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PubMed2006

Autocrine insulin action activates Akt and increases survival of isolated human islets.

AIMS/HYPOTHESIS: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in promoting the survival of pancreatic beta cells. Akt becomes activated in isolated human islets following overnight culture despite significant levels of cell death. The aim of the current study was to identify the cause of the observed increase in Akt phosphorylation in isolated islets. We hypothesised that a factor secreted by the islets in culture was acting in an autocrine manner to activate Akt. METHODS: In order to identify the stimulus of the PI3K/Akt pathway in culture, we examined the effects of different culture conditions on Akt phosphorylation and islet survival during the immediate post-isolation period. RESULTS: We demonstrated that islet-conditioned medium induced Akt phosphorylation in freshly isolated human islets, whereas frequent medium replacement decreased Akt phosphorylation. Following overnight culture, islet-conditioned medium contained significantly elevated levels of insulin, indicating that insulin may be responsible for the observed increase in Akt phosphorylation. Indeed, treatment with an anti-insulin antibody or with inhibitors of insulin receptor/IGF receptor 1 kinase activity suppressed Akt phosphorylation, leading to decreased islet survival. In addition, dispersion of islets into single cells also suppressed Akt phosphorylation and induced islet cell death, indicating that islet integrity is also required for maximal Akt phosphorylation. CONCLUSIONS/INTERPRETATION: Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets. These findings provide new information on how culturing islets prior to transplantation may be beneficial to their survival by allowing for autocrine activation of the pro-survival Akt pathway.

Cadaver↗
PubMed2005

The enlargement of the hormone immune deprivation concept to the blocking of TGFalpha-autocrine loop: EGFR signaling inhibition.

Transforming growth factor alpha (TGFalpha) is a potent ligand of the epidermal growth factor receptor (EGFR). EGFR is frequently over-expressed in epithelial tumors and endogenous ligands, mostly TGFalpha, are frequently co-expressed with EGFR, potentially resulting in autocrine stimulation of tumor cell growth. Therefore, different therapeutic approaches aim for the inactivation of TGFalpha/EGF/EGFR signaling system, but no approach is based on TGFalpha as a target. The principal goal of this work was to assess the potential of an active specific immunotherapy approach to block the TGFalpha/EGFR autocrine loop. For the proof of the concept, a fusion protein between human TGFalpha (hTGFalpha) and P64k protein from Neisseria meningitidis was generated, and its immunogenicity characterized in a mouse model using different adjuvants. All immunogens were effective for the generation of specific humoral responses against hTGFalpha. The inmunodominant epitope of hTGFalpha when immunizing mice with the fusion protein involved the C-loop/C-terminal region. This region includes key residues for hTGFalpha binding to EGFR. The anti-hTGFalpha immune mice sera recognized the natural hTGFalpha precursor in A431 cells and hTGFalpha-transfected 3T3 fibroblasts as revealed by flow cytometry analysis and immunoblotting. They inhibited the binding of (125)I-TGFalpha to the EGFR, EGFR-autophosphorylation, and downstream activation of MAP kinases as well as proliferation of two EGFR-expressing human carcinoma cell lines. These data suggest that EGFR signaling activation by the hTGFalpha autocrine loop may be inhibited in vivo by induction of specifically blocking antibodies. The fusion protein reported in this paper could be a potential immunogen for the development of a new cancer vaccine.

Animals↗
PubMed1992

Functional significance of human vascular smooth muscle cell-derived interleukin 1 in paracrine and autocrine regulation pathways.

