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PubMed2001

In-vitro evidence of autocrine secretion of vascular endothelial growth factor by endothelial cells from human placental blood vessels.

Vascular endothelial growth factor (VEGF), a highly specific mitogen for vascular endothelial cells, is involved in placental vascular growth and remodelling. The aim of this study was to investigate whether placental endothelial cells secrete VEGF in an autocrine manner and if this secretion is correlated with endothelial cell growth. Blood vessels, excised from the apical surface of three human placentae, were sectioned into 40 fragments per placenta and cultured in fibrin gel matrix for 27 days. Immunohistochemical detection of placental endothelial cells was performed by positive staining with anti-human factor VIII-associated antigen and negative staining with anti-human alpha-actin and desmin. To investigate the production and autocrine action of VEGF, VEGF concentrations in culture media were measured and the effect of an anti-VEGF neutralizing antibody on endothelial cell growth was observed. The results demonstrate that soluble VEGF is secreted by placental endothelial cells reaching a plateau from day 24 (68.74 +/- 7.52 pg/ml) to day 27 (67.20 +/- 6.28 pg/ml). Furthermore, VEGF concentrations in media collected on days 6, 12, 18, 21 and 27 of culture were found to be directly correlated to the sprouting parameter of endothelial cells, as calculated by image analysis on the same day ( P < 0.001, r (2) = 0.95 ). The use of 10 and 100 ng/ml of a neutralizing antibody against human VEGF suppressed cell proliferation, compared to that observed in the untreated controls, by 74.8 +/- 7.3 and 89.4 +/- 3.9% respectively. In conclusion, this study reports the first evidence of autocrine secretion of VEGF by human placental endothelial cells and demonstrates the involvement of VEGF in endothelial cell growth within a fibrin gel culture.

Autocrine Communication↗
PubMed1998

Autocrine mediators are required to act on the embryo by the 2-cell stage to promote normal development and survival of mouse preimplantation embryos in vitro.

Autocrine mediators released by the early embryo are implicated in the support of embryo development. Their mechanisms and timing of action, however, are uncertain. This study shows that their action is necessary during the 2-cell stage of development, at which time they do not act as classical growth factors, having no impact on the rate of cell-cycle progression. Rather, they act as survival factors, protecting embryos from subsequent cell death. Culture of zygotes for the first 48 h after insemination (but not the first 24 h only) at a high concentration of 1 embryo/microl before transfer to a concentration of 1 embryo/100 microl significantly improved development compared with culture at the lower concentration for 120 h. By contrast, if the initial 48 h of culture was at 1 embryo/100 microl, subsequent culture at 1 embryo/microl caused no improvement. Platelet-activating factor (PAF) supplementation (0.186 microM) of media for the 48-h period after insemination (but not 24 h only) improved the development of embryos cultured at low embryo concentrations (1 embryo/10 microl) even when transferred to PAF-free media for the subsequent 72-h culture period. The ability of PAF to mimic the effects of higher embryo density implicates embryo-derived PAF as one of the autocrine mediators stimulating early embryo development. The cell death that occurred at low embryo concentration had a mixed phenotype: some cells had lost membrane integrity whereas others had intact membranes but punctate or fragmented chromatin. It is concluded that the action of autocrine diffusible factors, including PAF, are necessary during the 2-cell stage for subsequent survival and normal development of embryos to the blastocyst stage.

Animals↗
PubMed2000

TGF-beta autocrine loop regulates cell growth and myogenic differentiation in human rhabdomyosarcoma cells.

