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PubMed1996

Roles of protein phosphatase 1 and 2A in an IL-6-mediated autocrine growth loop of human myeloma cells.

Deregulation of IL-6 production is one of the major causes for human multiple myeloma. Exogenous IL-6 stimulated the proliferation of fresh human myeloma cells and the myeloma cell line, U266, which produced IL-6 spontaneously. Anti-IL-6 antibody and IL-6 antisense oligonucleotide suppressed the IL-6 stimulated myeloma cell proliferation, indicating that IL-6 induced the myeloma cell proliferation via an autocrine loop. Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, inhibited the U266 cell proliferation at a concentration of less than 1 ng/ml. At this concentration, okadaic acid suppressed the IL-6-induced IL-6 gene expression of myeloma cells. It seems that the okadaic acid blocked the myeloma cell proliferation by reducing IL-6 synthesis in myeloma cells. In addition, IL-6 itself also regulated IL-6 receptor expression. Analysis by FACScan and RT-PCR showed that anti-IL-6 antibody treatment up-regulated IL-6 receptor expression. Interestingly, the presence of okadaic acid induced the up-regulation of IL-6 receptor expression as well as the down-regulation of IL-6-induced gp130 phosphorylation in the myeloma cells. Taken together, these data suggest that protein phosphatase 1 and 2A are involved in IL-6-mediated autocrine growth of human myeloma cells by modulating IL-6 signaling and IL-6 receptor expression in myeloma cells.

Animals↗
PubMed1996

Evidence for endogenous C1q modulates TNF-alpha receptor synthesis and autocrine binding of TNF-alpha associated with lipid A activation of murine macrophages for nitric oxide production.

The role of endogenously synthesized complement subcomponent C1q on autocrine binding of tumor necrosis factors (TNF-alpha) and on TNF-alpha receptor (TNF-R) mRNA synthesis by mouse macrophages was investigated. Activation of C3H mouse peritoneal macrophages (C3H-PM phi) by Lipid A induced TNF-alpha and nitric oxide (NO) to kill tumor targets. Such activation also increased macrophage-endogenous C1q synthesis and secretion in a dose-dependent fashion. Antibody for C1q markedly inhibited C3H-PM phi NO production in response to Lipid A, but had no effect on TNF-alpha production. C3H-PM phi treated with C1q or Lipid A displayed increased TNF-R mRNA synthesis and in combination with Lipid A and anti-C1q antibody inhibited TNF-R and nitric oxide synthase (NOS) mRNA synthesis compared with Lipid A only, but had no effect on TNF mRNA synthesis. In vitro treatment of C3H-PM phi with C1q also increased TNF-alpha binding to their surfaces. Taken together, the data indicate that endogenously synthesized C1q is operative in promoting TNF-R mRNA synthesis and resultant autocrine binding of TNF-alpha for induction of NOS in the process of NO-mediated tumor cytotoxicity by Lipid A-activated macrophages.

Adjuvants, Immunologic↗
PubMed2000

Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro.

Cell lines derived from human colon carcinomas secrete interleukin 8 (IL-8) in vitro and this chemokine has also been detected immunohistochemically in human colon carcinoma specimens, in which it is tumour cell associated. In these experiments, IL-8 was shown to comprise an important component of the angiogenic activity of colon carcinoma cell line supernatants. The effect of modulating IL-8 activity upon the growth of the colon carcinoma cell lines HCT116A, HT29 and CaCo2 was investigated. Supplementing endogenously produced IL-8 by recombinant chemokine led to stimulation of cell growth. Neutralization of the effect of endogenously produced IL-8, either with the specific antagonist peptide AcRRWWCR or with blocking anti-IL-8 antibody, resulted in around 50% inhibition of cell growth (P<0.05). All of the colon carcinoma cell lines tested expressed mRNA for both IL-8RA and RB when grown at confluence. At the protein level, all cell lines expressed IL-8RA. Expression of IL-8RB was weak, although increased expression was seen in HCT116A cells as they approached confluence. Antibodies to IL-8RA and RB did not affect proliferation at low cell density but were strongly inhibitory when cells were cultured at a higher density. These data suggest that IL-8 acts as an autocrine growth factor for colon carcinoma cell lines and would support the concept that a similar autocrine loop operates in vivo.

