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At least 865 records · Page 48Linked to original sources
PubMed1994

[Growth control of a human glioma cell line by multiple autocrine loop blockade].

Autocrine growth due to dysregulation of growth factor production may have a role in the development of neoplasia. We demonstrated that U251MG, a well characterized human malignant glioma cell line, had high affinity receptors for epidermal growth factor (EGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) by enzyme-linked immunosorbent assay. We assessed the inhibitory effect of anti-EGF receptor (EGFR), anti-FGF, and anti-PDGF monoclonal antibodies (MoAbs) on the growth of U251MG cells using the MTT assay and 3H thymidine uptake. At 50 micrograms/ml, the EGFR, FGF, and PDGF MoAbs significantly decreased cell numbers by 31.0%, 31.2%, and 31.0%, respectively, when compared to control cultures in the MTT assay. At the same concentration, the EGFR, FGF, and PDGF MoAbs reduced 3H thymidine uptake by 45.2%, 41.1%, and 40.0%, respectively, when compared to control cultures. At 50 micrograms/ml, a combination of the 3 MoAbs (16.6 micrograms/ml each) caused a 13.7% greater decrease in cell numbers in the MTT assay and an 11.9% greater decrease of 3H thymidine uptake. These findings suggest that the antigrowth factor MoAbs interrupted the autocrine loop at the growth factor receptor level. In conclusion, the demonstration that MoAbs directed against EGFR, FGF, and PDGF inhibit the growth of malignant glioma cells in vitro raises the possibility that these antibodies could be used clinically to treat malignant glioma either alone or conjugated to other agents.

Antibodies, Monoclonal↗
PubMed1994

Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor.

Human platelets contain platelet-derived growth factor (PDGF) in their alpha-granules which is released during platelet exocytosis. We show by immunoprecipitation and 125I-PDGF binding experiments that human platelets have functionally active PDGF alpha-receptors, but not beta-receptors. The PDGF alpha-receptor (PDGFR-alpha) was identified as a 170-kDa glycosylated protein-tyrosine kinase as found in other cell types. Stimulation of platelets with 0.1 unit/ml thrombin resulted in a significant increase (2-5-fold) of the tyrosine phosphorylation of the PDGFR-alpha, as determined by immunoprecipitation with phosphotyrosine antiserum as well as with PDGFR-alpha antiserum. The observed thrombin-induced autophosphorylation of the PDGFR-alpha was inhibited by the addition of a neutralizing monoclonal PDGF antibody. Thus, our results suggest that the platelet PDGFR-alpha is stimulated in an autocrine manner by PDGF secreted during platelet activation. Preincubation of platelets with PDGF inhibited thrombin-induced platelet aggregation and secretion of ATP + ADP and beta-hexosaminidase. Thrombin-induced platelet aggregation was also reversed when PDGF was added 30 s after thrombin stimulation. Inhibition of the autocrine PDGF pathway during platelet activation by the PDGF antibody led to a potentiation of thrombin-induced beta-hexosaminidase secretion. Thus, the PDGFR-alpha takes part in a negative feedback regulation during platelet activation. Our demonstration of PDGF alpha-receptors on human platelets and its inhibitory function during platelet activation identifies a new possible role of PDGF in the regulation of thrombosis.

Becaplermin↗
PubMed1994

Kirsten sarcoma virus-immortalized mast cell lines. Reversible inhibition of growth by dexamethasone and evidence for the presence of an autocrine growth factor.