Transforming growth factor beta (TGF) is a well-known inhibitor of myogenic differentiation as well as an autocrine product of rhabdomyosarcoma cells. We studied the role of the TGF-beta autocrine loop in regulating growth and myogenic differentiation in the human rhabdomyosarcoma cell line, RD. We previously reported that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces growth arrest and myogenic differentiation in these cells, which constitutively express muscle regulatory factors. We show that TPA inhibits the activation of secreted latent TGF-beta, thus decreasing the concentration of active TGF-beta to which the cells are exposed. This event is mediated by the TPA-induced alteration of the uPA/PAI serine-protease system. Complete removal of TGF-beta, mediated by the ectopic expression of a soluble type II TGF-beta receptor dominant negative cDNA, induces growth arrest, but does not trigger differentiation. In contrast, a reduction in the TGF-beta concentration, to a range of 0.14-0.20 x 10(-2) ng/ml (which is similar to that measured in TPA-treated cells), mimics TPA-induced differentiation. Taken together, these data demonstrate that cell growth and suppression of differentiation in rhabdomyosarcoma cells require overproduction of active TGF-beta; furthermore, they show that a 'critical' concentration of TGF-beta is necessary for myogenic differentiation to occur, whereas myogenesis is abolished below and above this concentration. By impairing the TGF-beta autocrine loop, TPA stabilizes the factor concentration within the range compatible for differentiation to occur. In contrast, in human primary muscle cells a much higher concentration of exogenous TGF-beta is required for the differentiation inhibitory effect and TPA inhibits differentiation in these cells probably through a TGF-beta independent mechanism. These data thus clarify the mechanism underlying the multiple roles of TGF-beta in the regulation of both the transformed and differentiated phenotype.

Animals↗
PubMed1998

Autocrine growth stimulation as a potential source of asymmetry in melanocytic skin tumors.

The presence of asymmetry is a major diagnostic criterion for the differentiation of melanoma from benign melanocytic proliferations. It is helpful in both clinical and histological evaluation. The underlying biological features that determine asymmetry have not yet been evaluated. Using computer simulation of the growth of neoplasms, we demonstrate that a functionally homogeneous cell population can give rise to asymmetric lesions when the cells respond to autocrine growth signals. In contrast, neoplastic cells that depend on paracrine stimuli tend to form symmetric lesions. Since the progression of melanocytic neoplasms has been demonstrated to be accompanied by increasing independence of paracrine growth signals and the development of autocrine loops, autocrine growth stimulation has to be considered as a potential source of asymmetry in melanoma.

Autocrine Communication↗
PubMed1999

Autocrine loops, signal transduction, and cell cycle abnormalities in the molecular biology of lung cancer.

Lung cancers produce a variety of mitogenic neuropeptides and growth factors and express receptors for these signaling peptides leading to autocrine and paracrine loops that stimulate tumor cell proliferation and migration and promote neovascularization. The effects of these autocrine and paracrine factors are mediated by a variety of intracellular signal transduction pathways that ultimately converge on the regulation of cell cycle proteins whose expression and activity are abnormal in lung cancer cells. During the past year, further advances have been made in unraveling autocrine loops, signal transduction pathways, and cell cycle abnormalities in both small cell lung carcinoma (SCLC) and in non-SCLC. In addition, the hunt for novel tumor suppressor genes has continued. As our understanding of the fundamental cell and molecular biology of lung cancer increases, novel possibilities for translational research are emerging for improving the diagnosis, prognosis, and treatment of the disease.

Autocrine Communication↗
PubMed2002

Dura mater biology: autocrine and paracrine effects of fibroblast growth factor 2.

