Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Paracrine Communication”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources
PubMed2005

How the turtle forms its shell: a paracrine hypothesis of carapace formation.

We propose a two-step model for the evolutionary origin of the turtle shell. We show here that the carapacial ridge (CR) is critical for the entry of the ribs into the dorsal dermis. Moreover, we demonstrate that the maintenance of the CR and its ability to attract the migrating rib precursor cells depend upon fibroblast growth factor (FGF) signaling. Inhibitors of FGF allow the CR to degenerate, with the consequent migration of ribs along the ventral body wall. Beads containing FGF10 can rearrange rib migration in the chick, suggesting that the CR FGF10 plays an important role in attracting the rib rudiments. The co-ordinated growth of the carapacial plate and the ribs may be a positive feedback loop (similar to that of the limbs) caused by the induction of Fgf8 in the distal tips of the ribs by the FGF10-secreting mesenchyme of the CR. Once in the dermis, the ribs undergo endochrondral ossification. We provide evidence that the ribs act as signaling centers for the dermal ossification and that this ossification is due to bone morphogenetic proteins secreted by the rib. Thus, once the ribs are within the dermis, the ossification of the dermis is not difficult to achieve. This relatively rapid means of carapace formation would allow for the appearance of turtles in the fossil record without obvious intermediates.

Animals↗
PubMed2006

c-Fos is required for TGFbeta1 production and the associated paracrine migratory effects of human colon carcinoma cells.

In tumor cells that have lost responsiveness to the growth inhibitory effects of transforming growth factor beta (TGFbeta), increased TGFbeta production by the tumor cells often contributes to cancer progression, primarily through paracrine mechanisms. Here we investigated the major components of the activator protein-1 (AP-1) complex in the TGFbeta1 promoter of human colon carcinoma cells (HCCCs). In contrast to untransformed epithelial cells (UECs), HCCCs displayed constitutive activation of AP-1 at the proximal AP-1 site in the human TGFbeta1 promoter. Further, in contrast to the JunD and Fra-2 components present in the AP-1 complex at this AP-1 site in UECs, c-Fos was the major detectable AP-1 component in HCCCs. Thus, transcriptional factor switching had occurred in HCCCs relative to the UECs, with regard to the proximal AP-1 site of the human TGFbeta1 promoter. Small interfering RNAs (siRNAs) against c-Fos significantly suppressed AP-1 activity at the relevant AP-1 site, and led to a decrease in TGFbeta1 secretion by the HCCCs. Our results indicate for the first time that c-Fos binding at the TGFbeta1 promoter proximal AP-1 site in HCCCs is required for TGFbeta1 production by the tumor cells. Further, we demonstrated that blockade of TGFbeta1 secretion by c-Fos siRNA led to a suppression of the cellular migration and mitogenesis of NIH 3T3 fibroblasts in a paracrine fashion. Thus, c-Fos may have utility as a target for blocking tumor cell-secreted TGFbeta1, thereby suppressing the migratory behavior associated with the malignant phenotype of HCCCs.

Animals↗
PubMed2002

Regulated expression of heparin-binding EGF-like growth factor (HB-EGF) in the human endometrium: a potential paracrine role during implantation.

