaction. Transplanted cells, vascular endothelial growth factor, flt-1, and flk-1 were identified by immunohistology. RESULTS: Flt-1 and flk-1 levels were low in all areas of control hearts. Upregulation of flt-1 and flk-1 after cell transplantation occurred primarily in host cells in the border zone rather than the scar (zone, p < 0.0001). Flt-1 and flk-1 expression was doubled by heart cells and skeletal myoblasts and increased eightfold by vascular endothelial growth factor transfected heart cells and skeletal myoblasts (group, p < 0.0001). Flk-1 expression peaked at 1 week, whereas flt-1 peaked at 2 weeks (time, p < 0.0001). CONCLUSIONS: Flk-1 and flt-1 upregulation may mediate the angiogenic effect of cell transplantation and are augmented by vascular endothelial growth factor transgene expression, perhaps through a paracrine effect. Optimizing the angiogenic response to cell transplantation may maximize the benefit of cell transplantation strategies.

Animals↗
PubMed2005

Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction.

BACKGROUND: There are several reports that engrafted mesenchymal stem cells (MSCs) stimulate angiogenesis in the ischemic heart, but the mechanism remains controversial. We hypothesize that transplantation of MSCs enhances vascular regeneration through a paracrine action. METHODS: A transmural myocardial infarction was created by ligation of the left anterior descending coronary artery in rats. Those with an ejection fraction less than 0.70 1 week after myocardial infarction were included. Autologous MSCs (1 x 10(7); 0.2 mL) or culture medium (0.2 mL) was injected intramyocardially into the periinfarct zone (50 microL/injection at four sites; n = 20/group). At 2 weeks after transplantation, Western blot analysis was used to assay the paracrine factors and proapoptotic proteins. Echocardiography to assess heart function was performed on additional groups at 8 weeks after implantation. RESULTS: The angiogenic factors basic fibroblast growth factor, vascular endothelial growth factor, and stem cell homing factor (stromal cell-derived factor -1alpha) increased in the MSC-treated hearts compared with medium-treated hearts. This was accompanied by a downregulation of proapoptotic protein Bax in ischemic myocardium. Similarly, capillary density increased about 40% in MSC-treated hearts compared with medium-treated hearts (p = 0.001). Left ventricular contractility, indicated by fractional shortening, improved in MSC-treated hearts at 2 months after implantation (MSCs: 48.6% +/- 19.9%; medium: 18.7% +/- 6.4%; p = 0.004). CONCLUSIONS: Autologous MSC transplantation attenuates left ventricular remodeling and improves cardiac performance. The major mechanism appears to be paracrine action of the engrafted cells, increasing angiogenesis and cytoprotection.

Angiogenesis Modulating Agents↗
PubMed2005

Endothelial stress induces the release of vitamin D-binding protein, a novel growth factor.

Endothelial cells (EC) under stress release paracrine mediators that facilitate accumulation of vascular smooth muscle cells (VSCM) at sites of vascular injury. We found that medium conditioned by serum-starved EC increase proliferation and migration of VSCM in vitro. Fractionation of the conditioned medium followed by mass spectral analysis identified one bioactive component as vitamin D-binding protein (DBP). DBP induced both proliferation and migration of VSMC in vitro in association with increased phosphorylation of ERK 1/2. PD 98059, a biochemical inhibitor of ERK 1/2, abrogated these proliferative and migratory responses in VSMC. DBP is an important carrier for the vitamin-D sterols, 25-hydroxyvitamin-D, and 1alpha,25-dihydroxyvitamin-D. Both sterols inhibited the activity of DBP on VSMC, suggesting that vitamin D binding sites are important for initiating the activities of DBP on VSMC. Release of DBP at sites of endothelial injury represents a novel pathway favoring accumulation of VSMC at sites of vascular injury.

Amino Acid Sequence↗
PubMed2005

Keratinocyte-fibroblast paracrine interaction: the effects of substrate and culture condition.

