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At least 595 records · Page 33Linked to original sources
PubMed1996

Interferon-beta, an autocrine cytokine, suppresses human fetal skin fibroblast migration into a denuded area in a cell monolayer but is not involved in the age-related decline of cell migration.

The migration of human skin fibroblasts into a denuded area in a cell monolayer declined during in vitro and in vivo aging. We carried out a study to determine whether this age-related decline in cell migration was mediated by the autocrine cytokine interferon-beta (IFN-beta), which has been reported to suppress the proliferation, chemotaxis and collagen synthesis of human fibroblasts. Actually, IFN-beta specifically suppressed the migration of TIG-3S human fetal skin fibroblasts into a denuded area in a cell monolayer, as shown by the dose response experiments of IFN-beta and neutralizing anti-IFN-beta antibody. IFN-beta also inhibited their collagen synthesis but the addition of type I collagen could not reverse IFN-beta-induced inhibition of cell migration. Double strand RNA, which has been generally known to induce IFN-beta in human skin fibroblasts, suppressed the migration of TIG-3S cells. Next, a study was done to determine whether IFN-beta and double strand RNA suppressed the migration of TIG-3S cells in late passages as well as early passages, or whether neutralizing anti-IFN-beta antibody stimulated the migration of TIG-3S cells in late and middle passages. IFN-beta and double strand RNA suppressed the migration of TIG-3S cells in middle (PD45) and late (PD55) passages as well as in early passages (PD23-28). Neutralizing anti-IFN-beta antibodies could not reverse the low migratory activity of middle and late passage cells to the high migratory activity of early passage cells. These results indicated that the autocrine cytokine IFN-beta did not seem to be involved in the age-dependent decline of fibroblast migration.

Antigen-Antibody Reactions↗
PubMed1984

Coexpression of a PDGF-like growth factor and PDGF receptors in a human osteosarcoma cell line: implications for autocrine receptor activation.

The expression of both a PDGF-like growth factor and functional PDGF receptors within a clonal human osteosarcoma cell line (U-2 OS Cl 6) is demonstrated. These molecules are able to interact and induce tyrosine-specific phosphorylation and early actin reorganization in the osteosarcoma cells, effects similar to those that PDGF induces in normal responsive cells. Furthermore, immunoprecipitation with an antiserum against phosphotyrosine revealed that a 115 kd protein was constitutively phosphorylated in U-2 OS Cl 6 cells. A phosphorylated protein of similar apparent molecular weight has been found in human fibroblasts, but only after stimulation with PDGF. These data indicate that the PDGF-receptor-dependent pathway is constitutively activated in this cell line. Extracellularly added PDGF antibodies did not, however, affect the transformed properties or growth rate of U-2 OS Cl 6 cells in vitro. This indicates that autocrine PDGF receptor activation may be insignificant for maintaining the transformed state of this tumor cell line, or that autocrine receptor activation occurs in a compartment where it is inaccessible to extracellularly added antibodies.

Antibodies↗
PubMed1994

The role of low-affinity interleukin-2 receptors in autocrine ligand binding: alternative mechanisms for enhanced binding effect.

T-cell proliferation is regulated by the autocrine ligand interleukin-2 (IL-2), for which these cells possess dual, low-affinity and high-affinity receptor populations. Proliferation stimulated by IL-2 is dependent upon ligand binding to p75, a component of the high-affinity receptor. As with other cells exhibiting dual receptor systems, a central question is, therefore: what is the role of the low-affinity receptor population? We apply a mathematical modeling approach to examine three alternative mechanisms that have been suggested for the role of low-affinity receptors: a ligand reservoir, a receptor reservoir, and a ligand carrier. Using model parameter values specific to the IL-2/T-cell system, we find that only the ligand carrier mechanism leads to binding of autocrine ligand to high-affinity receptors that is increased over levels found on a single, pre-formed high-affinity receptor population. With the ligand reservoir and the receptor reservoir mechanisms, the presence of the low-affinity receptors actually diminishes high-affinity receptor binding due to competition. In contrast, excess low-affinity receptors can act to enhance the level of high-affinity receptor complexes when membrane transport is included, indicating that should this mechanism be inhibited, cell response could potentially be reduced or eliminated. The ligand carrier effect is especially significant for cells expressing a large number (> 10(5) receptors/cell) low-affinity receptors, and at low cell densities (< 10(4) cells/ml). This may at least partially account for the behavior demonstrated by early phase adult T-cell leukemia cells.

