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PubMedDate not supplied

Radioimmunoscintigraphy of tumors autocrine for human met and hepatocyte growth factor/scatter factor.

Inappropriate expression of the c-met-protooncogene product (Met) and/or of its ligand, hepatocyte growth factor/scatter factor (HGF/SF), has been correlated with poor prognosis in a variety of human solid tumors. We are developing animal models for nuclear imaging of Met and HGF/SF expression in tumors in vivo. We radioiodinated a mixture of monoclonal antibodies (MAbs) that bind to human HGF/SF and to the external ligand-binding domain of human Met, and then injected the I-125-MAb mixture intravenously into mice bearing tumors either autocrine for human HGF/SF and human Met or autocrine-paracrine for murine HGF/SF and murine Met. Serial total body gamma camera images were obtained, and regional activity was determined by quantitative region-of-interest (ROI) analysis. Tumors autocrine for human HGF/SF and Met demonstrated significantly more rapid uptake and more rapid clearance of the I-125-MAb mixture than tumors expressing one or both murine homologues, reaching a mean tumor to total body activity ratio of > 0.3 by 1 day postinjection. We conclude that radioimmunodetection of tumors autocrine for human HGF/SF and Met is feasible with an I-125-MAb mixture reactive against the ligand-receptor pair.

Animals↗
PubMed1999

Interleukin-12 production by human alveolar macrophages is controlled by the autocrine production of interleukin-10.

By releasing interleukin (IL)-12 in the lung, alveolar macrophages (AM) may profoundly modify an immune response. The autocrine regulation of the heterodimeric, biologically active form of IL-12 (IL-12 p70) by IL-10 was studied, as well as the expression of its subunits of 35 kD (p35) and 40 kD (p40). AM cultured in medium alone expressed only p35 mRNA. Both p35 and p40 mRNA levels were induced by lipopolysaccharide (LPS) and were further increased by interferon-gamma (IFN-gamma). LPS alone induced IL-12 p40 but not IL-12 p70 production in monocytes and in AM. However, IL-12 p70 was released when the autocrine production of IL-10 was neutralized by IL-10 blocking antibody, and IL-12 p40 production increased. Although IFN-gamma markedly decreased LPS-induced IL-10 production in AM, neutralizing IL-10 further enhanced the level of LPS and IFN-gamma-induced IL-12 p70 in AM. In contrast, neutralizing the trace amount of IL-10 released by AM stimulated by CD40 crosslinking and IFN-gamma did not increase IL-12 p70. Thus, IL-12 p70 production by AM appears to be tightly controlled by the autocrine release of IL-10 when stimulated by LPS, or by LPS and IFN-gamma, whereas CD40 crosslinking triggered IL-12 p70 production in the absence of autocrine regulation by IL-10.

Base Sequence↗
PubMed2005

CLL, but not normal, B cells are dependent on autocrine VEGF and alpha4beta1 integrin for chemokine-induced motility on and through endothelium.

Vascular endothelial cell growth factor (VEGF) is a multifunctional cytokine involved in tumor formation. In chronic lymphocytic leukemia (CLL), it is known that the malignant cells secrete VEGF and possess VEGF receptors. This suggests that an autocrine loop might be important in the pathogenesis of CLL. Here we show that, in patients with lymphadenopathy, autocrine VEGF and alpha(4)beta(1) integrin are involved in the chemokine-dependent motility of CLL cells on and through endothelium-processes important for the invasion of lymphoreticular tissues, a major determinant of disease outcome. In contrast, normal lymphocytes were not dependent on autocrine VEGF or alpha(4)beta(1) for either type of cell movement. Moreover, in contrast to normal B lymphocytes, CLL cells failed to cluster and activate alpha(L)beta(2) in response to chemokines, unless VEGF receptor(s) and alpha(4)beta(1) were also engaged by their respective ligands. This is the first demonstration that autocrine VEGF is involved in CLL-cell motility, and that the alpha(L)beta(2) on the malignant cells is functionally altered compared with that of normal B cells in not undergoing activation in response to chemokine alone. Given the importance of cell motility for tissue invasion, the present results provide a rationale for a trial of VEGF and alpha(4) blockade in patients with CLL who have tissue disease.