Expansion of mast cell numbers occurs in vivo during certain inflammatory reactions, including active fibrosis, parasite infestations, and immediate hypersensitivity reactions. T cell-produced cytokines, including IL-3 and IL-4, are thought to control this mast cell proliferation in part, and glucocorticoid regulation of T cell-produced cytokines is thought to account for diminished mast cell proliferation during administration of glucocorticoids in vivo. Here we show that glucocorticoids have a direct inhibitory effect on proliferation of Kirsten sarcoma virus-immortalized mast cells (KiSV-MC) in vitro, with an ID50 of 1.0 +/- 0.2 nM dexamethasone (mean +/- SD, n = 4). At 10 nM dexamethasone, KiSV-MC proliferation was inhibited by 83 +/- 5% (mean +/- SD, n = 4). As determined by trypan blue staining and [3H]TdR incorporation, the glucocorticoid-mediated growth inhibition was due to diminished mast cell proliferation rather than cell death and was completely reversible after 6 days of glucocorticoid treatment. By cell cycle analysis, glucocorticoids diminished the percentage of mast cells in S phase and increased the percentage in G0-G1 phase. Although we show that the KiSV-MC proliferate via an autocrine mechanism, glucocorticoid treatment of the KiSV-MC did not inhibit their production of the autocrine growth factor. During 6 days of treatment with 1 to 1000 nM dexamethasone, mast cell carboxypeptidase activity increased by a maximum of 3.5-fold. In contrast, total chymotryptic and tryptic esterase activities diminished by as much as 40% with dexamethasone treatment. We conclude that glucocorticoids directly affect mast cell growth and differentiation at levels equal to the reported Kd for glucocorticoid receptors on other immune cells.

Animals↗
PubMed1993

Chemotaxis and haptotaxis of human malignant mesothelioma cells: effects of fibronectin, laminin, type IV collagen, and an autocrine motility factor-like substance.

A human malignant pleural mesothelioma cell line (STAV) was studied with respect to production of the extracellular matrix components laminin, type IV collagen, and fibronectin, and interactions with these proteins in vitro. We also analyzed STAV cell serum-free conditioned medium with respect to the possible presence of "autocrine motility factor-like" substance. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of biosynthetically labeled STAV serum-free conditioned medium showed that STAV cells released several proteins into the medium, including components with molecular weights of 850,000, 540,000 and 440,000. Using Western blotting we identified these proteins as laminin, type IV collagen, and fibronectin, respectively. By immunocytochemistry laminin, type IV collagen, and fibronectin were detected as a matrix surrounding the cells. Plastic culture dishes coated with microgram quantities of laminin, type IV collagen, and fibronectin induced attachment and spreading of STAV cells. Laminin, type IV collagen, and fibronectin stimulated directional (chemotactic) migration of STAV cells in Boyden chambers fitted with 8 microns filters. The same cells also migrated to insoluble step gradients of filter-bound extracellular matrix components (haptotaxis). When STAV serum-free conditioned medium was separated by using fast protein liquid chromatography Superose 6 gel filtration, two motility-inducing protein peaks were detected. The first peak contained proteins with molecular weight > 220,000 that had both chemotactic and haptotactic properties, while the second peak contained material with apparent molecular weights of approximately 67,000 that had chemotactic and chemokinetic (random motility) but not haptotactic properties. Analysis of the M(r) 67,000 material indicated that it was a heat-sensitive and trypsin-digestible protein. The production of both soluble and insoluble extracellular matrix components by human mesothelioma cells and the motile response to these molecules as well as the production of a M(r) 67,000 autocrine motility factor-like substance may be important for the highly invasive motile behavior of this tumor.

Cell Adhesion↗
PubMed1993

Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression.

Ovarian tumor cells produce macrophage colony stimulating factor, a potent chemoattractant for monocytes. Monocytes and macrophages produce tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha or interleukin 1 beta (IL-1 beta) that can stimulate ovarian tumor cell growth. The present study has explored whether paracrine stimulation by monocyte derived cytokines might induce autocrine growth stimulation of normal and malignant ovarian epithelial cells. Endogenous expression of TNF-alpha mRNA was detected in ascites ovarian cancer cells isolated directly from patients, but not in established cultures of normal or malignant ovarian epithelial cells. When ascites tumor cells were cultured for 7 days, TNF-alpha expression ceased but could be reinduced by treatment with TNF-alpha or IL-1 beta. Ascites fluid contained concentrations of the cytokines that could mediate these effects. Similarly, treatment of normal or malignant ovarian epithelial cells with purified recombinant IL-1 beta or TNF-alpha induced transcription of TNF-alpha mRNA within 1 h. TNF-alpha protein could be detected by enzyme-linked immunosorbent assay in conditioned medium from IL-1 beta treated ovarian cancer cells. [3H]thymidine incorporation by normal or malignant ovarian epithelial cells was stimulated by a 24-h incubation with IL-1 beta or TNF-alpha. Stimulation of proliferation by IL-1 beta could be partially blocked by an antibody against TNF-alpha or by soluble TNF-alpha-receptor. Thus, TNF-alpha may function as both an autocrine and a paracrine growth factor in ovarian cancer.