Interleukin 1 (IL1), a key mediator in the cytokine network, alters many pathophysiologically important functions of blood vessel wall cells. Vascular cells, such as endothelial cells and smooth muscle cells (SMC) can themselves transcribe IL1 genes, raising the possibility that IL1 regulates blood vessel wall functions by local autocrine or paracrine mechanisms. However, IL1 lacks a recognizable signal sequence and it is still unclear how vascular cells might release IL1 or if IL1 derived from vascular cells can actually produce autocrine or paracrine effects. We explored these issues in human vascular SMC, the most numerous cell type in arteries and veins, using cultured SMC and short term organoid cultures. SMC treated with lipopolysaccharide recombinant tumor necrosis factor (recTNF), or recIL1 itself ("activated SMC") elaborated thymocyte costimulatory activity, a biological activity traditionally ascribed to IL1. However, neutralization experiments with monospecific antibodies disclosed that the more recently recognized cytokine IL6 rather than IL1 accounted for most of the soluble thymocyte costimulatory activity released by activated SMC. Using the D10S assay that distinguishes IL1 from IL6 and TNF we found that the culture supernatant of activated SMC contained little or no IL1, but that the cytosol and surface of these cells did exhibit this activity. Antiserum to recIL1 alpha inhibited stimulation of D10S cells by surface-associated IL1 of activated SMC, while treatment with acid to elute receptor- or nonspecifically bound IL1 did not abrogate this D10S proliferation. Short term organoid cultures of both normal veins and human arteriosclerotic plaque also expressed tissue-associated IL1 activity upon stimulation with LPS but did not release significant soluble IL1 activity. To establish further the biological functions of cell-associated IL1, we incubated stimulated or unstimulated SMC that were fixed with paraformaldehyde and washed extensively (fixed SMC) with overlayered viable SMC of the same donor (responder SMC). Contact with fixed SMC that bore surface IL1 following TNF or IL1 stimulation evoked up to 20-fold higher IL6 release from responder SMC than did exposure to unstimulated SMC (57 vs 1052 ng/ml/day). Addition of anti-IL1 antibody inhibited the release of IL6 from the responder SMC. These results demonstrate that cytokine-activated SMC express biologically active IL1 on their cell surface and illustrate how these cells might actually participate in autocrine and paracrine signaling in the vessel wall. The requirement for direct intercellular contact for IL1 effects could facilitate local information exchange among vascular wall cells and/or infiltrating leukocytes and permit costimulation while limiting undue propagation of inflammatory stimuli.

Animals↗
PubMed1990

Autocrine growth of leukemic cells.

Autocrine growth is a process whereby a cell both secretes and responds to a growth factor. This paper describes the stepwise malignant progression of leukemic cells which has been demonstrated in many experimental models of autocrine leukemic growth. In contrast, autocrine growth has not been proven as a major physiopathological mechanism for the growth of leukemic cells in vivo in human myeloid and lymphocytic leukemias. Growth-factor independency of human leukemic cell lines may be due to clonal selection.

Cell Division↗
PubMed1990

Lack of tumorigenicity of interleukin 4 autocrine growing cells seems related to the anti-tumor function of interleukin 4.

Recently, the failure of interleukin 4 (IL4) autocrine growing CT4S cells to grow in vivo has been demonstrated. Because it could not be excluded that the cells produce insufficient amounts of IL4 to support their growth in vivo, subclones were established which are unresponsive to exogenous IL4 and therefore have acquired full growth autonomy. From the fact that the subclones likewise did not give rise to tumors when injected into nude mice, one may conclude that the IL4 production of autocrine growing CT4S prevents their growth in vivo. To test this hypothesis, a retroviral vector containing the IL4 gene under the control of the immunoglobulin heavy chain (Igh) enhancer/promoter was constructed and used to infect the myeloma cell line J558L. An IL4 producing clone was established (J558L-XEPIL4) and the tumor progression in comparison to the parental clone J558L was monitored in nude mice. The IL4 production significantly delayed the growth of J558L-XEPIL4 in vivo. Tumor suppression was much more evident when J558L-XEPIL4 cells were injected into syngeneic BALB/c mice. These results may explain why autocrine growing CT4S do not grow in vivo and suggest the involvement of functional T lymphocytes in the effectiveness of the host dependent anti-tumor action of IL4.

Animals↗
PubMed1994

Autocrine regulation of ICAM-1 expression on bladder cancer cell lines: evidence for the role of IL-1 alpha.

We have studied the autocrine regulation of essential expression of the intercellular adhesion molecule-1 (ICAM-1) on 8 transitional cell carcinoma (TCC) cell lines (histopathological grades 1-3). The constitutive expression of ICAM-1 was regulated by soluble factors in an autocrine fashion. These factors were produced by all cell lines, with the exception of the MGH-U1 cell line. The effects observed could be largely attributed to IL-1 alpha. However, the residual ICAM-1 inducing activity (up to 30% of ICAM-1 induction) could not be associated with any known ICAM-1 inducers (IFN gamma, TNF alpha, TNF beta, IL-1 alpha, IL-1 beta, IL-4, retinoic acid, LPS). In contrast to recombinant derived cytokines, the IL-1 alpha present in tissue culture supernatant was only able to induce ICAM-1 on high-grade tumours and not low-grade cells. This discriminative effect is similar to that noted following in vitro culture of tumour cells with bacillus Calmette-Guerin organisms. Whether the production of soluble factors (e.g., IL-1 alpha) by TCC cell lines plays an essential autocrine role for bladder tumours and/or affects the interaction with cells of the immune system needs to be investigated further.