Carcinoma↗
PubMed1994

Acute myocardial infarction leads to upregulation of the IGF-1 autocrine system, DNA replication, and nuclear mitotic division in the remaining viable cardiac myocytes.

Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are required for cell proliferation in vitro, raising the possibility that an autocrine IGF-1-IGF-1R system may be present in vivo and become activated in the viable ventricular myocytes shortly after infarction. Therefore, following the in vivo documentation of left ventricular failure in rats subjected to occlusion of the left coronary artery, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF-1R and IGF-1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of expression of IGF-1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary ligation. In addition, an increased level of IGF-1R protein on these cells was found. This phenomenon was coupled with the enhanced expression of IGF-1 mRNA in the muscle cells at all intervals. Myocardial infarction was also accompanied by an upregulation of proliferating cell nuclear antigen (PCNA) mRNA in myocytes and the detection of PCNA protein in nearly 1% of the cells. Similarly, bromodeoxyuridine labeling demonstrated that a comparable number of myocytes was positively stained. Finally, mitotic images in myocytes were observed. Thus, the IGF-1R-IGF-1 autocrine system may modulate myocyte cellular hyperplasia in the failing heart.

Animals↗
PubMed1997

Schwann cells express NDF and SMDF/n-ARIA mRNAs, secrete neuregulin, and show constitutive activation of erbB3 receptors: evidence for a neuregulin autocrine loop.

Cultured Schwann cells secreted low levels (30 pg/ml/1.5 x 10(6) cells) of a 45-kDa neuregulin protein and showed constitutive activation of a neuregulin receptor, Erb-B3, suggesting the existence of an autocrine loop involving neuregulins in Schwann cells. RT-PCR analyses indicated that Schwann cells and fibroblasts in culture produced SMDF/n-ARIA and NDF but not GGF neuregulin messages. Schwann cell and fibroblast neuregulin messages encoded both beta and alpha domains; Schwann cell transcripts encoded only transmembrane neuregulin forms while fibroblast messages encoded transmembrane and secreted forms. SMDF/n-ARIA and NDF messages were also expressed in early postnatal rat sciatic nerve, suggesting a role for neuregulins in peripheral nerve development. An anti-neuregulin antibody inhibited the mitogenic response of Schwann cells to cultured neurons and to extracts of cultured neurons or embryonic brain, consistent with the accepted paracrine role of neuregulins on Schwann cells. Surprisingly, the same antibody inhibited Schwann cell proliferation stimulated by several unrelated mitogens including bFGF, HGF, and TGF-beta1. These data implicate both paracrine and autocrine pathways involving neuregulin form(s) in Schwann cell mitogenic responses.

Animals↗
PubMed1996

Cultured endometrial cancer cells exhibit autocrine growth factor stimulation that is not observed in cultured normal endometrial cells.

OBJECTIVE: To evaluate the autocrine stimulation hypothesis, primary cultures of malignant and normal endometrium were assayed for differences in response to growth factors (GF) GF and receptor blocking antibodies. METHODS: Thirteen normal and 10 malignant endometrial samples were collected. Cells were enzymatically dispersed and maintained in serum-free medium. They were incubated with epidermal GF (EGF), transforming GF-alpha (TGF-alpha), insulin-like GF-I (IGF-1), anti-EGF receptor antibody (Ab528), and anti-IGF-1 receptor antibody (alpha IR3) at physiologic concentrations. Tritiated thymidine incorporation was measured. RESULTS: Malignant endometrial cells increased thymidine incorporation when incubated with EGF (20.75%), TGF-alpha (19.8%), or IGF-1 (32.8%) compared to untreated control cells. When incubated with Ab528 or alpha IR3 antibodies alone, proliferation of malignant cells was inhibited (-12.4 and -23%, respectively, P < 0.003). Normal endometrial cells were inhibited by EGF (-24.9%), TGF-alpha (-25.6%), and IGF-1 (31.9%). Incubation of normal cells with Ab528 and alpha IR3 antibodies stimulated growth (125 and 115%, respectively, P < 0.02). CONCLUSIONS: These data are consistent with the autocrine stimulation hypothesis for neoplastic endometrium and illustrate differences compared to nonneoplastic endometrial growth factor-mediated proliferation.