Heparin-binding epidermal growth factor (HB-EGF) is a recently identified member of the EGF growth factor family found to be expressed in the uterus of both mouse and human at the time of implantation. In the present study, we investigated the expression patterns of HB-EGF in normal cycling endometrium and compared its expression with the fertility-associated endometrial epithelial biomarkers alpha(v)beta(3) integrin, leukemia inhibitory factor (LIF) and homeobox gene, HOXA-10. RNase protection assay (RPA) using RNA made from endometrium collected from different phases of the menstrual cycle demonstrated increased HB-EGF expression during the mid-secretory phase, a pattern similar to, but slightly preceding the expression of alpha(v)beta(3) integrin and HOXA-10. In vitro studies demonstrated stimulation of HB-EGF expression by estradiol-17beta (E(2)) and progesterone (P(4)) alone or in combination in stromal cells. Combined treatment with E(2) + P(4) was, however, required to stimulate epithelial HB-EGF expression. In vitro experiments demonstrated the ability of HB-EGF to stimulate epithelial expression of the key endometrial proteins including LIF, HOXA-10, and the beta(3) integrin subunit. Each has previously been demonstrated to be an important epithelial biomarker expressed during the implantation window. In addition, conditioned media from endometrial stromal cells treated with E(2) + P(4) + relaxin mimicked the stimulatory effect of HB-EGF on epithelial expression of the beta(3) integrin subunit. The stimulatory effect of the stromal-conditioned medium was blocked by antibodies that neutralize a known receptor for HB-EGF. These data suggest that uterine receptivity may be regulated in part by the stromal-derived HB-EGF.

Embryo Implantation↗
PubMed2003

Primary breast myoepithelial cells exert an invasion-suppressor effect on breast cancer cells via paracrine down-regulation of MMP expression in fibroblasts and tumour cells.

In normal breast and ductal carcinoma in situ, myoepithelial cells form an incomplete layer separating the epithelial compartment from the stromal environment. Transition to invasive disease is marked by penetration of the myoepithelial-basement membrane (BM) interface. One mechanism involved in tumour invasion is breakdown of extracellular matrices by matrix metalloproteinases (MMPs). It was hypothesized that myoepithelial cells may modulate tumour invasion by controlling MMP gene expression, both in tumour cells and in peri-ductal fibroblasts. To investigate this, myoepithelial cells from normal breast were purified and characterized and their effect on tumour cell invasive potential was assessed. The effect on MMP gene expression of breast cancer cells cultured alone or in combination with primary normal breast fibroblasts was also analysed using RT-PCR with ELISA quantitation, with zymographic analysis to measure enzyme activity. Normal breast myoepithelial cells significantly reduced invasion by the breast cancer cell lines MCF-7, T47D, MDA-MB 231, and MDA-MB 468 when they were cultured alone or in the presence of a fibroblast population. Reduced invasion was associated with changes in MMP gene expression. In those tumour cells expressing MMP, there was a significant down-regulation of MMP-2 (MDA-MB 468, p<0.001), MMP-9 (MDA-MB 231, p=0.05; MDA-MB 468, p<0.001), and MT1-MMP (p<0.001 for both MDA-MB 231 and MDA-MB 468). Myoepithelial cells also caused a significant decrease in MMP gene expression in co-cultured fibroblasts. Furthermore, this was associated with reduced gelatinolytic activity as identified by zymography. This study demonstrates for the first time that primary myoepithelial cells from normal breast reduce breast cancer cell invasion and that this is mediated via modulation of both tumour cell and fibroblast function. This emphasizes the importance of the myoepithelial cell in controlling the breast microenvironment and focuses on the potential significance of the loss of this population with disease progression.

Antineoplastic Agents↗
PubMed2005

Expression of tumor-associated trypsinogens (TAT-1 and TAT-2) in prostate cancer.

BACKGROUND: Trypsinogens are pancreatic serine proteinases and expressed in several cancers as tumor-associated trypsinogens (TAT). Trypsin mediates activation of pro-uPA and pro-MMPs, thus promoting angiogenesis and tumor invasion. Recently, we described expression of TAT in the human male genital tract and now we studied TAT in relation to PSA in PCa. METHODS: TAT expression was studied by immunohistochemistry, in situ hybridization, RT-PCR, DNA-sequencing and IFMA. LNCaP cells were used to study secretion of TAT and PSA after androgen stimulation. RESULTS: Immunoreactive TAT was localized in all prostatic tumors (n = 109), lymph node (n = 16), and bone metastases (n = 17). Immunostaining intensity increased with higher Gleason's grade, whereas PSA immunostaining decreased significantly. PSA and TAT were not identically distributed in benign and malignant cells. Androgen stimulation of LNCaP cells decreased secretion of TAT and increased that of PSA. TAT mRNA was demonstrated in tissue sections and identified as TAT-1 and -2 by RT-PCR and DNA-sequencing. CONCLUSIONS: Expression of TAT is better preserved than PSA in high-grade PCa. Expression of TAT and PSA is regulated by different mechanisms as demonstrated in tissue sections and in vitro. Locally produced TAT may act in a paracrine mode to promote angiogenesis and tumor invasion in PCa by both activating and degrading of other proteinases. Further studies on the role of TAT in invasive PCa and on the mechanisms involved in the regulation of TAT expression are warranted.