Biological Transport↗
PubMed1993

IGF receptor function and regulation in autocrine human neuroblastoma cell growth.

Insulin-like growth factor-II (IGF-II) and its receptors (type I and II IGF receptors) are expressed in the nervous system in a tissue and developmentally specific manner. We have previously shown that SH-SY5Y human neuroblastoma cells synthesize and secrete high levels of IGF-II, and respond to it with increased neuritic outgrowth, DNA synthesis, and cell proliferation. SH-SY5Y cells also produce type I IGF and IGF-II/M6P receptors; however, it is not known whether these receptors mediate the observed growth promoting effects of IGF-II. In this study, we assayed the role of type I IGF receptor and IGF-II/M6P receptor expression in mediating autocrine IGF-II induced growth. Using anti-receptor antibodies, we found that IGF-II stimulates cell proliferation via the type I IGF receptor but not via the IGF-II/M6P receptor. By Northern analysis, we detected increased mRNA expression of both receptors, with more dramatic changes in type I IGF receptor expression. Collectively, our results indicate a role for the type I IGF receptor in mediating IGF-II induced autocrine neuroblastoma cell growth.

Animals↗
PubMed1991

Autocrine control of adipose cell differentiation by prostacyclin and PGF2 alpha.

The mitogenic-adipogenic effect exerted by arachidonic acid, which leads to terminal differentiation of Ob1771 mouse preadipocytes, has been shown to be (i) blocked by cyclooxygenase inhibitors, (ii) mimicked by a stable analogue of prostacyclin (carbaprostacyclin) and (iii) potentiated by PGF2 alpha. Since these prostanoids are known to be synthesized and secreted by preadipocytes, we have proposed that both prostacyclin as the key mediator and PGF2 alpha as a modulator control the expression of terminal events of adipose conversion by means of an autocrine mechanism (Gaillard, D. et al. and Negrel, R. et al. Biochem. J. (1989) 257, 389-397 and 399-405). In order to test this hypothesis, the release of prostacyclin, characterized under the form of its stable degradation product 6-keto-PGF1 alpha, and that of PGF2 alpha have been studied in the culture medium of Ob1771 cells. A striking increase in the release of 6-keto-PGF1 alpha and to a minor degree of PGF2 alpha was observed when cells were exposed to arachidonic acid as shown by using [3H]arachidonic acid prelabelled cells or by radio-immunoassays. Since antagonists of PGF2 alpha and PGI2 receptors were not available, specific antibodies directed against PGF2 alpha and 6 beta-PGI1, another stable analogue of prostacyclin, were added as neutralizing agents in the culture medium. These antibodies were able to counteract the mitogenic-adipogenic effect of arachidonic acid. Prostacyclin and PGF2 alpha thus appear as autocrine mediators in the process of adipose conversion.

Adipose Tissue↗
PubMed1989

Evidence for autocrine production of IGF-1 in human thyroid adenomas.

We have recently shown that epithelial cells from a high proportion of benign human thyroid tumours (follicular adenomas) have escaped from the requirement of the normal cell for an exogenous source of insulin-like growth factor 1 (IGF-1), suggesting either autocrine production or intracellular generation of an IGF-1-induced growth signal. We show here that conditioned medium from these adenoma cells can confer IGF-1 independence on normal thyroid epithelial cells and that this activity is abolished by immunoadsorption with an anti-IGF-1 antibody. In addition, tumour but not normal cells contain immunoreactive IGF-1. Our data provide the first evidence for autocrine production of IGF-1 (or a related factor) in a benign epithelial tumour and suggest that this may be a key early step in thyroid tumorigenesis.

Adenoma↗
PubMed1994

Autocrine growth factors produced in the thyroid.

This catalogue of autocrine growth factors is limited to proteins--metabolites of iodine and prostaglandins are omitted and they are undoubtedly of autocrine importance in the thyroid, as elsewhere. However, this summary of polypeptide growth factors secreted by the thyroid illustrates the potential cells have to condition their environment to modify their responses to external stimuli. This enables cells in different tissues to respond to agonists in different ways. The effects of TSH on IGF, IGFBP and IGF receptor production and the effects of IGFBPs on IGF action are good examples of this amplified response. Many pieces of the jigsaw, however, remain to be found and put in place before a clear picture of the regulation and roles of these factors can be made.