Antibodies↗
PubMed1996

IL-6 antisense-mediated growth inhibition of a choriocarcinoma cell line: an intracellular autocrine growth mechanism.

The growth of tumor cells can be regulated by a variety of cytokines. To investigate the pathogenesis of choriocarcinoma and explore a new therapeutic approach for the carcinoma, we examined the role of IL-6 in the growth of a human choriocarcinoma cell line (JEG-3). IL-6 was identified in the supernatant of the cell culture medium by enzyme-linked immunosorbent assay, indicating that this cell secreted IL-6. The mRNAs of IL-6, IL-6 receptor and gP130, the IL-6 signal transducer, in this cell were shown to be present by reverse transcriptase polymerase chain reaction assay and confirmed by Southern blot hybridization and direct sequencing. The addition of hrIL-6 to the cell culture failed to stimulate cell growth. Monoclonal antibodies against IL-6, IL-6 receptor, and gP130 were also unable to inhibit the proliferation of this cell line. The antisense oligonucleotides targeting IL-6 mRNA, however, inhibited both cell growth and IL-6 production. Taken together, these findings indicate that endogenous IL-6 plays an important role in the growth of the JEG-3 cell line, and it exerts its action by an intracellular autocrine growth mechanism. The results also suggest that the therapeutic trials with monoclonal antibodies designed to neutralize IL-6 or block its receptor will likely fail, whereas the antisense oligonucleotides targeted to IL-6 mRNA may have some value for the treatment of choriocarcinoma and other cancers with intracellular autocrine growth fashion mediated by IL-6.

Antibodies, Monoclonal↗
PubMed1994

Functional glucocorticoid receptor modulates pancreatic carcinoma growth through an autocrine loop.

Several peptide hormones have been shown to influence growth and function in pancreatic carcinoma and have given evidence for an autocrine feedback loop governing the proliferation of these malignant cells. Conversely, steroid hormones including glucocorticoids have been shown to inhibit the growth of pancreatic cancer cells; however, the prevalence of the glucocorticoid receptor or its mechanism of growth suppression in these tumors is unknown. The ability of growth factors thought to be active in this autocrine loop to reverse the glucocorticoid-induced growth inhibition was studied in vitro in a human pancreatic adenocarcinoma (HPAC) cell line with a well-characterized glucocorticoid receptor (GR). The glucocorticoid dexamethasone (DEX) inhibited growth in a dose-dependent manner as measured by a [3H]thymidine incorporation assay as well as an MTT cell proliferation assay. Maximal effects were seen within 48 hr at a concentration of 100 nM DEX, suppressing growth to approximately 18% of control. When the maximally suppressed DEX-treated cells were exposed to exogenous growth factors, they rapidly attained or exceeded the growth rate of control cells: insulin-like growth factor = 106%, transforming growth factor-alpha = 134%, insulin = 151%, and epidermal growth factor = 187% (all P < 0.05, Student's t test). In order to determine the frequency of the GR in pancreatic cancer and the clinical relevance of our findings, immunohistochemical staining for the GR was performed on 20 human tumors. Twelve (60%) of all cancers, as well as all normal pancreatic tissues (n = 4), stained positively for cytoplasmic and/or nuclear GR with expression correlating highly with degree of tumor differentiation (Kruskal-Wallis test, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma↗
PubMed1995

Transforming growth factor-beta 1 serves as an autocrine inhibitor of human endothelial cell/lymphocyte adhesion.