Gene Expression Regulation, Enzymologic↗
PubMed2000

The SepOvotropin: a new ovarian peptide regulating oocyte transport in Sepia officinalis.

In the cuttlefish Sepia officinalis, the successive steps of egg laying are controlled by multiple neuropeptides. Recent experiments led us to suppose that there was possible involvement of a second regulation pathway by the release of ovarian regulatory peptides in the genital tract. Using HPLC fractionation and an in vitro biological test, a C-terminal amidated peptide modulating the motility of the Sepia officinalis oviduct was isolated from an extract of vitellogenic ovarian follicles. The mass of this peptide as determined by MALDI-TOF (1501.8 Da) and analysis by Edman degradation led to the following sequence: Pro-Lys-Asp-Ser-Met-Leu-Leu-Leu-Gln-Val-Pro-Val-Tyr-amide. The peptide mapping performed by LC/MS revealed a distribution restricted to the follicles, the full grown oocytes and the eggs. This new peptide, called SepOvotropin, modulated contractions of the whole genital tract in physiological conditions from a threshold concentration between 10(-20) and 10(-19) M, demonstrating for the first time the occurrence of a specific peptidergic control of egg-laying in cephalopods.

Amino Acid Sequence↗
PubMed2002

Paracrine repercussions of preconditioning on angiogenesis and apoptosis of endothelial cells.

The mechanisms of cytoprotection conferred by stress preconditioning remain largely uncharacterized in endothelial cells (EC). We report that stress preconditioning of EC with serum starvation induces the release of soluble mediator(s) that confer resistance to apoptosis, increase proliferation, and enhance angiogenesis in a second set of "non-preconditioned" EC. Preconditioning was found to target specifically the mitochondrial control of apoptosis in EC with increased protein levels of Bcl-2, decreased protein levels of Bax, and decreased cytosolic release of cytochrome c. Regulators of apoptosis acting upstream and downstream of the mitochondria such as p53, cIAP-1, cIAP-2, and XIAP were not altered. Mediators classically associated with preconditioning in other cell types such as adenosine, opioids, and nitric oxide are not implicated in this cytoprotective loop. Blockade of protein kinase C-dependent signaling inhibited cytoprotection of EC. Further characterization of this paracrine pathway should provide insights into the molecular regulation of preconditioning in endothelial cells.

Apoptosis↗
PubMed2002

Paracrine action of transforming growth factor-alpha in rectal crypt epithelium of humans.

Colon and rectal mucosal crypt epithelium is a rapidly renewing cell population, where cell proliferation is normally balanced by cell loss. This report concerns the putative paracrine action of transforming growth factor alpha(TGF-alpha) in this homeostatic process. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and TGF-alpha was performed on biopsy specimens of rectal mucosa taken from consenting patients. The height of the proliferative compartment in mid-axially sectioned crypts in each individual was determined from the distribution of PCNA stained cells. The number of TGF-alpha stained cells that exhibited intense positive staining in a continuous column from the mouth down the side of the crypt was also scored in each individual patient. There was a significant positive correlation (P=0.05,n =22 patients) between the height of the proliferative compartment and the number of cells staining for TGF-alpha. Non-cellular TGF-alpha reactivity was also observed in the lamina propria adjacent to the TGF-alpha reactive epithelial cells, indicating secretion of TGF-alpha by these epithelial cells. These findings suggest that TGF-alpha is released from epithelial cells in the upper compartment of the crypt into the adjacent lamina propria and then diffuses to the epithelial cells in the lower part of the crypt, resulting in expansion of the proliferative compartment.