Animals↗
PubMed1993

Understanding the roles of growth factors in carcinogenesis: modulation of autocrine growth control by differentiation.

It is widely believed that abnormal proliferation of tumor cells is due, at least in part, to the production of autocrine growth factors that are not produced by their normal counterparts. However, direct support for this belief is seriously lacking. The normal counterparts of the vast majority of tumor cells have not been identified adequately and, thus, the growth factors produced by the normal counterparts of tumor cells have not been described. This review summarizes the remarkable similarity in the types of growth factors and growth factor receptors produced by early mouse embryos and by mouse embryonal carcinoma cells, the stem cells of teratocarcinomas. Based on these similarities and the likelihood that embryonal carcinoma cells are derived from the totipotent cells of the mammalian embryo, it is argued that there is reason to suspect that ectopic production of growth factors is not a major cause of tumor induction and tumor growth. It is further proposed that differentiation under normal conditions can limit autonomous cell proliferation by shifting cells from a population that produces growth stimulatory factors to cell types that produce growth inhibitory factors instead. Consequently, blocks in differentiation may lead to tumor growth by maintaining the production of growth stimulatory autocrine factors.

Animals↗
PubMed1993

Interleukin-11 acts as an autocrine growth factor for human megakaryoblastic cell lines.

The cytokine interleukin-11 (IL-11) promotes normal human megakaryocytopoiesis in vitro. However, its role in abnormal megakaryocytopoiesis is not well known. Accordingly, we studied its effects on human megakaryoblastic cell lines CMK and Meg-J. IL-11 stimulated the proliferation of CMK and Meg-J in a dose-dependent manner with maximal growth being achieved at the concentration of 50 and 500 ng/mL, respectively. The growth of the cells was inhibited by anti-IL-11 antibody and IL-11 antisense oligonucleotides. IL-11 transcripts were detected in these two cell lines using a reverse transcriptase-polymerase chain reaction assay. These findings indicate that IL-11 might be an autocrine growth factor for megakaryoblastic cells. IL-11 transcripts also existed in other leukemia cell lines: HL-60, U937, and K562. However, the growth of these cells was not stimulated by IL-11, and was not inhibited by IL-11 antisense oligonucleotides. These results suggested that IL-11 might regulate malignant cells of the megakaryocytic lineage, in part by an autocrine loop.

Base Sequence↗
PubMed1993

Glucocorticoids coordinately disrupt a transforming growth factor alpha autocrine loop and suppress the growth of 13762NF-derived Con8 rat mammary adenocarcinoma cells.

We have demonstrated previously that the synthetic glucocorticoid dexamethasone suppresses the growth of Con8 rat mammary tumor cells, which are derived from the 13762NF transplantable, hormone-responsive rat mammary adenocarcinoma. Dexamethasone inhibited [3H]thymidine incorporation into Con8 cells at high cell density under both serum and serum-free conditions. Fractionation in nonreducing sodium dodecyl sulfate-polyacrylamide gels of proteins secreted from dexamethasone-treated and untreated Con8 mammary tumor cells revealed two size classes of glucocorticoid inhibited mitogenic activities; a larger M(r) 27,000-33,000 and a smaller M(r) 5,000-12,000 activity. Both size classes of mitogens restimulated the growth of glucocorticoid-suppressed Con8 cells suggesting that they can act in an autocrine fashion. The smaller mitogen was identified as transforming growth factor alpha (TGF-alpha) since this activity competed with 125I-epidermal growth factor (EGF) for EGF receptor binding and was selectively immunodepleted with monoclonal TGF-alpha antibodies but not with EGF antibodies. Western blots and radioreceptor assay of Con8-secreted proteins revealed that glucocorticoids inhibited the production of a M(r) 5500 immunoreactive TGF-alpha protein by 10-fold. Consistent with a steroid effect on the level of TGF-alpha production, rather than on its activity, the specific mitogenic activities of the TGF-alpha s secreted by dexamethasone-treated and untreated Con8 cells were identical to that of recombinant human TGF-alpha. Treatment of intact cells with suramin, which dissociates ligand-receptor complexes, revealed that the EGF receptor-mediated mitogenic response is functional in both glucocorticoid-treated and untreated cells. Taken together, our results demonstrate that glucocorticoids suppress Con8 mammary tumor cell growth and disrupt a potential TGF-alpha autocrine loop which results in a dramatic reduction in the level of extracellular TGF-alpha.