The dura mater, the outermost layer of the meninges, is thought to be essential for calvarial morphogenesis, postnatal suture fusion, and osseous repair of calvarial defects. Despite numerous studies illustrating the fundamental role of the dura mater, there is little information about the autocrine and paracrine mechanisms regulating dural cell biology during calvarial ossification. Previous work conducted in the authors' laboratory demonstrated that non-suture-associated dural cells from 6-day-old rat pups expressed high levels of fibroblast growth factor 2 (FGF-2), whereas dural cells from 60-day-old adult rats expressed very little FGF-2. Because young mammals can successfully heal large calvarial defects, the authors sought to investigate the autocrine and/or paracrine effects of FGF-2 on the proliferation, gene expression, and alkaline phosphatase production of dural cells. Cultures of non-suture-associated dural cells were established from 6-day-old Sprague-Dawley rat pups and then stimulated with recombinant human FGF-2 (rhFGF-2; 10 ng/ml). Dural cells stimulated with rhFGF-2 proliferated significantly faster than untreated dural cells at 24 hours (2.1 x 10(5) +/- 3.2 x 10(4) versus 1.1 x 10(5) +/- 1.8 x 10(4), p < or = 0.001) and 48 hours (2.3 x 10(5) +/- 4.2 x 10(4) versus 1.2 x 10(5) +/- 1.3 x 10(4), p < or = 0.001). Moreover, dural cells stimulated with rhFGF-2 expressed 7-fold more proliferating cell nuclear antigen than did control cultures. Treatment with rhFGF-2 increased dural cell expression of genes important for skeletal repair: FGF-2 (7-fold), transforming growth factor beta 1 (3-fold), transforming growth factor beta 3 (4-fold), and type I collagen (4-fold). Furthermore, rhFGF-2 increased dural cell expression of osteopontin (2-fold), a "late" marker of osteoblastic differentiation. Interestingly, dural cell alkaline phosphatase activity, an "earlier" marker of osteoblast differentiation, was significantly decreased by treatment with rhFGF-2 compared with control cultures at 24 hours (0.005 +/- 0.001 versus 0.01 +/- 0.003, p < or = 0.01) and 48 hours (0.004 +/- 0.0009 versus 0.01 +/- 0.0009). Together these data provide insight into the autocrine and paracrine effects of FGF-2 on the biology of the dura mater.

Alkaline Phosphatase↗
PubMed2004

A model for mechanotransduction in cardiac muscle: effects of extracellular matrix deformation on autocrine signaling.

We present a computational model and analysis of the dynamic behavior of epidermal growth factor receptor (EGFR) signaling in cardiac muscle tissue, with the aim of exploring transduction of mechanical loading into cellular signaling that could lead to cardiac hypertrophy. For this purpose, we integrated recently introduced models for ligand dynamics within compliant intercellular spaces and for the spatial dynamics of intracellular signaling with a positive feedback autocrine circuit. These kinetic models are here considered in the setting of a tissue consisting of cardiomyocytes and blood capillaries as a structural model for the myocardium. We show that autocrine EGFR signaling can be induced directly by mechanical deformation of the tissue and demonstrate the possibility of self-organization of signaling that is anisotropic on the tissue level and can reflect anisotropy of the mechanical deformation. These predictions point to the potential capabilities of the EGFR autocrine signaling circuit in mechanotransduction and suggest a new perspective on the cardiac hypertrophic response.

Animals↗
PubMed2004

Interleukin-13 overexpression by tax transactivation: a potential autocrine stimulus in human T-cell leukemia virus-infected lymphocytes.

The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein induces growth transformation and is critical for the pathogenesis of the HTLV-1-induced adult T-cell leukemia (ATL). It stimulates the cell cycle and transactivates cellular genes. Here we show that the expression of interleukin-13 (IL-13) is upregulated as a consequence of Tax in HTLV-1-transformed T cells and ATL-derived cultures. IL-13 exerts proliferative and antiapoptotic functions and is linked to leukemogenesis, since it stimulates Hodgkin lymphoma cells by an autocrine mechanism. Overexpression of IL-13 RNA and protein was confirmed in HTLV-1-positive and Tax-transformed cells. Induction of endogenous IL-13 levels in tax-transfected Jurkat cells and in conditional Tax-expressing transformed T lymphocytes suggested that Tax can replace signals required for IL-13 synthesis. For functional analysis, the IL-13 promoter and deletion variants were cloned into luciferase reporter plasmids. Experiments with transfected human T lymphocytes revealed a 16-fold stimulation of the IL-13 promoter by Tax. Experiments with Tax mutants indicated that none of the classical transactivation pathways (SRF, CREB, and NF-kappaB) is sufficient for the transactivation; at least two different Tax functions are required for full transactivation. The IL-13 promoter is stimulated via two elements; one is a NF-AT binding P element, and the other is a putative AP-1 site. The following observations suggest that IL-13 may stimulate HTLV-1-transformed cells by an autocrine mechanism: (i) the HTLV-1-transformed cells express the IL-13 receptor on their surface, and (ii) STAT6, a downstream effector of IL-13 signaling, is constitutively activated. Thus, in summary, Tax, by transactivating the promoter, induces IL-13 overexpression that possibly leads to an autocrine stimulation of HTLV-1-infected cells.