Aged↗
PubMed1999

Paracrine-mediated apoptosis in reproductive tract development.

In mammalian development, the signaling pathways that couple extracellular death signals with the apoptotic machinery are still poorly understood. We chose to examine Müllerian duct regression in the developing reproductive tract as a possible model of apoptosis during morphogenesis. The TGFbeta-like hormone, Müllerian inhibiting substance (MIS), initiates regression of the Müllerian duct or female reproductive tract anlagen; this event is essential for proper male sexual differentiation and occurs between embryonic days (E) 14 and 17 in the rat. Here, we show that apoptosis occurs during Müllerian duct regression in male embryos beginning at E15. Female Müllerian ducts exposed to MIS also exhibited prominent apoptosis within 13 h, which was blocked by a caspase inhibitor. In both males and females the MIS type-II receptor is expressed exclusively in the mesenchymal cell layer surrounding the duct, whereas apoptotic cells localize to the epithelium. In addition, tissue recombination experiments provide evidence that MIS does not act directly on the epithelium to induce apoptosis. Based on these data, we suggest that MIS triggers cell death by altering mesenchymal-epithelial interactions.

Animals↗
PubMed2001

fucosyltransferase1 and H-type complex carbohydrates modulate epithelial cell proliferation during prostatic branching morphogenesis.

The prostate undergoes branching morphogenesis dependent on paracrine interactions between the prostatic epithelium and the urogenital mesenchyme. To identify cell-surface molecules that function in this process, monoclonal antibodies raised against epithelial cell-surface antigens were screened for antigen expression in the developing prostate and for their ability to alter development of prostates grown in serum-free organ culture. One antibody defined a unique expression pattern in the developing prostate and inhibited growth and ductal branching of cultured prostates by inhibiting epithelial cell proliferation. Expression cloning showed that this antibody binds fucosyltransferase1, an alpha-(1,2)-fucosyltransferase that synthesizes H-type structures on the complex carbohydrate modifications of some proteins and lipids. The lectin UEA I that binds H-type 2 carbohydrates also inhibited development of cultured prostates. These data demonstrate a previously unrecognized role for fucosyltransferase1 and H-type carbohydrates in controlling the spatial distribution of epithelial cell proliferation during prostatic branching morphogenesis. We also show that fucosyltransferase1 is expressed by epithelial cells derived from benign prostatic hyperplasia or prostate cancer; thus, fucosyltransferase1 may also contribute to pathological prostatic growth. These data further suggest that rare individuals who lack fucosyltransferase1 (Bombay phenotype) should be investigated for altered reproductive function and/or altered susceptibility to benign prostatic hyperplasia and prostate cancer.

Androgens↗
PubMed2002

Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus.

Genes encoding components of the hedgehog signaling pathway are dynamically expressed in the mouse uterus preparing for implantation. Indian hedgehog (Ihh), patched (Ptc), and Gli3 are expressed at low levels in the endometrial epithelium on day 1 of pregnancy. Transcription of Ihh increases dramatically in the luminal epithelium and glands from day 3, reaching very high levels on day 4. Over the same period, Ptc, Gli1, Gli2, and noggin are strongly upregulated in the underlying mesenchymal stroma. Transcription of Ihh in ovariectomized mice is induced by progesterone but not by estrogen. Lower induction of Ihh, Ptc, and Hoxa10 is seen in response to progesterone in the uteri of Pgr(-/-) mutant mice lacking progesterone nuclear steroid receptor. This finding suggests that the hormone may regulate Ihh through both nuclear receptor-dependent and -independent pathways. We describe a method for culturing uterine explants in the absence of epithelium. Under these conditions, recombinant N-SHH protein promotes the proliferation of mesenchyme cells and the expression of noggin. We propose that IHH made by the epithelium normally functions as a paracrine growth factor for stromal cells during the early stages of pregnancy.