3T3 Cells↗
PubMed1993

A potential transforming growth factor alpha/epidermal growth factor receptor autocrine circuit in placental cytotrophoblasts.

A potential autocrine loop involving transforming growth factor alpha (TGF-alpha) and the epidermal growth factor (EGF) receptor (EGFR) in benign placental cytotrophoblasts was examined. EGFR were localized to villous cytotrophoblasts and syncytiotrophoblasts in frozen sections throughout gestation using immunoperoxidase (IP) and autoradiography with 125I-EGF. EGF and TGF-alpha stimulated uptake of [3H]-thymidine in cultured cytotrophoblasts from first and second trimester placentae, demonstrating both functional EGFR and the mitogenic ability of either growth factor in these cells. Using IP, TGF-alpha was localized consistently throughout gestation to cytotrophoblasts with little or no staining of syncytiotrophoblasts in formalin-fixed sections. Variable staining of villous stromal cells and intense staining of maternal decidua were also observed. TGF-alpha production by cultured cytotrophoblasts was confirmed in vitro via IP analysis of cytotrophoblasts cultured in serum-free media and enzyme-linked immunosorbent assay analysis of cytotrophoblast serum-free conditioned media. The results suggest that a TGF-alpha/EGFR autocrine loop stimulates proliferation of benign cytotrophoblasts.

Cells, Cultured↗
PubMed1995

Endothelin-1 as an autocrine growth factor for endothelial cells.

To elucidate the role of endothelin-1 (ET-1) as an autocrine growth factor for vascular endothelial cells (ECs), we studied the effects of phosphoramidon, an inhibitor of ET-1-converting enzyme, on the production of ET-1-like immunoreactivity (LI), [125I]ET-1 binding activity, ETB receptor mRNA expression, phosphoinositide breakdown, and DNA synthesis in cultured bovine carotid artery ECs. Phosphoramidon dose-dependently decreased ET-1-LI production but reciprocally increased [125I]ET-1 binding capacity. ET-1 and ET-3 equipotently inhibited the binding of [125I]ET-1 only in the presence of phosphoramidon. Northern blot analysis revealed that ETB receptor mRNA expression was more evident in phosphoramidon-treated cells than in nontreated cells. In the presence of phosphoramidon, ET-1 and ET-3 equipotently stimulated inositol 1,4,5-trisphosphate formation and [3H]-thymidine incorporation into cultured ECs. Both phosphoramidon and anti-ET-1 antibody inhibited basal [3H]thymidine incorporation. These data suggest that endogenous ET-1 constitutively secreted by ECs is an autocrine growth factor via ETB receptors.

Animals↗
PubMed1995

Autocrine regulation of the endothelin-1 gene in rat endothelial cells.