Other investigators have shown that exogenously administered transforming growth factor-beta (TGF-beta) inhibits lymphocyte adherence to vascular endothelial cells (VEC). We examined the role of TGF-beta 1 as an autocrine mediator of lymphocyte adhesion to adult human VECs. VECs were harvested from eight saphenous or cadaveric iliac veins using 0.2% collagenase. Low-passage VECs in MCDB + 0.1% BSA were pretreated for 24 hr with monoclonal anti-TGF-beta 1 antibody (5 micrograms/ml), LPS (5 micrograms/ml), or IL-1 (10 U/ml). Adherence of fluorescently labeled lymphocytes to pretreated VECs was quantitated and results were expressed as relative adhesion compared to untreated control. Total mRNA from LPS- or IL-1-treated VECs was subjected to Northern analysis to determine relative TGF-beta 1 expression. Total TGF-beta 1 protein concentration in supernatants from LPS- or IL-1-treated VECs was determined by ELISA. Data (means +/- SEM) were analyzed by ANOVA with a Newman-Keuls posttest. Neutralizing endogenous TGF-beta 1 with anti-TGF-beta 1 antibody significantly increased adhesion of lymphocytes to VEC monolayers compared to control (125 +/- 3 vs 101 +/- 2%, P < 0.01, n = 8). The level of adhesion was equivalent to that seen with IL-1 stimulation (131 +/- 6%). Spearman correlation of lymphocyte adherence to IL-1- or LPS-treated VECs vs TGF-beta 1 mRNA expression or vs relative TGF-beta 1 protein concentration showed significant inverse relationships (r = -0.82, P < 0.001, and r = -0.87, P < 0.001, respectively). Endogenous TGF-beta 1's inhibitory effect on lymphocyte adhesion was blocked by a specific neutralizing antibody. VEC TGF-beta 1 mRNA expression and TGF-beta 1 production were inversely proportional to lymphocyte adhesion, suggesting down-regulation of TGF-beta 1 in response to proinflammatory cytokines. Together, these observations support the hypothesis that TGF-beta 1 has an autocrine inhibitory role in regulation of lymphocyte adhesion to VECs.

Adult↗
PubMed1999

High-cell-density phorbol ester and retinoic acid upregulate involucrin and downregulate suprabasal keratin 10 in autocrine cultures of human epidermal keratinocytes.

Autocrine growth of human epidermal keratinocytes is initiated in subconfluent cell cultures in the absence of exogenous growth factors, at low calcium concentration of the medium and with sufficient cell density. Culture confluence inhibits keratinocyte proliferation and upregulates expression of early, keratin 10 (K10), and late, involucrin, markers of differentiation. In this report, the phenotype of autocrine keratinocytes was studied at high cell density (postconfluence), specifically after treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA), or all-trans retinoic acid (RA). At postconfluence, K10 is decreased but not involucrin. TPA upregulates involucrin expression, but not K10 in subconfluent keratinocytes. Treatment of confluent keratinocytes with RA downregulates K10, but upregulates involucrin. This in vitro culture model, unlike others, simulates for the first time the in vivo effects of RA, a member of the retinoid family which potently modulates keratinocyte differentiation and the expression of selected gene products. It thus can be developed to further examine epidermal differentiation.

Biomarkers↗
PubMed2000

Biosynthesis of interleukin-6, an autocrine growth factor for melanoma, is regulated by melanoma-derived histamine.

Interleukin-6 is an autocrine growth factor in advanced stage melanoma and biosynthesis of IL-6 is increased by histamine in various cell lines. In our study we analysed the direct relation of histamine and IL-6 synthesis in human melanoma cell lines. All melanoma cells contained IL-6 mRNA, but only metastatic melanoma cells secreted the IL-6 protein. The H1 histamine receptor antagonist triprolidine decreased gene expression and biosynthesis of IL-6, while other histamine receptor antagonists had no effect. These data indicate that endogenous histamine has a definite role in the regulation of local IL-6, suggesting that histamine and IL-6 could be part of autocrine growth regulation of the tumor.

Glucose-6-Phosphate Isomerase↗
PubMed2000

Examining new models for the study of autocrine and paracrine mechanisms of angiogenesis through FGF2-transfected endothelial and tumour cells.