Animals↗
PubMed2001

Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation.

Tumors arise from cells that have sustained genetic mutations resulting in deregulation of several of their normal growth-controlling mechanisms. Much of the research concerning the origins of cancer has focused on the genetic mutations within tumor cells, treating tumorigenesis as a cell-autonomous process governed by the genes carried by the tumor cells themselves. However, it is increasingly apparent that the stromal microenvironment in which the tumor cells develop profoundly influences many steps of tumor progression. In various experimental tumor models, the microenvironment affects the efficiency of tumor formation, the rate of tumor growth, the extent of invasiveness, and the ability of tumor cells to metastasize. In carcinomas, the influences of the microenvironment are mediated, in large part, by paracrine signaling between epithelial tumor cells and neighboring stromal fibroblasts. In this review, we summarize recent advances in understanding the paracrine signaling interactions between epithelial cancer cells and associated fibroblasts and examine the effects of these bidirectional interactions on various aspects of carcinoma formation. We note, however, that paracrine signaling between other cell types within the carcinomas, such as endothelial cells and inflammatory cells, may play equally important roles in tumor formation and we will refer to these heterotypic interactions where relevant.

Animals↗
PubMed2002

Cross-talk between mesenchyme and epithelium increases H19 gene expression during scattering and morphogenesis of epithelial cells.

The H19 gene is an imprinted gene expressed from the maternal allele. It is known to function as an RNA molecule. We previously reported that in breast adenocarcinoma, H19 is often overexpressed in stromal cells and preferentially located at the epithelium/stroma boundary, suggesting that epithelial/mesenchymal interactions can control H19 RNA expression. In some cases of breast adenocarcinoma with poor prognosis, H19 is overexpressed in epithelial cells. Therefore we examined whether mesenchymal factors can induce H19 expression in epithelial cells. Using quantitative RT-PCR and in situ hybridization, we found that when mammary epithelial cells were cultured in collagen gels, H19 expression was strongly up-regulated compared to when cells were cultured on plastic. Collagen gels allow three-dimensional growth of epithelial cells and morphogenetic responses to soluble factors. A conditioned medium from MRC-5 fibroblasts caused branching morphogenesis of HBL-100 cells and invasive growth of MDA-MB-231 cells, whereas MCF-7 cells were unresponsive. Induction of H19 expression correlated with morphological changes in HBL-100 and in MDA-MB-231 cells, whereas H19 expression was not induced in MCF-7 cells. Using a blocking antibody, HGF/SF was identified as the fibroblast-derived growth factor capable of inducing H19 expression and cell morphogenesis. We further demonstrated that H19 promoter activity was stimulated by various growth factors using transient transfection in MDCK epithelial cells. HGF/SF was more efficient than EGF or FGF-2 in transactivating the H19 promoter, whereas IGF-2, TGFbeta-1, and TNF-alpha were ineffective. This activation by HGF/SF was prevented by pharmacological inhibition of MAP kinase or of phospholipase C. We conclude that H19 is a target gene for HGF/SF, a known regulator of epithelial/mesenchymal interactions, and suggest that the up-regulation of H19 may be implicated in morphogenesis and/or migration of epithelial cells.

Animals↗
PubMed2001

Modified AdCTLA-4 vector blocks alloimmune response in vitro.