We studied whether endothelin (ET)-1 regulates its own transcription in cultured rat aortic endothelial cells (ECs) in an autocrine manner and attempted to elucidate its cellular and molecular mechanism. By Northern blot analysis using rat preproET-1 cDNA as a probe, ET-1 increased steady-state levels of preproET-1 mRNA as early as 30 min, which persisted during 4 h incubation. ET-1 also increased steady-state c-fos mRNA levels, which returned to an undetectable level by 2 h. ET-1 dose-dependently upregulated preproET-1 mRNA expression. The effect was inhibited by nonselective ETA/ETB receptor antagonist but not a selective ETA receptor antagonist. The ET-1-induced preproET-1 mRNA expression was suppressed by a protein kinase C (PKC) inhibitor and by pretreatment with phorbol ester, which depeleted engdogenous PKC. The approximate half-life of preproET-1 mRNA stimulated by ET-1 (approximately 20 min) was similar to that stimulated by phorbol ester. Our data demonstrate that ET-1 upregulates its own gene expression through ETB receptor-mediated PKC activation, suggesting a possible autocrine positive feedback system in vascular endothelium.

Animals↗
PubMed1996

Fc receptor-induced expression of Fas ligand on activated NK cells facilitates cell-mediated cytotoxicity and subsequent autocrine NK cell apoptosis.

Ligation of the Fc gamma R on NK cells by Ab-coated target cells initiates a mode of killing referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). There is clear evidence that the release from NK cells of granules containing pore-forming proteins and serine proteases can result in the rapid (within minutes) cell death of Ab-coated targets. However, little information is available as to whether NK cells can initiate subsequent killing through granule-independent mechanisms and as to the mechanisms that down-regulate NK cell-mediated responses. We demonstrate in this study that FcR stimulation of activated human NK cells not only induces granule exocytosis, but also subsequently results in the transcriptional up-regulation of Fas ligand. These FcR-stimulated NK cells can then kill targets that bear Fas (CD95/APO-1), as this cytotoxicity can be inhibited by blocking Abs to the Fas receptor. In addition, as resting NK cells become activated, their Fas receptors become competent to deliver autocrine suicide signals. We demonstrate in this work that the interaction of Fas ligand on the FcR-stimulated NK cells with their Fas receptors can result in apoptosis of the NK cells. These results suggest that the FcR-induced expression of Fas ligand on activated NK cells can critically influence the capacity of these cells to mediate paracrine and autocrine cell death.

Apoptosis↗
PubMed1996

The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer, and its relevance as an autocrine growth factor.

The presence of a direct extra-pituitary action of gonadotropin-releasing hormone (GnRH) via specific receptors in endometrial cancer (EC) has been suggested as an explanation for the therapeutic effect of GnRH analogue (GnRHa) in recurrent disease. We have sought the expression of the GnRH peptide and functional GnRH receptor (GnRH-R) in human tissues and cell lines to investigate the possibility of an autocrine growth regulation mechanism. Using reverse transcription-PCR, differing GnRH mRNA transcripts were detected in two EC cell lines (Ishikawa and HEC-1A), a choriocarcinoma (JEG3) cell line, and tissues from endometrium and placenta. However, secretion of immunoreactive GnRH could be detected by RIA in only 1 of 10 EC tissues in primary culture, and in none of the cell lines. Low levels of GnRH-R mRNA expression were found in the same cells, which were only detectable by reverse transcription-PCR and Southern blotting of the PCR product. In radioligand binding assays using GnRHa goserelin, no pituitary-like, high-affinity GnRH binding sites could be found in either EC cell lines or tissues. Low affinity binding (Kd = 1.0 - 3.1 x 10(-7)M) was detected in three of eight (37%) EC tissues. Furthermore, receptor signal transduction measurements carried out in these cells showed no increases in either total inositol phosphate, cyclic AMP production, or cytosolic Ca2+ in response to either GnRH or GnRHa. Finally, no effect of either GnRH or GnRHa on the growth of EC cell lines was detected in vitro, under estrogen-free conditions, assessed by DNA content. Our data suggest that although there is a potential for autocrine activity for GnRH in EC as judged by the presence of mRNA for peptide and receptor, no functional receptor activity could be detected in vitro. Alternative mechanisms should be studied to explain the in vitro action of GnRHa.

Animals↗
PubMed1996

Overexpression of the insulin-like growth factor-1 receptor and autocrine stimulation in human cervical cancer cells.