Antigens, CD↗
PubMed1992

Effects of calcitonin on human trophoblastic cells in culture: absence of autocrine control.

The purpose of this work was to investigate the effects of calcitonin (CT) on trophoblastic cells with respect to cAMP levels and human chorionic gonadotrophin (hCG) secretion in cultured cells from first-trimester and term placentas and in a choriocarcinoma cell line (JEG-3). The expression of the CT gene was investigated to elucidate a putative autocrine control of CT during pregnancy. The addition of salmon CT (10(-10) M and above) resulted in concentration-dependent increases in cAMP secretion by normal trophoblastic cells from term and first-trimester placentas. Moreover, CT was found to increase cAMP secretion preferentially in completely differentiated cells, i.e. after 4-7 days in culture. Addition to the culture medium of JEG-3 cells slightly increased cAMP secretion only at a concentration of 10(-8) M. The basal level of hCG in the medium was found to be higher in the first-trimester than in the term trophoblast culture, but salmon CT induced an increase in hCG secretion by term placenta cells only. CT gene expression in our experimental model was investigated to elucidate a putative autocrine control of CT action during pregnancy. It was not found to be expressed in syncytiotrophoblast cells from either first-trimester or term placenta cells by the method used. Our data demonstrate the absence of autocrine control of CT effects in trophoblastic cells, and suggest that CT is likely to exert its effect preferentially on differentiated cells.

Blotting, Northern↗
PubMed1998

Co-expression of prostaglandin receptors with opposite effects: a model for homeostatic control of autocrine and paracrine signaling.

Prostaglandins are ubiquitous autocrine mediators that exert their effects through a number of G protein-coupled receptors. Many organs and tissues express many of the prostaglandin receptors, and prostaglandins have diverse effects on individual organs and tissues. In some cases, several prostaglandin receptors are expressed on a single cell type. Co-expressed prostaglandin receptors frequently appear to have opposite actions, suggesting homeostatic control of prostaglandin effects. Co-expression of opposing receptors provides a molecular mechanism for weak or partial agonism and explains the action of a drug as a mixed agonist/antagonist. The physiological relevance of co-expressed opposing receptors for a single agonist perhaps can be explained in terms of the difference between endocrine and autocrine mediators. Endocrine hormones are generally produced by cells distant from their site of action so that they are diluted to an elevated but stable concentration by the time they reach their target cells. In contrast, autocoids are produced by the same cell type on which they act and may reach transiently high levels at their sites of action. The presence of a second type of receptor that negates the action of the first receptor would tend to buffer cellular responses to transient extremes of agonist concentration. The slow onset of inhibition would also allow for time-dependent buffering, providing additional control over autocoid release and effect. The mechanism is relevant to other autocrine and paracrine mediators including neurotransmitters, which reach transiently high concentrations in the synaptic cleft.

Amino Acid Sequence↗
PubMed1991

Inhibition of prostatic tumor cell proliferation by suramin: alterations in TGF alpha-mediated autocrine growth regulation and cell cycle distribution.

Suramin is a trypanocidal drug that has generated recent interest as an antineoplastic agent because of its ability to inhibit the binding of growth factors to their cell surface receptors. Our studies, and others, suggest that the androgen-independent human prostatic carcinoma cell lines PC3 and DU145 proliferate via autocrine growth mechanisms mediated by transforming growth factor alpha (TGFa) and its receptor, the epidermal growth factor (EGF) receptor. The present studies were designed to evaluate the ability of suramin to inhibit PC3 and DU145 proliferation by interfering with TGFa-mediated autocrine growth. Suramin induced a dose-dependent reduction of prostatic tumor cell proliferation which was reversed by removal of suramin from the culture medium. 3H-thymidine release studies showed that suramin had little direct cytotoxicity to either cell line. These findings suggest that the effects of suramin are mediated by cytostatic, rather than cytotoxic, mechanisms. Suramin also interfered with TGFa-mediated growth mechanisms. Specifically, suramin reduced the specific binding of TGFa to PC3 and DU145 cells. Additionally, the inhibitory effect of suramin on DU145 was reversed by cultivation of cells in the presence of excess TGFa. Further investigations revealed that suramin increased the percentage of cells in the S phase of the cell cycle for both cell lines. These studies show that the inhibitory effect of suramin on PC3 and DU145 cell growth is mediated, in part, by alteration of TGFa-mediated autocrine growth mechanisms and cell cycle kinetics.

