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PubMed2001

Human EGF receptor (HER) family and heregulin members are differentially expressed in epidermal keratinocytes and modulate differentiation.

Human EGF receptor (HER), also designated HER1, is an activatable tyrosine kinase receptor. HER1 activation regulates cell growth and differentiation in epidermal keratinocytes. Expression of other HER family members was investigated in human keratinocytes cultured under autocrine conditions. HER2 and HER3 are expressed and upregulated by confluence, concurrent with induction of epidermal differentiation. HER4 is not expressed by keratinocytes. Maximum expression of the cognate ligand, heregulin, is observed in subconfluent keratinocytes, and the expression of both heregulin alpha and beta isoforms is downregulated with confluence. Recombinant heregulin isoforms have no effect on colony formation and keratinocyte proliferation, but heregulin beta activates tyrosine phosphorylation of HER2 and HER3, with no effect on HER1, in confluent differentiating keratinocyte cultures. Also, heregulin beta increases HER2/HER3 heterodimerization under those conditions. Treatment of confluent cultures by heregulin beta correlates with cell signaling and inhibition of epidermal differentiation. Together, HER2, HER3, and heregulin constitute a potential autocrine-paracrine system involved in epidermal homeostasis and repair, as well as in hyperproliferative pathologies.

Autocrine Communication↗
PubMed2002

TGFbeta induced myofibroblast differentiation of rabbit keratocytes requires synergistic TGFbeta, PDGF and integrin signaling.

There is a growing consensus that corneal myofibroblasts are derived from adjacent stromal keratocytes which undergo an orderly phenotypic transition from quiescent keratocyte to activated fibroblast to myofibroblast. Both in vivo and in vitro studies have shown this transition to be dependent, in part, on transforming growth factor beta (TGFbeta). In many fibroblastic cells autocrine production of platelet derived growth factor (PDGF) is known to mediate the growth up-regulation by TGFbeta. In this study, blocking antibodies to PDGF significantly reduced by 80% (P<0.025) the TGFbeta1 stimulated cell cycle entry of serum-free cultured rabbit corneal keratocytes. AntiPDGF treatment also markedly reduced the TGFbeta1-induced intracellular actin filament re-organization, fibronectin fibril assembly, and focal contact formation as well as reducing by 80% the expression of alpha-smooth muscle (alpha-SM) specific isoform of actin characteristic of myofibroblast differentiation. Although PDGF treatment of quiescent keratocytes produced an activated, fibroblastic cell type, PDGF stimulated keratocytes exhibited the same temporal, myofibroblastic differentiation response to TGFbeta1 as did quiescent keratocytes. Furthermore, blocking TGFbeta1 induction of myofibroblast differentiation with the Arg-Gly-Asp containing peptide, GRGDdSP, for 3 days followed by allowing progression of myofibroblast differentiation by removing GRGDdSP did not change the temporal response or tyrosine phosphorylation cascade (2-72 hr) leading to myofibroblast differentiation. Nor did PDGF treatment of keratocytes reverse the RGD blockade of TGFbeta1 induced myofibroblast differentiation. Overall these cumulative findings indicate that myofibroblast differentiation in the rabbit corneal keratocyte requires synergistic growth factor/integrin signaling involving TGFbeta, PDGF, and the fibronectin receptor. Additionally, the similar TGFbeta1 temporal response of PDGF-stimulated compared to nai;ve keratocytes suggests that myofibroblast differentiation does not require transition through a fibroblast phenotype.

Actins↗
PubMed1998

Electrostimulation of catecholamine release in the eel: modulation by antagonists and autocrine agonists.