Interactions between epidermal-dermal cells via soluble factors provide important signals in regulating the reepithelialization of wounded skin. For example, keratinocytes regulate the expression of keratinocyte growth factor (KGF) in fibroblasts through the release of interleukin-1beta (IL-1beta). In this study, a previously developed polyethyleneglycol-based interpenetrating network (IPN) system was utilized as a platform for the delivery of keratinocyte-active factors. The effect of substrate chemistry, culture condition, and the delivery of exogenous keratinocyte-active factors on the keratinocyte behavior and the keratinocyte-fibroblast paracrine relationship was delineated. Adherent keratinocyte density on TCPS and glutaraldehyde-fixed gelatin hydrogels but not on IPN was significantly increased with culture time in the presence of growth supplements independent of the released KGF from the gelatin hydrogel and IPN. In the presence of fibroblasts, adherent keratinocyte density on gelatin hydrogels was higher than that without fibroblasts. This phenomenon was not observed on IPN and polycarbonate membrane. In summary, the delivered exogenous huKGF (i.e., released from a biomaterial matrix) operates in tandem with fibroblasts in regulating keratinocyte activation (i.e., IL-lbeta release and adhesion) in a surface-dependent manner. Immunoassay analysis of cell culture keratinocyte-fibroblast paracrine relationship as characterized by IL-1beta and KGF could not be established in the presence of IPNs, 0.1% glutaraldehyde-fixed gelatin hydrogels, and polycarbonate membranes.

Cell Adhesion↗
PubMed2004

Evidence for paracrine modulation of voltage-dependent calcium channels by amperometric analysis in cultured porcine adrenal chromaffin cells.

We investigated the endogenous control through vesicular contents of voltage-dependent Ca2+ channels (VDCCs) in cultured porcine adrenal chromaffin cells. To examine paracrine regulation of VDCCs, catecholamine release was monitored amperometrically together with patch-clamp recording under culture conditions at different cell densities. A depolarizing pulse evoked Ca(2+)- (ICa) and Ba(2+)-currents (IBa) in Ca(2+)- and Ba(2+)-containing solutions, respectively. In cells cultured at high density, stop-flow of the external solution decreased the I(Ba) concomitant with a sustained increase of amperometric current (Iamp), but not in cells at low density, suggesting the endogenous modulation of VDCCs in a paracine fashion. The degree of the prepulse facilitation was similar regardless of the flow condition. Application of noradrenaline (NA), ATP, methionine-enkephalin (ENK) or protons decreased IBa. The extent of the prepulse facilitation of the endogenous VDCC inhibition was similar to those induced by NA and ATP. GDPbetaS, pertussis toxin (PTX), blockers for alpha-adrenoceptors and P2-purinoceptors significantly reduced the endogenous VDCC inhibition. These results suggest that VDCCs are regulated by vesicular substances in a paracrine fashion, at least by noradrenaline and ATP, through activation of alpha-adrenoceptors and P2-purinoceptors, respectively, in porcine adrenal chromaffin cells.

Adrenal Medulla↗
PubMed2004

Pathways for degradation of connexins and gap junctions.

Gap junctional proteins, connexins, and gap junctional plaques are short-lived. Three pathways for their degradation have been proposed: (1) misfolded/abnormally oligomerized connexins are retrogradely translocated and degraded by the proteasome through endoplasmic reticulum-associated degradation; (2) connexins (as monomers or oligomers) may traffic directly from an early secretory compartment to the lysosome for degradation without reaching the plasma membrane; (3) connexins within gap junction plaques are degraded by the lysosome after endocytotic internalization. Degradation of gap junction plaques is proteasome-dependent in some cell types. Degradation may be regulated by ubiquitinylation, phosphorylation, or polypeptide domains that act as sorting signals.

Animals↗
PubMed2005

Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man.

OBJECTIVE: Ghrelin is the recently identified endogenous ligand for the ghrelin receptor GHS-R1a and known to regulate growth hormone secretion and appetite. Ghrelin also is a potent vasodilator and improves cardiac performance after systemic administration. Generally, the octanoyl modification on Ser3 has been considered essential for biological activity. Recently however, cardiovascular actions of des-octanoyl ghrelin have been reported in rodents. Our aim was to investigate if ghrelin and ghrelin receptor protein are expressed within the human vasculature, to determine if des-octanoyl ghrelin, like ghrelin, is a vasodilator in human artery and to test the acute effect of ghrelin peptides on cardiac contractility. METHODS: Distribution of ghrelin and ghrelin receptor was determined using standard immunocytochemistry and confocal microscopy. Ghrelin peptides were tested for vasodilator actions in human isolated arteries and their effect on cardiac contractility was investigated in human isolated paced atria. RESULTS: Immunoreactive ghrelin was detected in endothelial cells of human arteries and veins where it localized to intracellular vesicles but not to the Weibel-Palade bodies of the regulated pathway, suggesting constitutive ghrelin production. Specific antisera detected ghrelin receptor on vascular smooth muscle cells and cardiomyocytes. Ghrelin (pD2=8.60+/-0.1, Emax=55.8+/-8.9, mean+/-standard error of the mean) and des-octanoyl ghrelin (pD2=8.8+/-0.2, Emax=54.7+/-5.3) showed comparable (P>0.05) endothelium independent vasodilator potency and efficacy in reversing endothelin-1 induced constriction in human artery. Neither ghrelin nor des-octanoyl ghrelin had effects on contractile force in paced atria. CONCLUSIONS: We show widespread expression of ghrelin and its cognate receptor in the human cardiovascular system with functional evidence suggesting a role for both ghrelin and the more abundant endogenous form des-octanoyl ghrelin in the paracrine regulation of vascular tone in man.