Antineoplastic Agents↗
PubMed2002

Inhibition of proliferation of human small cell lung cancer cells expressing an autocrine system for gastrin releasing peptide by antisense oligodeoxynucleotides to gastrin releasing peptide receptor.

The objectives of this study were to investigate the effect of antisense (AS) oligodeoxynucleotides (ODNs) directed against gastrin releasing peptide (GRP) receptor mRNA on proliferation of human small cell lung cancer (SCLC) NCI-H345 cells which express the autocrine system for GRP. The methods used were to expose human SCLC cell lines to antisense ODNs or sense ODNs and to measure their proliferation by spectrophotometric assay or viable cell counts. Our results demonstrated that the single or combined AS ODNs against GRP receptor inhibited proliferation of human SCLC NCI-H345 cells significantly by 37% (P<0.01), but did not inhibit proliferation of either human bronchial epithelial BEAS 2B cells or human SCLC NCI-N417 cells, neither of which express the GRP autocrine system. The sense controls did not significantly inhibit proliferation compared with no treatment controls. Specificity was also demonstrated by the observation that cells exposed to AS ODNs had a decrease in GRP receptor expression as measured by specific binding of 34% (P<0.01), and when all three AS ODNs were used, binding was decreased by 60% (P<0.03). Furthermore, AS ODNs decreased by 75% the maximum percentage of cells responding to GRP in an intracellular calcium release assay. Our conclusions are that antisense ODNs directed against a GRP receptor which is involved in an autocrine loop in human SCLC cells inhibited proliferation of these cells by their impact on reducing GRP receptor expression. Further development of means of increasing AS ODN specificity and effectiveness in human SCLC cell is warranted.

Carcinoma, Small Cell↗
PubMed1995

Tumor-derived factor synergizes with IFN-gamma and LPS, IL-2 or TNF-alpha to promote macrophage synthesis of TNF-alpha and TNF receptors for autocrine induction of nitric oxide synthase and enhanced nitric oxide-mediated tumor cytotoxicity.

Evidence has previously been presented for an immunomodulatory role of a soluble activity, designated as tumor-derived recognition factor (TDRF), which was produced constitutively by P815 mastocytoma, L 1210 leukemia and other murine tumor targets. TDRF synergized with IFN-gamma and IL-2 to promote TNF-alpha and mRNA synthesis and release by murine macrophages for increased autocrine induction of nitric oxide (NO)-mediated tumor cytotoxicity. We have now further assessed the modulatory role of TDRF on TNF-alpha, TNF receptors (TNF-R) and NOS mRNA synthesis. Macrophages activated by INF-gamma priming and triggering by rTNF-alpha bacterial lipopolysaccharide (LPS) of IL-2 evoked greater NO generation in the presence than in the absence of L1210 targets. TDRF-containing culture fluid from L1210 targets was subsequently confirmed to synergize with IFN-gamma and rTNF-alpha, LPS or IL-2 triggering agents to promote increased TNF-alpha mRNA for autocrine induction of NOS mRNA synthesis with resultant augmentation of NO generation. IFN-gamma selectively upregulated TNF-R1 mRNA expression, whereas either IL-2 or LPS upregulated only TNF-R2 mRNA expression. TDRF combined with IFN-gamma to further upregulate TNF-R1 mRNA and with either IL-2 or LPS to further upregulate TNF-R2, mRNA expression. These findings indicate that TDRF activity synergizes with either IL-2 or LPS triggering agents for enhanced activation of IFN-gamma-primed macrophages by promotion of TNF-alpha and TNF-R mRNA synthesis for autocrine induction of NOS with resultant increased NO-mediated tumor cytotoxicity.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

Autocrine regulation of Leydig cell differentiated functions by insulin-like growth factor I and transforming growth factor beta.