The innervated chromaffin cells of the eel (Anguilla rostrata) release norepinephrine (NE) and epinephrine (E), while a component of the macrovascular wall releases dopamine (DA). The release of the three catecholamines is governed by complex controls which include adrenergic, nicotinergic, muscarinergic, and opioid mechanisms. To gain insight into the interactions between neural and autocrine factors in stimulated catecholamine release, we investigated the effect of adrenergic (phentolamine and propranolol) and muscarinergic (atropine) receptor antagonists, and of autocrine opioids (met-enkephalin, codeine, and morphine) on electrostimulated catecholamine secretion in situ. The hind brain (close to the root of nerve IX) of anesthetized eels was stimulated at four different time points, and segments of the posterior cardinal vein or the caudal vein were perfused with a saline solution, with or without test substances. Electrostimulation (30 s) four times within a total study duration of 14 min increased the release of DA, NE, and E into the perfusate of the cardinal vein. The vessel contains the innervated adrenomedullary equivalent. In the noninnervated caudal vein electrical stimulation had no impact on total DA release, while there was a slight decrease of NE release and a slight increase of E release. In the cardinal vein, both the alpha-adrenergic receptor antagonist phentolamine and the beta-adrenergic receptor antagonist propranolol strongly reduced the effect of electrostimulation on catecholamine release. Met-enkephalin reduced the release of all three catecholamines to a similar degree; its impact on NE release was especially strong. Codeine reduced the catecholamine release moderately, while morphine had no effect. Atropine reduced the release of all three catecholamines in a pattern similar to that of met-enkephalin. The findings on the posterior cardinal vein indicate that neurally stimulated NE and E release (1) involves autocrine/paracrine adrenergic mechanisms, (2) involves a muscarinergic mechanism, and possibly also endogenous codeine and morphine; and (3) is antagonized by met-enkephalin. The findings on the caudal vein are further evidence that macrovascular DA release is not under direct neural control.

Adrenergic Agonists↗
PubMed2000

Occurrence of immunoreactive Activin/Inhibin beta(B) in thyrotropes and gonadotropes in the bullfrog pituitary: possible Paracrine/Autocrine effects of activin B on gonadotropin secretion.

Occurrence of immunoreactive activin/inhibin beta(B) in the bullfrog (Rana catesbeiana) pituitary was investigated immunocytochemically by use of antibody against Xenopus activin/inhibin beta(B) subunit. Thyrotropes were demonstrated to contain activin/inhibin beta(B)-immunoreactive substances. Moreover, immunoelectron microscopy revealed that in the secretory granules of thyrotropes and, to a lesser extent, in those of gonadotropes, activin/inhibin beta(B)-immunoreactive substances were present. Based on this observation, we investigated the effect of activin B on the release of gonadotropins from dispersed anterior pituitary cells of the bullfrog. Activin B stimulated the release of not only follicle-stimulating hormone (FSH) but also luteinizing hormone (LH) dose dependently. Under the culture conditions used in this experiment, inhibin B, as well as follistatin, did not affect the basal levels of LH and FSH, but they suppressed the activin-induced release of these hormones. This is the first study on the effect of activin on pituitary hormone secretion in lower tetrapods.

Activins↗
PubMed1998

Transforming growth factor-alpha and insulin-like growth factor-I, but not epidermal growth factor, elicit autocrine stimulation of mitogenesis in endometrial cancer cell lines.