We characterized mechanisms of growth control involving insulin-like growth factor-1 (IGF-1), IGF-2, and IGF-1 receptor (IGF-1R) by investigating their expression in human cervical cancer cell lines, primary cervical tumor cell cultures, and normal ectocervical epithelial cells maintained in short-term culture. By reverse transcription followed by PCR, IGF-1 mRNA was not detected in any of the cell lines, whereas IGF-2 mRNA transcripts were detected in all of them. Using the RNase protection assay, low levels of IGF-2 mRNA were also detected in all of the cervical cancer cell lines, primary cervical tumor cell cultures, and normal ectocervical cultures tested, but no IGF-1 transcripts were detected. Scatchard analysis revealed 3- and 5-fold increases in IGF-1R expression by the primary cervical cancer cell cultures and cervical cancer cell lines, respectively, compared with the normal ectocervical cells. In proliferation assays, epidermal growth factor (EGF) consistently enhanced cervical cancer cell growth, but an antisense oligonucleotide to IGF-2 uniformly inhibited the EGF-induced mitogenic effect. These studies suggest that autocrine production of IGF-2 and overexpression of the IGF-1R are important components controlling the proliferation of cervical carcinoma cells, and that autocrine IGF-2 production in cervical cancer cells may participate in the mitogenic signaling of EGF.

Base Sequence↗
PubMed1996

Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion.

Several cytokines have been suggested to play a regulatory action on the neoplastic clone of patients with B-cell chronic lymphocytic leukemia (B-CLL) by interfering in the differentiation, proliferation, or death/survival pathways. Interleukin-8 (IL-8) is a chemoattractant protein constitutively expressed at the mRNA level and released by B-CLL cells. In view of the presence of the IL-8 receptor mRNA and of specific IL-8 binding, confirmed also by Scatchard analysis using 125I-IL-8, the study was extended to evaluate the possible regulatory role of this cytokine on B-CLL cells. IL-8 failed to show any in vitro proliferative effect on leukemic B-CLL cells. By contrast, the propidium iodide (PI) staining of the DNA content showed that IL-8 could prolong the survival of resting B-CLL cells in 11 of 16 cases studied. In the remaining 5 cases, 90.6% +/- 4.39% SD of the cells after culture remained viable and IL-8 could exert a significant death protection action after pretreatment with 10(-4) mol/L hydrocortisone, which reduced the percentage of viable B-CLL cells. The dose range of IL-8 capable of inducing the prolonging survival effect is comparable with the levels of IL-8 released constitutively by B-CLL cells, indicating that the death protection action is exerted at physiologic doses. The in vitro rescue from death induced by IL-8 is reflected by an increased expression of bcl-2 mRNA in B-CLL cases incubated in the presence of IL-8. These findings were further confirmed at the protein level, because in B-CLL cells that displayed a bimodal bcl-2 intracytoplasmatic protein expression IL-8 was capable of upmodulating the bcl-2high expression peak. The potential autocrine regulatory action exerted by IL-8 is supported by the evidence that exogenous IL-8 can upregulate IL-8 mRNA in B-CLL cells. These results, together with the demonstration that antibody-mediated neutralization of endogenous IL-8 could induce a significant in vitro reduction in the number of living cells, further support the hypothesis that, in B-CLL, the physiologic doses of IL-8 released constitutively by the leukemic clone may play an autocrine role in the process of cell accumulation characteristic of this disease.

Antigens, CD↗
PubMed1995

Iodide-dependent regulation of thyroid follicular cell proliferation: a mediating role of autocrine insulin-like growth factor-I.