The expression and the maintenance of specific differentiated function of Leydig cells are regulated not only by gonadotropin but by locally produced factors, which may act as autocrine regulators. Many factors, in particular growth factors, have been postulated to have such a type of effect on testicular cells, but very few fulfilled the three criteria required to establish a paracrine/autocrine role: (a) presence of receptors and biological action on local cells; (b) local secretion regulated by physiological signals; and (c) blockade of the factor or its receptors must modify the function of local cells. In the present work we demonstrate that two factors, insulin-like growth factor 1 (IGF-I) and transforming growth factor beta1 (TGFbeta1) fulfilled the three criteria: (a) IGF-I stimulates the transcription of the genes encoding Leydig cell differentiated function, leading to an enhanced steroidogenic responsiveness to LH/hCG; (b) Leydig cells (LC) express and secrete IGF-I and this secretion is enhanced by hCG; and (c) incubation of LC with IgG anti-IGF-I, but not with IgG-control, markedly reduced the steroidogenic responsiveness to LH/hCG. In contrast to IGF-I, TGFbeta is a potent inhibitor of LC differentiated function. Moreover, LC express TGFbeta1 mRNA and secrete this peptide. To prove that the locally produced TGFbeta has an autocrine role, LC were transfected with 10 microM of an antisense oligonucleotide (AON) complementary to the translation initiation region of TGFbeta1 mRNA. Transfection with AON but not with sense deoxynucleotide induces a complete disappearance of TGFbeta immunoreactivity in LC and an enhanced hCG-induced testosterone production by LC. This increased steroidogenic responsiveness was associated with a significant enhancement of both LH/hCG receptor mRNA and P450c17 mRNA. Taken together, the above results show that both factors play an autocrine role, although opposite, on Leydig cell function.

Animals↗
PubMedDate not supplied

Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer.

The autocrine hypothesis proposes that a cell produces and secretes a hormone-like substance that can interact with specific membrane receptors on its surface to induce effects such as proliferation. Thus, a cancer cell could act to stimulate its own growth. Bombesin and bombesin-like peptides (BLPs) such as gastrin-releasing peptide (GRP) cause various physiological responses in mammals, including stimulation of proliferation of 3T3 mouse fibroblasts and normal human bronchial epithelial cells in vitro and induction of gastrin cell hyperplasia and increased pancreatic DNA content in vivo in rats. Human small-cell lung cancer (SCLC) cell lines produce and secrete BLPs and can express a single class of high-affinity receptors for BLPs. Exogenously added BLPs can also stimulate the clonal growth and DNA synthesis of SCLC in vitro. These findings suggest that BLPs function as autocrine growth factors for this tumour. One way to test this hypothesis is to interrupt the function of the endogenously produced BLPs. Here, we demonstrate that a monoclonal antibody to bombesin binds to the C-terminal region of BLPs, blocks the binding of the hormone to cellular receptors and inhibits the clonal growth of SCLC in vitro and the growth of SCLC xenografts in vivo. These results demonstrate that BLPs can function as autocrine growth factors for human SCLC.

Animals↗
PubMed1995

Does autocrine growth factor secretion form part of a mechanism which paradoxically protects against tumour development?

Autocrine growth factor secretion has classically been considered as a mechanism by which tumour cells achieve autonomous growth. However, there is now considerable evidence that autocrine circuits operate in the growth regulation of normal adult tissues. Here we consider the possible advantages to the normal epithelial cell of utilising such an external growth factor circuit and suggest that autocrine growth factor secretion, when viewed in a multicellular context, could paradoxically form part of a mechanism for preventing tumour development.

Adult↗
PubMed1996

Dysregulation of autocrine TGF-beta isoform production and ligand responses in human tumour-derived and Ha-ras-transfected keratinocytes and fibroblasts.

This study examined the autocrine production of TGF-beta 1, -beta 2 and -beta 3 in culture supernatants from tumour-derived (H series, n = 7; BICR series, n = 5), Ha-ras-transfected (n = 4) and normal (n = 2) human keratinocytes using a sandwich enzyme-linked immunosorbent assay (ELISA). Detection limits were 39.0 pg ml-1 for TGF-beta 1, 78.0 pg ml-1 for TGF-beta 2 and 1.9 ng ml-1 for TGF-beta 3. Tumour-derived oral keratinocytes predominantly produced less TGF-beta 1 than normal oral epithelial cells; the expression of endogenous TGF-beta 2 was variable. In keratinocytes containing mutant Ha-ras, TGF-beta 1 production was enhanced and TGF-beta 2 was undetectable. TGF-beta 3 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) but the protein was not detected in conditioned media, most probably because of the low detection limits of the ELISA for this isoform. Neutralisation experiments indicated that the latent TGF-beta peptide was secreted in keratinocyte conditioned medium. Seven tumour-derived keratinocyte cell lines (H series) and fibroblasts separated from normal (n = 1) and tumour-derived (n = 2) keratinocyte cultures were examined for their response to exogenous TGF-beta 1, -beta 2 and -beta 3. Six of seven tumour-derived keratinocyte cell lines were inhibited by TGF-beta 1 and TGF-beta 2 (-beta 1 > -beta 2); one cell line was refractory to both TGF-beta 1 and TGF-beta 2. Keratinocytes were inhibited (4 of 7), stimulated (1 of 7) or failed to respond (2 of 7) to TGF-beta 3, TGF-beta 1, -beta 2 and -beta 3 stimulated both normal and tumour-associated fibroblasts, but the tumour-associated fibroblasts showed less response to the ligands than their normal counterparts following prolonged treatment with each isoform. The results demonstrate variable autocrine production of TGF-beta isoforms by malignant keratinocytes, with loss of TGF-beta 1 generally associated with the tumour-derived phenotype and modification of endogenous isoform production dependent on the genetic background of the tumour cells. Further, the variable response of the tumour-derived keratinocytes and contiguous fibroblasts to the TGF-beta isoforms suggests that dysregulation of TGF-beta autocrine and paracrine networks are common characteristics of squamous epithelial malignancy.