OBJECTIVES: Endometrial carcinoma cell lines were evaluated for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and insulin-like growth factor I (IGF-1) production and for autocrine stimulation. METHODS: Conditioned, serum-free media (CM) from cell lines RL95-2, KLE, HEC, and Ishikawa (ISH) were concentrated radioimmunoassayed (RIA). Samples for the IGF-1 assay were extracted with acid-ethanol to remove IGF-1 binding protein. Polymerase chain reaction (PCR) was used to validate the presence of mRNA for growth factors and receptors. Cells were incubated with Ab528, an antibody blocking EGF receptors, and alphaIR3, an antibody blocking IGF-1 receptors. Proliferation was quantified using [3H]thymidine incorporation. RESULTS: TGF-alpha was detected in CM: RL95-2 (0.4 +/- 0.001 ng/ml), KLE (0.7 +/- 0.003 ng/ml), HEC (0.8 +/- 0.01 ng/ml), ISH (1.2 +/- 0.05 ng/ml). No EGF was detected in CM. In extracted samples, IGF-1 was detected in CM: RL95-2 (0.8 +/- 0. 03 ng/ml), KLE (1.25 +/- 0.02 ng/ml), HEC (1.6 +/- 0.01 ng/ml), ISH (1.6 +/- 0.08 ng/ml). Unconditioned media served as the control. EGF, TGF-alpha, and IGF-1 mRNA was identified in all cell lines, as was the mRNA for EGF and IGF-1 receptors. Incubation with Ab528 or alphaIR3 resulted in significant inhibition of DNA synthesis in HEC 1A, KLE, and ISH. No inhibition was detected in the RL95-2 cell line. A control antibody did not inhibit the cell lines. CONCLUSION: Autocrine production and stimulation of endometrial carcinoma cell lines by TGF-alpha and IGF-1 are demonstrated in three of four endometrial cancer cell lines. No measurable EGF was produced by any of the cell lines.

Autocrine Communication↗
PubMed1999

Autocrine regulation of TGF beta expression in adult cardiomyocytes.

As shown before, TGF beta acts in an autocrine manner on the induction of hypertrophic responsiveness to beta-adrenoceptor stimulation in cultured ventricular cardiomyocytes of adult rat. We now investigated how TGF beta expression and activation is regulated in these cultures and how beta-adrenoceptor stimulation influences TGF beta -mRNA expression. It was found that freshly isolated cardiomyocytes secrete latent TGF beta in the culture medium. Supplementation of the cultures with 20% FCS resulted in activation of the secreted TGF beta to 4.1+/-0.2 ng/ml active TGF beta after 6 days. Presence of the protease inhibitor aprotinin (50 microg/ml) reduced TGF beta activity by 44+/-5% (n=5, P<0.05). In cultures supplemented with 5% FCS, TGF beta was not activated. Active TGF beta downregulated its mRNA-expression: after 6 days TGF beta(1)-mRNA was reduced to 55.1+/-11.0%, TGF beta(2)-mRNA to 30.1+/-16.5%, and TGF beta(3)-mRNA to 0.3+/-0.4% in 20% FCS-cultures as compared to their expression in freshly isolated cells (n=4, P<0.05). TGF beta-mRNA expression did not change in cultures without active TGF beta. Isoprenaline (1 microm) increased TGF beta(1)-mRNA only in cultures which had been pre-exposed to active TGF beta. This effect was also seen when hearts from normal mice were compared with hearts from transgenic mice overexpressing TGF beta(1): only in hearts from transgenic animals perfusion with isoprenaline increased TGF beta(1)-mRNA. In conclusion, isolated cardiomyocytes release latent TGF beta, which is activated by external proteases. Active TGF beta downregulates its own mRNA expression. Preexposure to TGF beta is necessary for a beta-adrenoceptor-mediated increase in TGF beta(1)-mRNA in cardiomyocytes.

Animals↗
PubMed2002

Interplay between the cardiac renin angiotensin system and JAK-STAT signaling: role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure.

Recent studies have shown that the JAK-STAT signaling pathway plays a central role in cardiac pathophysiology. JAK-STAT signaling has been implicated in pressure overload-induced cardiac hypertrophy and remodeling, ischemic preconditioning, and ischemia/reperfusion-induced cardiac dysfunction. The different STAT family members expressed in cardiac myocytes appear to be linked to different, and at times, opposite responses, such as cell growth/survival and apoptosis. Thus, differential activation and/or selective inhibition of the STAT proteins by agonists for G-protein coupled receptors, such as angiotensin II, may contribute to cardiac dysfunction during ischemia and heart failure. In addition, JAK-STAT signaling may represent one limb of an autocrine loop for angiotensin II generation, that serves to amplify the actions of angiotensin II on cardiac muscle. The purpose of this article is to provide an overview of recent findings that have been made for JAK-STAT signaling in cardiac myocytes and to highlight some unresolved issues for future investigation. The central focus of this review is on recent studies suggesting that modulation or activation of JAK-STAT signaling by ANG II has pathological consequences for heart function.