Autocrine Communication↗
PubMed2003

Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes.

Vascular endothelial growth factor (VEGF) is expressed by renal glomerular epithelial cells (podocytes) and is thought to be protective against nephrotoxic agents. VEGF has been shown to be an autocrine survival factor in neuropilin-1-positive, VEGF receptor-negative breast carcinoma cells. Normal human podocytes are also known to express neuropilin-1, VEGF, and are VEGF-R2 negative. Here, we investigated whether a similar VEGF autocrine loop may exist in podocytes. Podocyte cytosolic calcium concentration ([Ca(2+)](i)) was analyzed in primary cultured and conditionally immortalized podocytes using ratiometric fluorescence measurement. Cytotoxicity was determined by lactate dehydrogenase assay, proliferation by [(3)H]-thymidine incorporation, and cell counts by hemocytometric assay. VEGF decreased [Ca(2+)](i) in primary podocytes (from 179 +/- 36 to 121 +/- 25 nM, P < 0.05) and conditionally immortalized podocytes (from 95 +/- 10 to 66 +/- 8 nM, P < 0.02) in the absence of extracellular calcium. The type III receptor tyrosine-kinase inhibitor PTK787/ZK222584 abolished this reduction. VEGF increased podocyte [(3)H]-thymidine incorporation (3,349 +/- 283 cpm, control 2,364 +/- 301 cpm, P < 0.05) and cell number (4.5 +/- 0.7 x 10(4)/ml, control 2.6 +/- 0.5 x 10(4)/ml, P < 0.05) and decreased cytotoxicity (5.9 +/- 0.7%, control 12 +/- 3%, P < 0.05), whereas a monoclonal antibody to VEGF increased cytotoxicity. Electron microscopy of normal human glomeruli demonstrated that the glomerular VEGF is mostly podocyte cell membrane associated. These results indicate that one of the functions of VEGF secreted from podocytes may be to act as an autocrine factor on calcium homeostasis and cell survival.

Adult↗
PubMed2002

Autocrine extracellular purinergic signaling in epithelial cells derived from polycystic kidneys.

ATP and its metabolites are potent autocrine agonists that act extracellularly within tissues to affect epithelial function. In polycystic kidneys, renal tubules become dilated and/or encapsulated as cysts, creating abnormal microenvironments for autocrine signaling. Previously, our laboratory has shown that high-nanomolar to micromolar quantities of ATP are released from cell monolayers in vitro and detectable in cyst fluids from microdissected human autosomal dominant polycystic kidney (ADPKD) cysts. Here, we show enhanced ATP release from autosomal recessive polycystic kidney (ARPKD) and ADPKD epithelial cell models. RT-PCR and immunoblotting for P2Y G protein-coupled receptors and P2X purinergic receptor channels show expression of mRNA and/or protein for multiple subtypes from both families. Assays of cytosolic Ca(2+) concentration and secretory Cl(-) transport show P2Y and P2X purinergic receptor-mediated stimulation of Cl(-) secretion via cytosolic Ca(2+)-dependent signaling. Therefore, we hypothesize that autocrine purinergic signaling may augment detrimentally cyst volume expansion in ADPKD or tubule dilation in ARPKD, accelerating disease progression.

Adenosine Triphosphatases↗
PubMed1999

Can an autocrine loop explain sex-hormone-dependent tumor growth? A brief overview.

Sex hormones and their related compounds have been known to regulate the target cell growth positively or negatively in the receptor-dependent manner. The molecular mechanism of these complicated events, especially sex hormone-dependent growth enhancement, has been studied extensively. In MCF-7 cells, estrogen-induced autocrine loop has been demonstrated to play the important role for estrogen-dependent growth. Androgen has been also found to promote the growth of SC-3 cell through the induction of an autocrine growth factor (FGF 8). The blockade of FGF 8 activity resulted in a complete inhibition of androgen-dependent growth of SC-3 cells, suggesting that FGF 8 acts as an essential component of androgen-dependent growth. However, the constitutional expression of FGF 8 failed to convert SC-3 cells from an androgen-dependent to an androgen-independent phenotype. These observations would suggest that sex hormone-induced autocrine loop is an obligatory but not sufficient component for the growth of sex hormone-dependent tumor.