B-Lymphocytes↗
PubMed2006

Autocrine growth hormone prevents lactogenic differentiation of mouse mammary epithelial cells.

We have examined the expression, postnatal ontogeny, and localization of mouse GH (mGH) and its relative expression during pregnancy, lactation, and weaning in the mouse. mGH mRNA and protein was expressed predominantly in the epithelial component of the mammary gland, and maximal expression was observed during the pubertal period. Autocrine mGH expression dramatically decreased during late pregnancy and lactation. Concordantly, autocrine mGH expression is repressed during forced differentiation of mouse HC11 mammary epithelial cells in culture. Forced expression of mGH in HC11 cells abrogated lactogenic differentiation as indicated by reduced expression of beta-casein and reduced expression and loss of lateral epithelial localization of E-cadherin. Forced expression of mGH in mouse mammary epithelial cells increased cell survival and proliferation and consequently increased the size of mammary acinar-like structures formed in three-dimensional Matrigel. Thus, autocrine mGH expression in the mouse mammary epithelial cell is maximal at puberty and prevents mammary epithelial cell differentiation. Autocrine GH will therefore participate in mammary morphogenic processes at puberty.

Animals↗
PubMed1992

Prolactin isoform 2 as an autocrine growth factor for GH3 cells.

Because PRL has growth factor activities in several tissues, we have asked whether it also has autocrine growth factor activity in pituitary GH3 cells. GH3 cells were grown at increasing densities in the presence or absence of antirat PRL (polyclonal and monoclonal) or nonspecific antibodies. Cell proliferation increased with increasing cell density, as did the concentration of PRL in the medium. Antirat PRL, but not control antibody, markedly inhibited but did not eliminate cell proliferation, and this effect was diminished with increasing PRL concentration in the medium. PRL receptors were demonstrated on 40-50% of the cells by indirect immunofluorescence using a specific antirat PRL receptor monoclonal antibody. Cell surface PRL was colocalized to the same 40-50% of the cells and copatched or cocapped along with the receptors. Absence or presence of PRL receptors did not correlate with stage of the cell cycle, as judged by ethidium bromide dual labeling. Cell surface PRL was found to be on PRL-containing cells. These data have fulfilled four criteria necessary for establishment of a substance as a secreted autocrine growth factor: 1) the factor must be secreted; 2) in log growth phase, increased cell proliferation should occur at increased cell densities; 3) the cells must display a receptor for the factor; and 4) there must be a growth response to the factor. Thus we have established that PRL is an autocrine growth factor for at least 40-50% of the GH3 cell population. This, to our knowledge, is the first example of autocrine growth factor activity of a major hormone normotopically expressed.

Animals↗
PubMed1996

Nerve growth factor controls proliferation and progression of human prolactinoma cell lines through an autocrine mechanism.

Two different human prolactinoma phenotypes (responders and nonresponders), which are distinguished by different tumorigenic potential and different responsiveness to dopaminergic therapy, have recently been identified. Responders show low proliferation rate, low tumorigenic potential, and expression of D-2 receptors for dopamine (DA), while nonresponders are characterized by high proliferation rate, high tumorigenic potential, and lack of expression of DA D-2 receptors. In this study it has been shown that both gp140trk and gp75 components of nerve growth factor (NGF) receptor are expressed in responder prolactinoma cell lines. High levels of both NGF gene transcript and protein were also found in responders, and biologically active NGF was detectable in the media conditioned by these cells. Ablation of NGF production in responder cells by hybridization arrest of translation through NGF antisense oligonucleotides resulted in: 1) loss of secreted NGF; 2) loss of expression of gp75; 3) loss of expression of DA D-2 receptors; and 4) a remarkable increase in the cell proliferation rate. These results thus suggest that a NGF-mediated autocrine loop essential to control cell proliferation and to preserve some phenotypical characteristics of mammotroph cells is present in responder prolactinoma cell lines. Analysis of nonresponders showed that these cells express gp140trk but no detectable levels of gp75. In addition, no NGF mRNA or protein was detectable in nonresponders. Exposure of these cells to NGF resulted in the permanent expression of NGF mRNA and in the production and secretion of NGF protein, thus establishing the same NGF-mediated autocrine loop present in responders. As a result, it has been shown that nonresponder cells treated with NGF acquire and maintain most of the phenotypic characteristics of normal mammotroph cells. In conclusion, the present work reports that a NGF-mediated autocrine loop with an inhibitory role in the control of cell proliferation and tumor progression is active in the more differentiated DA-sensitive prolactinoma cell lines and is lost in the most malignant prolactinoma cells refractory to the dopaminergic therapy. Alterations in the expression of this autocrine loop thus may lead to cell transformation and tumor progression.