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumour neovascularization. Several growth factors and cytokines have been shown to stimulate endothelial cell proliferation in vitro and in vivo and among them FGF2 was one of the first to be characterised. FGF2 is a Mr 18,000 heparin-binding cationic polypeptide that induces proliferation, migration, and protease production in endothelial cells in culture and neovascularization in vivo. FGF2 interacts with endothelial cells through two distinct classes of receptors, the high affinity tyrosine-kinase receptors (FGFRs) and low affinity heparan sulfate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix. Besides experimental evidence for paracrine mode of action for FGF2, some observations raise the hypothesis that FGF2 may also play an autocrine role in endothelial cells. FGF2 may therefore represent a target for anti-angiogenic therapies. In order to assess the angiostatic potential of different classes of compounds, novel experimental models have been developed based on the autocrine and/or the paracrine capacity of FGF2.

Angiogenesis Inhibitors↗
PubMed1995

Endocrine, paracrine and autocrine regulation of testicular steroidogenesis.

Testicular steroidogenesis takes place almost exclusively in Leydig cells. Some metabolism of the androgens produced by Leydig cells takes place in seminiferous tubules, especially in the immature animal (e.g. aromatization and 5 alpha- reduction). Luteinizing hormone (LH) is the main tropic regulator of Leydig cell function, without which quantitatively important androgen production is not possible. LH acts through a receptor that belongs to the seven times cell membrane spanning, G protein associated, receptor family, and cyclic AMP is the main second messenger of its signal transduction. Information about the involvement of other signal transduction systems in LH action has also emerged recently. The action of LH is under manyfold modulation by other hormones (e.g. prolactin, growth hormone and insulin), growth factors and bioactive peptides. In this modulation, various paracrine and autocrine mechanisms play an important role. Seminiferous tubules influence the development and function of adjacent Leydig cells through several growth factors. When germ cells are damaged, Leydig cells in the vicinity proliferate faster. Leydig cell morphology also depends on the germ cell composition in the neighbouring seminiferous tubules, and certain stages of the seminiferous epithelial cycle increase the Leydig cell capacity to produce testosterone. Also negative modulation of Leydig cells by Sertoli/germinal cell derived factors has been demonstrated. However, the physiological importance of the paracrine and modulatory influences of the different hormones and growth factors still remains obscure since almost all information has so far been obtained from in vitro studies. In the study of testicular steroidogenesis, the main switch of the function, LH action, is well known whereas the role of the "in house" circuits of paracrine and autocrine regulation remain to be elucidated.

Amino Acid Sequence↗
PubMed1989

Suramin inhibits binding and degradation of platelet-derived growth factor in arterial smooth muscle cells but does not interfere with autocrine stimulation of DNA synthesis.

During in vitro culture arterial smooth muscle cells of adult rats are able to produce a platelet-derived growth factor (PDGF)-like protein and to promote their own growth in an autocrine manner. Here, this process has been studied using suramin, a polyanionic drug that has been reported to interfere with the cellular binding of several growth factors. Our results indicate that suramin speeds up the transition of the cells from a contractile to a synthetic phenotype early in primary culture. It inhibits the binding of PDGF to the cells, displaces PDGF bound to the cell surface, and slows down the degradation of PDGF internalized by the cells. It reduces the specific activities of the lysosomal enzymes acid phosphatase, beta-N-acetylglucosaminidase and beta-glucuronidase, and gives rise to an accumulation of lysosomes with myelin-like inclusions. It blocks PDGF- and serum-induced DNA synthesis and cellular proliferation in secondary cultures, but lacks a distinct inhibitory effect on DNA synthesis in primary cultures under serum-free conditions. The results suggest that the PDGF-like protein produced by the smooth muscle cells under the latter conditions may bind to its receptor and exert its autocrine effect intracellularly, without prior release into the pericellular space.

Animals↗
PubMed1988

Autocrine growth stimulation of human keratinocytes by epidermal cell-derived thymocyte-activating factor: implications for skin aging.