Androgens↗
PubMed2005

Autocrine and paracrine transcriptional regulation of type IIA secretory phospholipase A2 gene in vascular smooth muscle cells.

OBJECTIVE: The inflammation that occurs during the development of atherosclerosis is characterized by a massive release of sPLA2-IIA (group IIA secretory phospholipase A2) from vascular smooth muscle cells (VSMCs). We have investigated the autocrine function of sPLA2-IIA in rat aortic and human VSMCs. METHODS AND RESULTS: We found that the transcription of the endogenous sPLA2-IIA gene increased by adding a cell supernatant containing human sPLA2-IIA proteins. We show that this effect was independent of the sPLA2 activity using sPLA2-IIA proteins lacking enzyme activity. Transient transfections with various sPLA2-IIA rat promoter-luciferase constructs demonstrated that the C/EBP, NK-kappaB, and Ets transcription factors are involved in the increase in sPLA2-IIA gene transcription. We also found the M-type sPLA2 receptor mRNA in VSMCs, and we showed that the sPLA2-luciferase reporter gene was induced by the specific agonist of the sPLA2 receptor, aminophenylmannopyranoside (APMP), and that this induction was mediated by the same transcription factor-binding sites. Finally, we used a sPLA2-IIA mutant unable to bind heparan-sulfate proteoglycans to show that the binding of wild-type sPLA2-IIA to proteoglycans is essential for the induction of an autocrine loop. CONCLUSIONS: We have thus identified new autocrine and paracrine pathways activating sPLA2-IIA gene expression in rat and human VSMCs.

Animals↗
PubMedDate not supplied

Disruption of cadherin-related junctions triggers autocrine expression of vascular endothelial growth factor in bovine aortic endothelial cells : effects on cell proliferation and death resistance.

The mechanisms involved in the blockade of proliferation in confluent endothelial cells are insufficiently understood. In this regard, the continuity of intercellular junctions appears to be critical to the regulation of endothelial monolayer cell growth. The present study examined the hypothesis that the disruption of the intercellular adherens junctions will trigger both endothelial cell proliferation and autocrine production of growth factors. With this purpose, we assessed the changes in growth, death resistance, and expression of vascular endothelial growth factor (VEGF) under conditions of disruption of the intercellular junctions between endothelial cells. Disruption of cell junctions was produced by means of a specific anti-vascular endothelial cadherin monoclonal antibody, EGTA, or cytochalasin D. Our results disclosed that these maneuvers induce an increase in VEGF mRNA production, with transcription of the 121-, 165-, and 189-amino acid isoforms of VEGF. Further evidence of the relationship between endothelial cells monolayer continuity and VEGF protein expression was obtained by the demonstration of an increase in VEGF protein, as determined by Western blot, induced by the aforementioned maneuvers, as well as by immunocytochemical detection of increased VEGF staining in the areas surrounding a mechanical endothelial injury and in endothelial cells at subconfluence. In functional terms, the autocrine expression of VEGF was associated with growth-promoting and cytoprotective effects, as assessed by [(3)H]thymidine uptake, (51)Cr release, and flow cytometry. In conclusion, our results reveal that disruption of homophilic interendothelial junctions induces VEGF expression. Under these conditions, autocrine VEGF appears to have a relevant role in death inhibition and proliferation of endothelial cells.

Animals↗
PubMed2002

TGF-beta1 is an autocrine mediator of renal tubular epithelial cell growth and collagen IV production.