Animals↗
PubMed1984

Effects of retinoids on the proliferation of murine sarcoma virus-transformed cells in serum-free culture: potentiation of autocrine stimulation.

In a recent report, we described a growth stimulatory effect of vitamin A derivatives (retinoids) on murine sarcoma virus (MSV)-transformed cell lines when tested in a serum-free culture condition. These cell lines were presumed to proliferate via autostimulatory (autocrine) mechanism when serum was omitted from culture medium. In the present communication, we examined the effect of 6 synthetic derivatives on the serum-free proliferation of 2 MSV-transformed cell lines. We confirmed essentially the previous results and found that one of them (Ro 11-1430) was a very weak growth stimulator. Further evidence indicated that retinoid-mediated growth stimulator. was not the result of increased production of growth factors but the result of potentiation of autocrine stimulation.

Animals↗
PubMed1995

Insulin-like growth factor-I is an autocrine regulator for the brain metastatic variant of a human non-small cell lung cell line.

Insulin-like growth factor (IGF-I) is associated with autocrine and paracrine stimulation for cell growth and development of brain tumor cells. The function of IGF-I in the brain metastatic variant of human lung cancer cells is investigated. The cells used here were derived in vivo with intracarotid injection of human non-small cell lung carcinoma NCI-H226. The tumor was developed as a cultured cell line, H226Br. Unlike the parental cells, H226Br was tumorigenic in nu/nu nude mice. Reverse transcriptase-polymerase chain reaction showed that IGF-I transcript of H226Br is increased compared to that of parental cells. The amount of IGF-I secreted in cultured medium of H226Br is higher than that of cultured parental cells. The IGF-I receptor-specific antibody, alpha IR3, inhibits H226Br growth in serum-free culture. The results established that IGF-I is an autocrine growth regulator for human non-small cell lung cancer cells that progressed to brain.

Animals↗
PubMed1989

The human serum amyloid A (SAA)-encoding gene GSAA1: nucleotide sequence and possible autocrine-collagenase-inducer function.

We have determined the genomic sequence of the human GSAA1 gene, a member of the family of acute-phase human serum amyloid A (SAA)-encoding genes. This sequence predicts a mature protein of 104 amino acids (aa), several of which differ from residues usually conserved in the sequence of SAA proteins isolated from serum. Despite coding differences, however, the four-exon structure of GSAA1 resembles that of other SAA genes in humans and mice. The N-terminal 25 aa of the mature GSAA1 protein are virtually identical to those of an 'SAA-like' autocrine collagenase inducer produced by rabbit synovial fibroblasts; the latter also differ from the corresponding aa found in SAA in serum. We propose that GSAA1 is the human gene coding for a protein closely related to the SAA, but which is adapted to this important autocrine cytokine function.

Amino Acid Sequence↗
PubMed1991

Autocrine secretion of an EGF-like substance by a cell line (HSC-1) derived from a human skin squamous cell carcinoma.

The presence of EGF-autocrine secretion was investigated in a cell line derived from a human squamous cell carcinoma (HSC-1). The cell line was found to secrete the epidermal growth factor (EGF)-like substance. Meanwhile, normal human and uninvolved and involved psoriatic epidermal cells did not show any evidence of EGF secretion in culture. Not was any evidence of EGF secretion observed in vitro in several malignant cell lines other than HSC-1 derived from human squamous cell carcinomas, adenocarcinoma and melanoma. The addition of EGF did not stimulate, but rather inhibited, the growth of HSC-1 cells in GIT medium as well as Dulbecco's modified essential medium with low concentrations of fetal calf serum (0.5-1%) in vitro. Overexpression of EGF receptors is known to occur in HSC-1. The results suggest that HSC-1 cells exhibit autocrine secretion of the EGF-like substance but not autostimulation in anchorage-dependent cell culture.

Carcinoma, Squamous Cell↗
PubMed1995

An essential role of androgen-induced growth factor in glucocorticoid-dependent autocrine loop in Shionogi carcinoma 115 cells.