Cell Line↗
PubMed1997

Interleukin 2 exerts autocrine stimulation on murine T-cell leukaemia growth.

As it has been suggested that an autocrine mechanism may control tumour cell growth, in this work cells from a spontaneous murine T lymphocyte leukaemia (LB) expressing the interleukin-2 receptor (IL-2R) (CD25) were evaluated in vitro for IL-2-mediated autocrine growth. Cells grew readily in culture and proliferation was enhanced by the addition of recombinant IL-2 but inhibited by monoclonal antibodies against either IL-2 or IL-2 receptor, in the absence of exogenous IL-2. Cyclosporin A also inhibited LB cell growth. However, when exogenous IL-2 was added together with cyclosporin A, cell proliferation proved similar to controls. Using reverse transcription polymerase chain reaction (PCR), mRNA for IL-2 was found to be present in tumour cells. Our findings support the hypothesis that LB tumour cell proliferation is mediated by an autocrine pathway involving endogenous IL-2 generation, despite the fact that these cells are not dependent on exogenous IL-2 to grow in culture.

Animals↗
PubMed1997

Autocrine growth induced by transferrin-like substance in bladder carcinoma cells.

Ample evidence confirms that certain cancer cells have the capacity to produce multiple peptides as growth factors and that expression of their receptor may act in tumour cell paracrine and/or autocrine loop mechanisms, either by extracellular release of the growth factor or by the tumour itself. To study the possibility of an autocrine growth mechanism in bladder carcinoma, we investigated the ability of various bladder carcinoma cell lines to proliferate in serum-free medium. A rat bladder carcinoma cell line, BC47, demonstrated exponential and density-dependent growth in serum-free medium. Furthermore, conditioned medium from BC47 cells induced growth-stimulating activity for BC47 cells themselves. Purification and further characterization of this activity was performed by chromatographic methods, SDS-PAGE and N-terminal amino acid analysis. Finally, we have identified that a transferrin-like 70-kDa protein is found to be the main growth-promoting factor in this conditioned medium. In addition, specific antibodies against transferrin and the transferrin-receptor inhibit the in vitro growth of this cell line. Our data suggest that this transferrin-like factor possibly acts as an autocrine growth factor for cancer cells.

Amino Acid Sequence↗
PubMedDate not supplied

Activation of hepatocyte growth factor-met autocrine loop enhances tumorigenicity in a human lung adenocarcinoma cell line.

Hepatocyte growth factor (HGF) is a multifunctional cytokine with effects on the proliferation, motility, and differentiation of cells that express its receptor Met. The co-expression of HGF and Met is common among nonsmall-cell lung cancers, especially adenocarcinoma. However, the biologic consequences of this putative HGF-Met autocrine signaling remain speculative. We have used retroviral gene transduction technique to express high levels of HGF in the NCI-H358 lung adenocarcinoma cells that have functionally active cell surface Met receptor. The activation of autocrine HGF-Met signaling was confirmed by the induction of spontaneous cell scattering activity. Compared to the parent and control cells transduced with the retroviral vector alone, HGF overexpressing H358 cells show enhanced capacity to colonize soft agar medium and to form xenograft tumors when implanted in the subcutaneous tissue of immune-deficient mice. These effects were not accompanied by changes in their growth rate in monolayer culture condition, or in the expression of vascular endothelial growth factor. The tumors formed by HGF overexpressing cells also showed more prominent glandular cell arrangement and functional activity. This report provides the direct in vivo evidence that autocrine HGF-Met signaling plays significant roles in the growth and differentiation of human lung adenocarcinoma cells.

Adenocarcinoma↗