BACKGROUND: Gene transfer of the costimulatory blockade molecule CTLA-4Ig into cold-preserved rat liver allografts results in indefinite allograft survival. Despite local delivery, this mode of immunomodulation is associated with systemic immunosuppression. In an effort to restrict immunosuppression to the graft, we have constructed a novel adenoviral vector, AdCTLA-4ex-TAG, in which the Ig sequence of CTLA-4Ig DNA has been deleted to destabilize the gene product to promote rapid extrahepatic degradation while maintaining its immunosuppressive activity within the graft milieu. METHODS: (1) Vector construction. CTLA-4 extracellular binding domain (CTLA-4ex) was prepared by PCR-based cloning methods and fused in frame to a genetic element encoding an epitope TAG allowing identification of the transgene product CTLA-4exTAG. CTLA-4exTAG was subcloned into a shuttle vector enabling isolation of AdCTLA-4exTAG. (2) In vitro transfection: AdCTLA-4exTAG was transfected into MH(1)C(1) cells and then supernatant was recovered for Western blot analysis. (3) In vitro alloimmune response was characterized by CFSE proliferation assay. (4) Extrahepatic effect of AdCTLA-4exTAG was characterized by the ability to control tumor growth after implantation of a regressive, immune sensitive cancer cell line (REGb) in the skin of BDIX rats after liver transduction with AdCTLA-4exTAG. RESULTS: Expression and secretion of the recombinant protein were documented by Western blot after infection of the MH(1)C(1) cell line() with AdCTLA-4exTAG. Addition of infected MH(1)C(1) cell supernatant resulted in abrogation of alloimmune response as shown by markedly diminished division of CD4(+) T cells in a CFSE proliferation assay. Extrahepatic tumor regressed normally after liver transduction with AdCTLA-4exTAG. CONCLUSIONS: These results show efficient in vitro expression of CTLA-4exTAG after transfection with AdCTLA-4exTAG. The modified protein retains its ability to abrogate in vitro alloimmune response. Efficient control of extrahepatic tumor growth after liver-directed delivery of AdCTLA-4exTAG suggests that the immunosuppressive effect of this vector is restricted to the liver. These results set the ground for the utilization of this novel adenoviral vector in the transplant setting.

Abatacept↗
PubMed2003

A fully coupled binary biochemical reactive-diffusion model with analytic solution.

Coupled multicomponent biochemical reactive diffusion underlies a variety of biological signalling processes and pharmacokinetic applications, such as paracrine signalling involving "cocktails" comprised of growth promoter/inhibitor factors and proteases associated with tumor angiogenesis, invasion and metastasis, extravascular drug delivery, and polymeric controlled-release drug codelivery design. Here, we present a model and develop a new analytic solution to illustrate the spatiotemporal behavior associated with fully coupled binary biochemical reactive diffusion. The complete coupling renders the solution appreciably more complex in structure and behavior than solutions for unicomponent or partially coupled models. Concentration behavior is illustrated by the computational simulation of binary-species tumor angiogenesis factor reactive-diffusion in the extravascular tissue matrix. The computational results indicate that (a) steady-state concentration profiles are achieved within 1 h of a change in factor production; (b) in the steady state, the spatial profiles of the two components tend to be similar; (c) exceedingly steep concentration gradients, involving several orders-of-magnitude differences in concentration over a few tenths of a millimeter, can occur in the vicinity of boundary sources due to inter-species reaction; (d) the concentration profiles of the two species differ from unicomponent predictions due to the simultaneous mass interchange between the two species. The analytic solution predictions are also used to provide a first-ever validation of a time-dependent, binary-component Crank-Nicholson numerical solution. The ability to quantitatively model interacting and often strongly varying concentration levels as a function of time and position can serve as a powerful complementary tool to experimental analyses for assessing disease state and interventional pharmacological efficacy, especially when the spatial scales on which in vivo behavior occurs taxes the limits of imaging capabilities.

Angiogenesis Inducing Agents↗
PubMed2000

Paracrine mechanisms of mouse mammary ductal growth.

Ductal growth during puberty is stimulated by estrogens, which elicit their effects via specific estrogen receptors, ER alpha and ER beta. Analysis of mice with targeted disruption of ER alpha or ER beta has emphasized the importance of ER alpha in mammary gland development. In the mouse mammary gland, ER alpha are expressed in both epithelial and stromal cells (Kurita and Cunha, unpublished), which raises the possibility that the growth and morphogenetic effects of estrogen could be mediated via either epithelial or stromal ER. The aim of this paper is to review the role of epithelial versus stromal ER in mammary ductal-alveolar growth to assess the importance of paracrine mechanisms.

Aging↗