Animals↗
PubMed2000

Prohormone convertase and autocrine growth factor mRNAs are coexpressed in small cell lung carcinoma.

A hallmark of small cell lung carcinoma (SCLC) is the expression of autocrine growth factors such as neurotensin and gastrin-releasing peptide, which bind to cellular receptors and stimulate cell division. The biological activity of autocrine growth factors requires the concurrent expression of prohormone convertases that cleave the growth factors to their active form, suggesting the expression of these genes is linked in SCLCs. RNase protection assays were used to detect the expression of autocrine growth factor and prohormone convertase mRNAs in a panel of lung cancer cell lines. These mRNAs are coexpressed in SCLC and lung carcinoid cell lines, but not in normal lung epithelium or in non-small cell lung cancers. These findings, together with earlier results from our laboratory, suggest the expression of prohormone convertases has an important role in the development and maintenance of the SCLC phenotype and that autocrine growth factor and prohormone convertase genes respond to a common transcriptional activator in SCLC.

Carcinoma, Small Cell↗
PubMed1996

The proliferative responses of porcine thyroid follicular cells to epidermal growth factor and thyrotrophin reflect the autocrine production of transforming growth factor-beta 1.

The present study has investigated an involvement of autocrine transforming growth factor-beta 1 (TGF-beta 1) in regulating the proliferative response of porcine thyroid follicular cells (TFCs) to epidermal growth factor (EGF) and TSH. Primary monolayer TFC cultures exposed to EGF over the range 0-0.4 nmol/l showed a dose-dependent increase in [methyl-3H]thymidine incorporation, whereas higher EGF doses were associated with a reduction in the level of [methyl-3H]thymidine incorporation. TGF-beta immunoneutralisation had little effect on the stimulatory action of low EGF doses, but led to an increase in [methyl-3H]thymidine incorporation at higher EGF levels. In TFC cultures exposed to TSH, the level of [methyl-3H]thymidine incorporation attained at a dose of 1 U TSH/1 was enhanced in the presence of TGF-beta 1 antiserum, although the similar stimulatory effect of 8-bromo cAMP was unaffected. Treatment of TFCs with phorbol 12-myristate 13-acetate (8 nmol/l) to activate protein kinase C (PKC) led to an enhanced incorporation of [methyl-3H]thymidine which was increased further after neutralisation of endogenous TGF-beta 1. While confirming, therefore, a role for autocrine TGF-beta 1 in maintaining control of TFC DNA synthesis in vitro, these findings provide evidence that an increase in the availability of autocrine TGF-beta 1 effected by EGF and TSH may play an instrumental role in limiting the cellular hyperplasia induced by these factors within the thyroid follicular microenvironment. Moreover, the present data also suggest that the availability of active autocrine TGF-beta 1 to TFCs under such conditions may be dependent upon a PKC-mediated mechanism.

Animals↗
PubMed1994

Secretion of interleukin-6 by human meningioma cells: possible autocrine inhibitory regulation of neoplastic cell growth.