An inhibitory action of intracellular iodide on the autocrine production of insulin-like growth factor-I (IGF-I) by thyroid follicular cells (TFCs) in vitro has been investigated as a possible mechanism underlying the iodide-dependent control of TFC proliferation. IGF-I release from primary monolayer cultures of porcine TFCs increased 5-fold between 24 and 168 h of incubation. Confirmation of a mediating role of IGF-I in TFC proliferation was obtained by exposing TFCs to an immunoadsorbing IGF-I antiserum, which led to a significant (P < 0.05) decline in [methyl-3H]thymidine incorporation, relative to TFCs exposed to preimmune serum. Exposure of TFCs to sodium iodide (NaI; 0.1-100 mumol/l) led to an attenuation of the IGF-I content of the cell-conditioned medium. This was accompanied by a reduction in [methyl-3H]thymidine incorporation that was affected by IGF-I immunoneutralization. The inhibitory effect of NaI on IGF-I production and [methyl-3H]thymidine incorporation were reversed by the thionamide compound methimazole (MMI; 1 mmol/l), exposure to which also led to significant (P < 0.001) increases above control values. However, a residual suppressive effect of NaI on [methyl-3H]thymidine incorporation suggested that certain of the TFC growth-attenuating effects of iodide may not be dependent upon organification. While providing evidence, therefore, for a direct relationship between iodide exposure, suppression of autocrine IGF-I production and a regulation of TFC proliferation, the present studies also suggest that suppression of TFC proliferation by iodide may be partially mediated by MMI-insensitive events.

Animals↗
PubMed1996

Interleukin 1 induces an autocrine loop hepatocyte growth factor/c-Met in murine Kaposi-like spindle cells.

Several cytokines, growth factors and the HIV transactivator Tat were shown to be involved in the pathogenesis of Kaposi's sarcoma. BKV/tat transgenic mice develop Kaposi's sarcoma-like lesions, and spindle-shaped cells (TTB) have been derived from these lesions. Here we show that TTB cells co-express hepatocyte growth factor (HGF) and its receptor, the product of the oncogene c-Met. An autocrine loop HGF/Met sustains spindle cell proliferation in vitro; indeed, an antisense oligomer targeted against HGF markedly inhibited cell growth. Moreover, HGF and Met are overexpressed after exposing TTB cells to the proinflammatory cytokine interleukin 1 (IL-1). We argue that upon exposure to IL-1, an HGF/Met autocrine loop is induced which could explain the appearance of multiple foci of uncontrolled growth. In addition, due to its angiogenic activity, HGF may also sustain the neovascularization typical of Kaposi's sarcoma lesions.

Animals↗
PubMed1996

Identification of a hepatocyte growth factor autocrine loop in a murine mammary carcinoma.

Constitutive activation of growth factor receptors through autocrine/paracrine mechanisms occurs frequently in human cancers and is thought to play an important role in carcinogenesis. We have demonstrated previously that hepatocyte growth factor (HGF) is a potent mitogenic factor for murine mammary carcinoma (SP1) cells in vitro. We report here an autocrine HGF loop in SP1 cells. HGF receptor/Met is expressed in SP1 cells and is constitutively tyrosine phosphorylated. The phosphorylation of HGF receptor/Met is inhibited when cells are exposed to suramin or anti-HGF IgG. This finding suggests that constitutive tyrosine phosphorylation of HGF receptor/Met is sustained by an extracellular factor, most likely HGF. Using Northern blot and Western blot analysis, we detected expression of a 6-kb HGF mRNA in SP1 cells and a M(r) 85,000 HGF protein in SP1-conditioned medium, respectively. In vitro translation of mRNA from SP1 cells and metabolic labeling confirmed expression and synthesis of HGF by SP1 cells. SP1 cells also invade through Matrigel-coated transwell membranes in an in vitro invasion assay, and invasion of these cells was inhibited by neutralizing anti-HGF IgG. In addition, SP1-conditioned medium induced scatter activity of Madin-Darby canine kidney epithelial cells, and this activity was inhibited by neutralizing anti-HGF IgG. We have also shown that several signaling molecules including phosphatidylinositol 3-kinase, Src, focal adhesion kinase, and phospholipase C-gamma in SP1 cells are constitutively tyrosine phosphorylated, suggesting that coexpression of HGF and HGF receptor/Met may in part contribute to sustained tyrosine phosphorylation of these cytoplasmic proteins in SP1 cells. Our observations in the SP1 model suggest that HGF contributes to growth and invasive phenotypes of mammary carcinomas via both paracrine and autocrine mechanisms.

3T3 Cells↗