Angiotensinogen↗
PubMed2002

Somatostatin receptor subtype 2 gene therapy inhibits pancreatic cancer in vitro.

BACKGROUND: Most human pancreatic adenocarcinoma cells do not express somatostatin receptors and somatostatin does not inhibit the growth of these cancers. We have demonstrated previously that somatostatin inhibits the growth of pancreatic cancers expressing somatostatin receptor subtype 2 (SSR2) but not receptor-negative cancers. SSR2 expression may be an important tumor suppressor pathway that is lost in human pancreatic cancer. We hypothesized that SSR2 gene transfer would restore the growth inhibitory response of human pancreatic cancer to somatostatin. METHODS: We created adenoviral constructs containing the SSR2 or Lac-Z gene and transfected somatostatin receptor-negative human pancreatic cancer cells (Panc-1). Presence of functional cell surface SSR2 protein was assessed by whole-cell competitive binding assays. Parental cells, Lac-Z-transfected, and SSR2-transfected cells were cultured in the presence and absence of somatostatin. The rate of cell growth was determined by direct cell counting using a hemacytometer (n = 8 wells/group). Cells were analyzed for expression of tumor suppressor proteins by Western blot. RESULTS: Panc-1 cells transfected with the SSR2 transgene demonstrated high-affinity specific binding of (125)I-somatostatin at physiologic concentrations. Expression of somatostatin receptors caused 60% inhibition of cell growth compared with the Lac-Z virus-treated controls (P < 0.05 by Kruskal-Wallis/Bonferroni). There was no additional inhibition of cell proliferation with exogenous somatostatin. Furthermore, addition of somatostatin ligand antibody did not diminish the effect of SSR2 expression on cell proliferation. Western blot analysis revealed an upregulation of the cyclin-dependent kinase inhibitor p27 in the SSR2-transfected cells. CONCLUSIONS: Expression of SSR2 by human pancreatic cancer causes significant slowing of cell division by a mechanism independent of somatostatin. The mechanism may involve upregulation of known tumor suppressor proteins. Restoration of SSR2 gene expression deserves further study as a potential gene therapy strategy in human pancreatic cancer.

Adenocarcinoma↗
PubMed2000

Autocrine phosphorylation of p70(S6k) in response to acute stretch in myotubes.

Phosphorylation of 70-KDa S6 kinase (p70(S6k)) is correlated with in vivo skeletal muscle hypertrophy. Experiments tested whether mechanical stretch is sufficient to increase p70(S6k) phosphorylation in skeletal myotubes. Immediately following stretch, there was a small increase in p70(S6k) phosphorylation (63.2 +/- 8.5%) with maximal phosphorylation at 3 h (129.5 +/- 22.2%) and it remained elevated through 24 h (46.0 +/- 17.2%). To test whether an autocrine mechanism is involved, unstretched myotubes were incubated with medium from the stretch group for 10 min. Conditioned medium resulted in the phosphorylation of p70(S6k) in unstretched myotubes (92.8 +/- 28.9%) to levels comparable to the 3-h stretch group. These data indicate that p70(S6k) is phosphorylated in stretched myotubes via a mechanism that most likely involves an autocrine signaling pathway.

Animals↗
PubMed2000

Exogenous fibroblast growth factor-2 induces a transformed phenotype in vascular kaposi's sarcoma-like cells.