Recent studies in cultured cells have provided evidence that a variety of pathobiologic stimuli, including high glucose, angiotensin II, and thromboxane A(2), trigger a signaling pathway leading to autocrine induction of TGF-beta1. TGF-beta1 production through this pathway may profoundly affect cell growth, matrix synthesis, and response to injury. This study examines the role of autocrine versus exogenously added TGF-beta1 in cellular proliferation and collagen IV production, critical targets of TGF-beta1 signaling, using renal cells derived from TGF-beta1 knockout (KO) animals or wild-type (WT) controls. Growth of WT and KO cells was assessed by cell counting and [(3)H]thymidine uptake. Basal and TGF-beta1-stimulated collagen production was assessed by Northern and Western blotting; transcriptional activity of the alpha1(IV) collagen gene was assessed by transient transfection analysis. KO cells grew at a faster rate than WT cells carefully matched for plating density and passage number. This increased growth rate was paralleled by increases in [(3)H]thymidine uptake. KO cells expressed lower levels of the cell cycle inhibitors p21 and p27 than WT cells. KO cells failed to express TGF-beta1, as expected. Basal TGF-beta3 mRNA levels were higher in KO cells than in WT cells. WT cells expressed higher basal levels of TGF-beta2 mRNA than KO cells. Basal alpha1(IV) and alpha2(IV) collagen mRNA and protein expression were significantly lower in KO cells than WT cells. Administration of exogenous TGF-beta1 induced collagen IV production in both KO and WT cells. Although basal transcriptional activity of an alpha1(IV) collagen-CAT construct was lower in KO cells than WT cells, administration of exogenous TGF-beta1 was associated with significant increases in transcriptional activity of this construct in both KO and WT cells. These studies provide evidence that autocrine production of TGF-beta1 may play a critical role in regulation of growth and basal collagen IV production by renal tubular epithelial cells.

Animals↗
PubMed2005

Expression of vascular endothelial growth factor (VEGF) and its receptors in thyroid carcinomas of follicular origin: a potential autocrine loop.

OBJECTIVE: The aim of this study was to clarify the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) pathways in thyroid tumourigenesis. METHODS: We examined VEGF, VEGFR-1 and VEGFR-2 expression on 34 papillary thyroid carcinomas (PTCs), 18 follicular thyroid carcinomas (FTCs), eight poorly differentiated thyroid carcinomas (PDTCs) and on a thyroid tumour-derived cell line (NPA'87) by immunohistochemistry, reverse transcriptase PCR, immunofluorescence and Western blotting. RESULTS: We have demonstrated that VEGF expression was significantly (P < 0.05) more prevalent in PTCs (79%) than in FTCs (50%) or PDTCs (37%). Similarly, 76% of PTCs, 83% of FTCs and 25% of PDTCs expressed VEGFR-1, whereas 68% of PTCs, 56% of FTCs and 37% of PDTCs expressed VEGFR-2. Coexpression of VEGF and its receptors was observed in 50% of PTCs, 39% of FTCs and 12% of PDTCs, raising the possibility that VEGF may signal in an autocrine loop in these neoplasias, as observed previously for other types of cancer. In agreement with the idea that autocrine VEGF signalling plays an important role in thyroid carcinogenesis, the blockade of either VEGF or its receptors with neutralizing antibodies significantly reduced cell viability and increased apoptosis levels of the VEGFR-positive thyroid tumour cell line NPA'87. CONCLUSIONS: Our results highlight a previously undefined VEGF autocrine action in thyroid carcinomas which could play a crucial role in tumour cell survival and could represent a useful therapeutic target for thyroid tumours.

Adenocarcinoma, Follicular↗
PubMed2001

Transforming growth factor-beta1 autocrine stimulation regulates fibroblast proliferation in hereditary gingival fibromatosis.