The monocyte-derived cytokine interleukin-1 (IL-1) has growth-promoting activity for a variety of cell types, including lymphocytes and fibroblasts. We have previously shown that the epidermal cell-derived thymocyte-activating factor (ETAF) strongly resembles IL-1 in terms of biological, biochemical, and molecular biological properties. Because some lymphokines are known ot alter epidermal cell growth and differentiation and because cultured epidermal keratinocytes are capable of autocrine growth stimulation in vitro through "conditioning" of their culture medium, we sought to evaluate the effect of ETAF on keratinocyte growth. While there was marked donor variability in the responsiveness of keratinocytes to ETAF, partially purified preparations of ETAF showed substantial ability to stimulate the growth of keratinocytes, particularly those of newborn donors. In addition, in conditioned media there appeared to be activities distinct from ETAF that also promoted keratinocyte growth. Keratinocytes in serum-free medium secreted large amounts of ETAF, as reported previously, and keratinocyte cultures derived from newborn donors secreted significantly more than did those derived from adult donors. These results are consistent with an autocrine growth regulatory role of ETAF in human epidermis and with an age-associated loss of this phenomenon.

Adult↗
PubMed1997

Identification of an autocrine mechanism for regulating cell-cycle progression in murine keratinocytes.

Primary murine keratinocytes possess a limited doubling potential regardless of plating density or the inclusion of competence factors insulin, epidermal growth factor, and/or fetal bovine serum within the culture medium. In contrast, a murine cell line (CH-72), derived from a 7,12-dimethylbenz[a]-anthraceneinitiated, 12-O-tetra-decanoylphorbol-13-acetate-promoted mouse skin carcinoma, was found to exhibit unlimited proliferative potential; this was demonstrated by the ability of these cells to produce the progression factor required for entry into the DNA-synthesis phase in the absence of competence-factor stimulation. Conditioned medium, collected from murine carcinoma cells, was subsequently shown to increase the level of [3H]thymidine incorporation in competence-factor-deprived CH-72 cultures by more than a factor of 4 within 16 h. Moreover, consistent with its ability of recruit cells cycling within the first gap phase directly into the DNA-synthesis phase, the autocrine progression factor present in conditioned medium decreased the G1:S ratio from the 55:29 observed with growth medium controls to 38:46. Preliminary characterization of the autocrine factor produced by cultured murine carcinoma cells using gel-filtration chromatography revealed a molecular mass of less than 2 kDa, similar in size to the factor previously shown by our laboratory to promote G1-phase progression in cultures of normal human foreskin keratinocytes.

Animals↗
PubMed1986

8th San Antonio Breast Cancer Symposium--Plenary lecture. Autocrine and paracrine growth regulation of human breast cancer.

We consider the hypothesis that estrogen control of hormone dependent breast cancer is mediated by autocrine and paracrine growth factors secreted by the breast cancer cells themselves. Though we show direct, unmediated effects of estrogen on specific cell functions, we also provide evidence that human breast cancer cells secrete a collection of growth factors (IGF-I, TGF alpha, TGF beta, a PDGF-like competency factor, and at least one new epithelial colony stimulating factor). Some of these are estrogen-regulated in hormone dependent cells, and are constitutively increased in cells which acquire independence either spontaneously or by ras transfection. Collectively, the secreted growth factors are capable of promoting tumor formation by MCF-7 cells in nude mice, though not to the same extent as estrogens. There would seem to be potential for clinical intervention in the autocrine and paracrine control of breast cancer cells, including some cells which are no longer dependent on estrogens.

Breast Neoplasms↗
PubMed1991

Autocrine and paracrine growth factors in tumor growth: a mathematical model.

A mathematical model of tumor growth including autocrine and paracrine control has been developed. The model starts with the logistic equation of Verhulst: dV/dt = rV (1-V/K). Autocrine controls are described as modifiers of the Malthusian growth rate (r), while paracrine controls modify the carrying capacity (K) of the system. The control mechanisms are expressed in terms of "candidate" functions, which are based upon the dynamic distribution of TGF-alpha TGF-beta in the local tumor environment. Three paradigms of tissue growth have been modeled: normal tissue wound repair, unrestricted, unperturbed tumor growth, and tumor growth in a (radiation) damaged environment (the Tumor Bed Effect, TBE). These scenarios were used to test the dynamics of the system against known phenomena. Computer simulations are presented for each case. The mode is being extended to include the description of heterogeneous tumors, within which subpopulations can express differential degrees of growth activity. Heterogeneous tumor models, with and without emergent subpopulations, and models of terminal differentiation are also discussed.

Animals↗