Vascular TTB cells derive from murine Kaposi's sarcoma-like dermal lesions and share several phenotypic features with AIDS-associated KS spindle cells. We have recently reported that fibroblast growth factor-2 (FGF-2) promotes dramatic cytoskeletal and morphological alterations in TTB cells, concomitant with the induction of an autocrine loop for hepatocyte growth factor and a relocalization of the urokinase receptor. Since all these alterations are hallmarks of cell transformation. we attempted to verify whether FGF-2 induces a transformed phenotype in TTB cells. Our results show that FGF-2-treated TTB cells acquire the ability to grow under anchorage-independent conditions. In addition, FGF-2 markedly reduced the levels of thrombospondin-1, an antiangiogenic and tumor suppressor protein, in TTB cells. Therefore, FGF-2 induces KS-like spindle cells to acquire properties characteristic of transformed cells. This suggests that FGF-2 plays a pathogenetic role in KS not only by promoting angiogenesis, but also by conferring a transformed phenotype upon KS cells. In light of previous reports on Tat-induced release of FGF-2 into the extracellular space, our findings may provide an additional mechanism for the observed synergism between Tat and FGF-2 in the pathogenesis of KS.

Animals↗
PubMed1997

LIF is an autocrine factor for sympathetic neurons.

Leukemia inhibitory factor (LIF) alters neuronal phenotypes both in vitro and in vivo. Since it can be produced by glia and other nonneural cells, LIF is a candidate target-derived differentiation factor as well as an injury-response factor. We here provide evidence that LIF can be produced by neurons and can act on the neurons that produce it. A reverse transcriptase-polymerase chain reaction assay detects LIF mRNA in rat sympathetic neuron cultures, and in situ hybridization combined with MAP2 immunocytochemistry indicates that most of the cells expressing LIF mRNA are, in fact, neurons. The neuronal lysate as well as the conditioned medium contains proteins that are specifically recognized by anti-LIF antibodies, and these antibodies also specifically stain the cultured neurons. In addition, concentrated sympathetic neuron conditioned medium can mimic the effects of LIF, and incubation of high-density sympathetic neuron cultures with anti-LIF antibodies reduces basal expression levels of LIF target genes such as particular neuropeptides, indicating that the endogenously produced cytokine is acting on the neurons under these conditions. Since we show that LIF transcript is expressed in sympathetic and sensory neurons in vivo as well, LIF could act in an autocrine fashion under a variety of physiological conditions.

Animals↗
PubMed1998

Control of Schwann cell survival and proliferation: autocrine factors and neuregulins.

Postnatal rat Schwann cells secrete factors that prevent the programmed cell death (PCD) of low-density Schwann cells in serum-free culture. These autocrine survival signal(s) do not promote Schwann cell proliferation. Moreover, while NRG and bFGF, which promote proliferation, both rescue a subpopulation of neonatal Schwann cells from PCD, they do not rescue freshly isolated Schwann cells from older animals; other known protein factors tested also do not mimic the autocrine signal. These results suggest that Schwann cells switch their survival dependency around the time of birth from axonal signals such as NRG to autocrine signals. Such an arrangement would be advantageous for the regeneration of peripheral axons following injury. We also compared NRG-induced Schwann cell proliferation using autocrine signals or serum to promote survival. The autocrine signals increase the rate of NRG-stimulated proliferation of low-density Schwann cells in serum-free medium, whereas serum inhibits proliferation by inhibiting both the production of survival signals and the expression of erbB2 and erbB3 receptors; these inhibitions are all reversed by forskolin. In contrast, forskolin has no effect on proliferation when the cells are exposed to high levels of autocrine factors.

Animals↗
PubMed2001

Autocrine regulation of norepinephrine transporter expression.

The norepinephrine transporter (NET) is a neurotransmitter scavenger and site of drug action in noradrenergic neurons. The aim of this study was to identify mechanisms that regulate NET expression during the development of quail (q) sympathetic neuroblasts, which develop from neural crest stem cells. Neurotrophin-3 (NT-3) and transforming growth factor beta1 (TGF-beta1) cause an increase of qNET mRNA levels in neural crest cells. When combined, the growth factors are additive in increasing qNET mRNA levels. Both NT-3 and TGF-beta1 are synthesized by neural crest cells. Onset of NET expression precedes the onset of neural crest stem cell emigration from the neural tube. In older embryos, qNET is expressed by several crest-derived and noncrest tissues. The data show that qNET expression in presumptive sympathetic neurons is initiated early in embryonic development by growth factors that are produced by neural crest cells themselves. Moreover, the results support our previous observations that norepinephrine transport contributes to the regulation of the differentiation of neural crest stem cells into sympathetic neurons.