Arteries↗
PubMed2006

The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.

The Kaposi's sarcoma-associated herpesvirus (KSHV), the infectious causative agent of Kaposi's sarcoma (KS), encodes a G protein-coupled receptor (vGPCR) implicated in the initiation of KS. Here we demonstrate that Kaposi's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms. Pharmacologic inhibition of mTOR with rapamycin prevented vGPCR sarcomagenesis, while overactivation of this pathway was sufficient to render endothelial cells oncogenic. Moreover, mice haploinsufficient for TSC2 are predisposed to vascular sarcomas remarkably similar to KS. Collectively, these results implicate mTOR in KS initiation and suggest that the sarcomagenic potential of KSHV may be a direct consequence of the profound sensitivity of endothelial cells to vGPCR dysregulation of the TSC2/mTOR pathway.

Animals↗
PubMed2005

Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis.

Our understanding of cancer has largely come from the analysis of aberrations within the tumor cell population. Yet it is increasingly clear that the tumor microenvironment can significantly influence tumorigenesis. For example, the mesenchyme can support the growth of tumorigenic epithelium. However, whether fibroblasts are subject to genetic/epigenetic changes as a result of selective pressures conferred by oncogenic stress in the epithelium has not been experimentally assessed. Recent analyses of some human carcinomas have shown tumor-suppressor gene mutations within the stroma, suggesting that the interplay among multiple cell types can select for aberrations nonautonomously during tumor progression. We demonstrate that this indeed occurs in a mouse model of prostate cancer where epithelial cell cycle disruption via cell-specific inhibition of pRb function induces a paracrine p53 response that suppresses fibroblast proliferation in associated stroma. This interaction imposes strong selective pressure yielding a highly proliferative mesenchyme that has undergone p53 loss.

Actins↗
PubMed2005

Under pressure: stromal fibroblasts change their ways.

In this issue of Cell, Hill et al. (2005) demonstrate in a mouse model of prostate cancer that the tumor cells can initiate and promote expansion of stromal fibroblasts that lack the tumor-suppressor protein p53 through a paracrine mechanism. This results in selection of highly proliferative fibroblasts associated with the carcinoma that further promote tumor progression.

Animals↗
PubMed2006

Inhibition of MCF-7 breast cancer cell proliferation by MCF-10A breast epithelial cells in coculture.

A coculture system was developed to investigate the interactions between MCF-10A breast epithelial cells and MCF-7 breast cancer cells stably expressing the green fluorescent protein (MCF-7-GFP). Studies with this MCF-10A/MCF-7-GFP coculture system on microtiter plates and on reconstituted basement membrane (Matrigel), revealed paracrine inhibition of MCF-7-GFP cell proliferation. Epidermal growth factor, which in monocultures modestly enhanced MCF-7-GFP and markedly increased MCF-10A cell proliferation, greatly inhibited MCF-7-GFP cell proliferation in MCF-10A/MCF-7-GFP cocultures. 17beta-Estradiol, which stimulated MCF-7-GFP but not MCF-10A cell proliferation in monoculture, inhibited MCF-7-GFP cell proliferation in MCF-10A/MCF-7-GFP cocultures, an effect that was blocked by the antiestrogen, ICI 182,780. On Matrigel, complex MCF-10A/MCF-7-GFP cellular interactions were observed in real time that resulted in the formation of acinus-like structures. These results indicate a role of normal epithelial cells in inhibiting tumor-cell proliferation and demonstrate the utility of this coculture system as a model of early paracrine control of breast cancer.

Breast↗