Androgen-induced growth factor (AIGF) is essential for the androgen-induced autocrine growth of a mouse mammary Shionogi carcinoma cell line (SC-3 cells). Because glucocorticoid and estrogen have been observed to weakly stimulate DNA synthesis in SC-3 cells, the expression of AIGF mRNA after stimulation with various concentrations of androgen, glucocorticoid, or estrogen was examined by Northern blot analysis. Testosterone, dexamethasone, and estradiol-17 beta (E2) induced AIGF mRNA expression, although the maximum AIGF mRNA expression levels induced by dexamethasone or E2 were lower than that by testosterone. Yet, diethylstilbestrol showed no induction, suggesting that the effect of E2 could be mediated through the androgen receptor. The induction levels of AIGF mRNA by each steroid hormone were correlated positively with hormone-induced DNA synthesis. In addition, the DNA synthesis induced by each steroid hormone was almost completely inhibited by AIGF antisense oligonucleotides, indicating that AIGF is an obligatory component in not only the androgen- but also the glucocorticoid-inducible autocrine loop in SC-3 cells.

Androgens↗
PubMed1992

Autocrine growth stimulation by transforming growth factor-alpha in human non-small cell lung cancer.

We studied the biological response to and production of transforming growth factor-alpha (TGF-alpha) by the non-small cell lung carcinoma (NSCLC) clonal cell lines H226b, H322a, H460a, H596b. Each of these cell lines expressed epidermal growth factor receptor (EGFR) as determined by [125I]EGF competitive binding and Scatchard analysis and by phosphorylation. The receptors were functionally active as determined in immune complex kinase assays. H322a, H226b, H460a, and H596b cells showed stimulated [3H]thymidine (Thd) uptake in response to TGF-alpha. Exogenously added TGF-alpha increased colony formation in soft agar for three of the cell lines in media containing serum. All cell lines expressed TGF-alpha detected by immunohistochemistry and TGF-alpha mRNA, although to differing degrees. Cell lysates and spent media competed for EGFR binding with EGF, thus demonstrating production of TGF-alpha-like activity. The anti-TGF-alpha monoclonal antibody AB-3 inhibited the uptake of [3H]Thd by proliferating H322a and H226b cells but not H460a and H596b cells. No inhibition occurred with MOPC21 antibody and inhibition was completely reversed by addition of TGF-alpha to the culture. Suramin inhibited cell proliferation and [3H]Thd uptake by all cell lines. Inhibition of H460a and H596b cells was reversed with exogenous TGF-alpha but not PDGF. Our data suggests that TGF-alpha is a mediator of autocrine growth stimulation for NSCLC cells, and that for some NSCLC cells cytoplasmic binding of receptor and ligand is the primary mechanism for autocrine growth stimulation.

Animals↗
PubMed2004

Proteolytic processing of TGFalpha redirects its mitogenic activity: the membrane-anchored form is autocrine, the secreted form is paracrine.

Wild-type transforming growth factor alpha (TGFalpha) expression in lactotrope cells in the pituitary gland led to lactotrope-specific pituitary hyperplasia and adenomata. To indicate whether the EGF receptor is involved in this TGFalpha-mediated phenotype, we bred TGFalpha mice with mice expressing the cytoplasmic truncated-EGF receptor (EGFR-tr), which is dominant-negative in other models. These bitransgenic mice developed pituitary pathology despite expression of the dominant-negative receptor. To further characterize this observation, we generated two lineages of transgenic mice that overexpress mutant forms of TGFalpha: a processed soluble form (s TGFalpha) and a cytoplasmic-deleted form (TGFalphaDeltaC). While sTGFalpha expression in lactotrope cells failed to induce autocrine lactotrope hyperplasia, the pituitary became very enlarged due to proliferation of neighboring interstitial cells. In contrast, the TGFalphaDeltaC mice did not develop a phenotype, although the mRNA and protein were present in the pituitary and this form of TGFalpha was confirmed to be biologically active and targeted properly to the plasma membrane of cultured CHO cells. The results suggest that the cytoplasmic domain of TGFalpha is required for autocrine parenchymal tumor formation in the pituitary gland. This signal cannot be inhibited by the EGFR-tr. Conversely, the released form of TGFalpha appears to have primarily paracrine activity.