Animals↗
PubMed2002

beta-Neuregulin and autocrine mediated survival of Schwann cells requires activity of Ets family transcription factors.

Members of the Ets transcription factor family function in many biological processes. We show the presence of Ets transcription factors, most prominently Net, in neonatal rat Schwann cells, and demonstrate Ets-dependent transcription under conditions where the cells are exposed to autocrine signals or autocrine signals plus beta-neuregulin. Using the potent MAPK kinase inhibitor U0126 we also confirm that the MAP kinase pathway, an activator of Ets transcription, is involved in beta-neuregulin mediated Schwann cell survival. Furthermore, we find that expression of dominant negative Ets1 (N70-Ets1) inhibits both the beta-neuregulin and autocrine survival of Schwann cells. In contrast, the survival of Schwann cells mediated by lysophosphatidic acid (LPA) is unaffected by expression of a dominant negative Ets molecule. These data demonstrate that distinct autocrine and beta-neuregulin survival signals converge in their requirement for Ets dependent transcription in Schwann cell survival.

Animals↗
PubMed1999

Insulin stimulates the growth and tube formation of human microvascular endothelial cells through autocrine vascular endothelial growth factor.

Insulin treatment is known epidemiologically as an independent risk factor for the progression of diabetic retinopathy. However, how insulin exacerbates the retinopathy is not yet fully understood. In this study, we investigate the effects of insulin on the growth and tube formation of microvascular endothelial cells (EC). When human skin microvascular EC were grown under various concentrations of insulin, DNA synthesis as well as tube formation of EC was found to be significantly stimulated. We obtained evidence that it is mainly vascular endothelial growth factor (VEGF) that mediates the angiogenic activity of insulin as follows. (1) Insulin upregulates the level of mRNA coding for secretory forms of VEGF, while the expression of the two VEGF receptor genes, kinase insert domain-containing receptor (kdr) and fms-like tyrosine kinase1 (flt1), was essentially unchanged by exposure to insulin. (2) A monoclonal antibody against human VEGF can completely neutralize both the proliferation and the tube formation of EC induced by insulin. The angiogenic effects of insulin were additive with those of hypoxia, a principal factor that causes angiogenesis. Further, insulin significantly stimulated plasminogen activator inhibitor-1 activity in EC. The results thus suggest that insulin not only elicits angiogenesis through the induction of autocrine VEGF but also is a predisposing factor for thrombogenesis, which may give rise to focal ischemia that could superdrive angiogenesis, thereby leading to the exacerbation of diabetic retinopathy.

Autocrine Communication↗
PubMed2001

Evidence that nitric oxide-induced synthesis of cGMP occurs in a paracrine but not an autocrine fashion and that the site of its release can be regulated: studies in dorsal root ganglia in vivo and in vitro.

As nitric oxide is a gas, it cannot be stored and has to be synthesized as required. This suggests that it could be released wherever nitric oxide synthase (NOS) is activated and due to its unstable state will react with appropriate targets at this site of production. In both dissociated dorsal root ganglion (DRG) cultures and in acutely isolated, but intact, DRG, treatment with capsaicin or bradykinin caused cGMP synthesis, which could be blocked by NOS inhibitors. The cGMP was synthesized in cells different from those expressing the neuronal isoform of NOS (nNOS). In dissociated cultures many of the cells stimulated to produce cGMP were neurons, whereas in isolated ganglia they were always satellite glia cells. Surprisingly, the satellite glia cells surrounding the nNOS-containing neurons did not contain cGMP. Following nerve section in adult rats, many axotomized ganglion neurons expressed nNOS. Again in these axotomized ganglia, most cGMP was expressed in the satellite glia surrounding nNOS-negative neurons. However, an nNOS-selective inhibitor reduced the cGMP present in these axotomized ganglia, suggesting that the cGMP synthesized is stimulated by NO (nitrogen monoxide) produced by nNOS. In both dissociated cultures and axotomized ganglia, nNOS-containing processes were observed close to cGMP-positive cells. These observations lead to the suggestion that NO acts in a paracrine fashion when stimulating the synthesis of cGMP and may not be synthesized at all sites containing nNOS.