BACKGROUND: Hereditary gingival fibromatosis (HGF) is a rare oral disease characterized by a slow and progressive enlargement of both the maxilla and mandible gingiva. Increased proliferation, elevated synthesis of extracellular matrix, particularly collagen, and reduced levels of matrix metalloproteinases seem to contribute to the pathogenesis of gingival overgrowth in HGF patients. Transforming growth factor-beta1 (TGF-beta1) is an important cytokine thought to play a major role in fibrotic disorders such as HGF due to its ability to stimulate the synthesis and reduce the degradation of extracellular matrix. In HGF fibroblasts, TGF-beta1 autocrine stimulation reduces expression and production of matrix metalloproteinases. However, the role of TGF-beta1 in fibroblast growth modulation has not been established in this disease. METHODS: The aim of this study was to confirm the increased proliferation rate of HGF fibroblast cell lines and to explore a possible autocrine role of TGF-beta1 as a cell growth stimulator by blocking production of this endogenous cytokine using 2 well-established systems: antisense oligonucleotides and neutralizing antibodies. RESULTS: Four different cellular proliferation assays, bromodeoxyuridine labeling, argyrophilic nucleolar organizing region staining, proliferating cell nuclear antigen, and mitotic indexes, confirmed that fibroblasts from HGF proliferate significantly faster than those from normal gingiva. Antisense oligonucleotides reduced TGF-beta1 production as demonstrated by capture enzyme-linked immunosorbent assay, whereas TGF-beta1 expression levels were not significantly modified. Blocking TGF-beta1 synthesis with oligonucleotides or its activity with specific antibodies resulted in a decreased magnitude of HGF fibroblast proliferation. CONCLUSION: These results are consistent with the existence of an autocrine role of TGF-beta1 as a stimulator of HGF fibroblast proliferation.

Adult↗
PubMed2001

SF/HGF-c-Met autocrine and paracrine promote metastasis of hepatocellular carcinoma.

AIM: To explore the role of SF/HGF-Met autocrine and paracrine in metastasis of hepatocellular carcinoma (HCC). METHODS: SF/HGF and c-met transcription and protein expression in HCC were examined by RT-PCR and Western Blot in 4 HCC cell lines, including HepG2, Hep3B, SMMC7721 and MHCC-1, the last cell line had a higher potential of metastasis. sf/hgf cDNA was transfected by the method of Lipofectin into SMMC7721. SF/HGF and c-met antibody were used to stimulate and block SF/HGF-c-met signal transduction. Cell morphology, mobility, and proliferation were respectively compared by microscopic observation, wound healing assay and cell growth curve. RESULTS: HCC malignancy appeared to be relative to its met-SF/HGF expression. In MHCC-1, c-met expression was much stronger than that in other cell lines with lower potential of metastasis and only SF/HGF autocrine existed in MHCC-1. After sf/hgf cDNA transfection or conditioned medium of MHCC-1 stimulation, SMMC7721 changed into elongated morphology, and the abilities of proliferation (P < 0.05) and mobility increased. Such bio-activity could be blocked by c-met antibody (P < 0.05). CONCLUSION: The system of SF/HGF-c-met autocrine and paracrine played an important role in development and metastasis potential of HCC. Inhibition of SF/HGF-c-met signal transduction system may reduce the growth and metastasis of HCC.

Autocrine Communication↗
PubMed2000

Granulocyte-macrophage colony-stimulating factor as an autocrine survival factor for mature normal and malignant B lymphocytes.

The role of GM-CSF in B cell (patho)physiology is unclear. Although B cells can respond to GM-CSF, there is controversy concerning the extent to which various resting and activated B cell types can themselves produce this cytokine, and the possibility that it can function in an autocrine fashion has not previously been considered. The aim of the present study was to address these issues using hairy cells (HCs) and chronic lymphocytic leukemia cells, two intrinsically activated mature malignant B cell types (with activation being more uniform and more pronounced in HCs). Normal B cells were used for comparison. Using a number of techniques, we demonstrated the constitutive production of GM-CSF by all three cell types and showed that the cytokine was biologically active. GM-CSF mRNA and protein were increased after cell activation by PMA, and constitutive production of the cytokine was highest in HCs, suggesting that the level of GM-CSF production is influenced by cell activation. Because GM-CSF is known to be antiapoptotic for myeloid cells, we used blocking anti-GM-CSF Abs to examine the contribution of autocrinely produced cytokine to cell survival. The Abs produced marked reduction in the in vitro survival of HCs, chronic lymphocytic leukemia cells, and normal B cells by promoting apoptosis. Taken together, these findings suggest that, in combination with other known rescue factors, autocrinely produced GM-CSF may contribute to normal and malignant B cell survival in vivo.

Autocrine Communication↗