Animals↗
PubMed2006

Autocrine activation of cultured macrophages by brain-derived neurotrophic factor.

To elucidate a significance of the expression of brain-derived neurotrophic factor (BDNF) in the activated microglia/macrophages of the injured central nervous system, we examined BDNF actions on or BDNF synthesis by macrophages cultured from the mouse peritoneal cavity. They synthesized BDNF and neurotrophin-3 (NT-3) in addition to expressing high-affinity neurotrophin receptors, full-length TrkB (FL), truncated TrkB (TK(-)), and TrkC, thus suggesting an autocrine influence of BDNF and NT-3. BDNF, but not NT-3, enhanced phagocytic activity and stimulated synthesis/secretion of interleukin-1beta in the same manner as lipopolysaccharide (LPS). Furthermore, there was a significant correlation of the phagocytic activity with the expression of BDNF or TrkB (FL). These results imply that the phagocytic activity of macrophages depends on BDNF synthesis and/or TrkB (FL) expression, suggesting that BDNF participates in the activation processes of macrophages by acting in an autocrine manner.

Animals↗
PubMed2004

Autocrine erythropoietin signaling inhibits hypoxia-induced apoptosis in human breast carcinoma cells.

Disordered perfusion and the resulting hypoxia are important features conferring tumor heterogeneity, which may contribute to relapse. Hypoxic tumor cells have been associated with resistance both to radiation and to cytotoxic drugs. Hypoxia may also serve as a selection pressure in tumors by promoting apoptosis of some cells and expanding variants with decreased apoptotic potential, and thus play a role in the development of a more aggressive phenotype. Erythropoietin (Epo), induced by hypoxia, controls erythropoiesis and plays a role in protection of neurons from hypoxic damage. We have recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervix cancers, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas. In the current study we provide evidence that increased autocrine Epo signaling induced by moderate levels of hypoxia inhibits hypoxia-induced apoptosis and promotes survival in MCF-7 human breast cancer cells. The anti-apoptotic effect of Epo correlates with upregulation of bcl-2 and bcl-XL, suggesting a mechanism similar to those described in hematopoietic cells. The resulting decreased apoptotic potential of hypoxic tumor cells may contribute to increased aggressiveness and therapy resistance of breast cancers.

Apoptosis↗
PubMed2004

Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis.

We deleted the hypoxia-responsive transcription factor HIF-1alpha in endothelial cells (EC) to determine its role during neovascularization. We found that loss of HIF-1alpha inhibits a number of important parameters of EC behavior during angiogenesis: these include proliferation, chemotaxis, extracellular matrix penetration, and wound healing. Most strikingly, loss of HIF-1alpha in EC results in a profound inhibition of blood vessel growth in solid tumors. These phenomena are all linked to a decreased level of VEGF expression and loss of autocrine response of VEGFR-2 in HIF-1alpha null EC. We thus show that a HIF-1alpha-driven, VEGF-mediated autocrine loop in EC is an essential component of solid tumor angiogenesis.

Animals↗
PubMed2004

PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma.

PDGFs and their cognate tyrosine kinase alpha- and beta-receptors are involved in multiple tumor-associated processes including autocrine growth stimulation of tumor cells, stimulation of tumor angiogenesis and recruitment and regulation of tumor fibroblasts. The recent development of clinically useful PDGF antagonists, like STI571/Glivec, has increased the interest in PDGF receptors as cancer drug targets. Autocrine PDGF receptor signaling occurs in certain malignancies characterized by mutational activation of PDGF or PDGF receptors, for instance, dermatofibrosaracoma protuberans, gastrointestinal stromal tumors, and hypereosinophilic syndrome. The roles of PDGF in regulation of tumor angiogenesis and tumor fibroblasts are more general, and probably occur in most common solid tumors. Concerning tumor angiogenesis recent studies have predominantly focused on the importance of PDGF receptor signaling for tumor pericyte recruitment. PDGF receptors in the tumor stroma have also attracted attention as interesting drug targets because of their function as regulators of tumor interstitial fluid pressure, tumor transvascular transport and tumor drug uptake. In summary, the improved understanding of the role of PDGF signaling in tumor biology, and the introduction of PDGF antagonists, has set the stage for a continued development of PDGF antagonists as novel cancer drugs.

Animals↗