Animals↗
PubMed1999

Evidence for autocrine actions of neuromedin B and gastrin-releasing peptide in non-small cell lung cancer.

Gastrin-releasing peptide (GRP), a member of the bombesin family of peptides, has been shown to have mitogenic activity in small cell lung carcinoma (SCLC), and to be produced by SCLC in an autocrine fashion. In this report, we demonstrate that both GRP and another member of the bombesin family of peptides, neuromedin B (NMB), are also autocrine growth factors for non-small cell lung carcinoma (NSCLC). Using the reverse transcription-polymerase chain reaction (RT-PCR), we have detected mRNA for the neuromedin B receptor (NMBR) in all 14 of the NSCLC cell lines examined. GRP receptor (GRPR) mRNA was also expressed in the majority of NSCLC cell lines (nine of 14). By immunoblotting using SDS-PAGE gradient gels fixed in trichloroacetic acid, GRP and NMB were found in fractions of culture medium that had been purified by high pressure liquid chromatography (HPLC) from NSCLC cell lines. NMB was detected in the conditioned medium of seven of nine cell lines and GRP in seven of nine cell lines; both peptides were produced in six cell lines. In four of the cell lines where both peptides were produced, the relative amount of NMB secreted into the medium was 7-15 times that of GRP; in the other two cases, the relative amounts of GRP and NMB were equivalent. Cultured human bronchial epithelial (HBE) cells expressed the GRPR and NMBR but did not produce either peptide. A subline of A549 cells that was adapted to grow in serum-free and growth factor-free conditions, termed A549-R(0), secreted both bombesin-like peptides (BLPs) into the culture medium. Using either a colony-forming assay or a BrDU incorporation assay, both NMB and GRP were found to be mitogens for three NSCLC cell lines that express mRNA for BLP receptors and secrete BLPs, regardless of which peptide and/or receptor subtype was detected. The monoclonal antibody 2A11, which preferentially recognizes GRP, was able to block the in vitro proliferative response to GRP in the BrDU incorporation assay, and partially blocked the response to NMB. The 2A11 antibody could only partially block the in vivo growth of cell lines that showed proliferative responses to BLPs. 2A11 antibody was more effective against the 239T cell line, which secreted a low amount of GRP into the medium (0.6 nM), compared to the 201T cell line, which secreted a higher amount of both GRP and NMB (4.2 nM and 36.6 nM, respectively). These results suggest that both NMB and GRP are autocrine growth factors for NSCLC, but that the production of NMB and expression of the NMBR may be more prominent than the production of GRP and expression of the GRP receptor. If BLP ligand-receptor systems are to be targeted therapeutically in NSCLC, it will be necessary to inhibit both NMB and GRP.

Animals↗
PubMed2000

Histamine as an autocrine growth factor: an unusual role for a widespread mediator.

The involvement of histamine in cancer growth represents an old controversy and direct experimental evidence proving this hypothesis is not still available. In this paper we review the most relevant mechanisms referring to the role of histamine receptors, histidine decarboxylase and histamine release in the onset of an autocrine loop, that enables histamine to act as an autocrine growth factor. We postulate that this autocrine loop, that has been studied in an experimental mammary carcinoma model induced in rats, may be present in different human neoplasias. Therefore, the better understanding of this novel regulatory pathway that is controlled by histamine may contribute to identifying new therapeutic targets.

Animals↗