Using cell culture techniques, the authors have previously shown that human meningioma cells secrete an autocrine growth stimulator related to platelet-derived growth factor. Here, they further demonstrate potential autocrine inhibitory regulation of meningioma cell growth by interleukin (IL)-6. Constitutive IL-6 production was detected in all meningiomas studied, in the form of protein as well as IL-6-specific messenger ribonucleic acid. The IL-6 immunoreactivity in conditioned medium from three different meningioma cultures eluted from a Sephadex G-100 column was evidenced by a single peak corresponding to a molecular weight of about 32 kD. Interleukin-6 secretion was remarkably stimulated by tumor necrosis factor-alpha, IL-1 beta, and IL-4, and was also influenced by a combination of epidermal growth factor and bromocriptine. Recombinant IL-6 exhibited a significant dose-dependent inhibitory effect on meningioma cell proliferation. The maximum effect was observed at concentrations of 10 to 100 pg/ml, with the decrease in thymidine incorporation ranging from 21% to 35% versus control. Addition of an anti-IL-6 antibody enhanced the growth-stimulating effect of meningioma-derived conditioned medium. The rate of IL-6 secretion tended to show an inverse correlation with meningioma growth rate. The results presented here and the previous results suggest that the regulation of meningioma cell proliferation is defined by a complex network of autocrine stimulation, autocrine inhibition, and influences from multiple exogenous factors.

Blotting, Northern↗
PubMed1995

Inhibition of proliferation of human cerebral meningioma cells by suramin: effects on cell growth, cell cycle phases, extracellular growth factors, and PDGF-BB autocrine growth loop.

The growth of human cerebral meningiomas depends on various growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and TGF-beta, platelet-derived growth factor (PDGF)-BB, insulin-like growth factor (IGF)-I and IGF-II, and acidic and basic fibroblast growth factors. The latter three have been shown to form autocrine loops that are thought to be a major component of uncontrolled growth in meningioma tissue. Suramin is known to prevent binding of a variety of growth factors to their receptors in mammalian tissue, thus abolishing para- and/or autocrine-mediated cell growth. The authors therefore tested the effect of suramin on the proliferation of cultured human meningioma cells. Suramin (10(-5) to 10(-4) M) significantly inhibited the growth of meningioma cells in culture. The maximum effect observed was with the higher dose (10(-4) M), which resulted in a 40% to 70% reduction in cellular proliferation. This effect was observed in all 15 tumor samples studied and was confirmed by [3H]thymidine uptake. In studies using DNA flow cytometry, suramin inhibited meningioma cell proliferation in five tumor samples by arresting cells in the S and G2/M phases of the cell cycle. Growth factor (EGF, IGF-I, and PDGF-BB)-induced cell proliferation was completely abolished in five tumor samples when 10(-4) M suramin was applied to meningioma cells. Western blot analysis of three tumor samples showed that the intracellular PDGF-BB content of meningioma cells was significantly reduced after treating the cells with 10(-4) M suramin. Binding of iodinated growth factors (that is, [125I]EGF, [125I]IGF-I, and [125I]PDGF-BB) to their receptor sites was prevented by suramin in a dose-dependent manner in 10 meningioma membrane fractions. Lowering of the intracellular PDGF content and prevention of extracellular growth factor receptor binding demonstrates that suramin disrupts autocrine loops and paracrine growth stimulation in meningioma tissue. These data provide evidence that growth of cerebral meningiomas in culture is strongly inhibited by suramin at a concentration of 10(-4) M. Suramin acts as a scavenger neutralizing exogenous growth factors; thus it can interrupt autocrine loops and paracrine stimulation of human meningioma cell growth. The evidence favors suramin as a therapeutic option for controlling meningioma proliferation in patients with inoperable and recurrent high-grade meningiomas.

Blotting, Western↗
PubMed2002

Affinity regulates spatial range of EGF receptor autocrine ligand binding.

Proper spatial localization of EGFR signaling activated by autocrine ligands represents a critical factor in embryonic development as well as tissue organization and function, and ligand/receptor binding affinity is among the molecular and cellular properties suggested to play a role in governing this localization. We employ a computational model to predict how receptor-binding affinity affects local capture of autocrine ligand vis-a-vis escape to distal regions, and provide experimental test by constructing cell lines expressing EGFR along with either wild-type EGF or a low-affinity mutant, EGF(L47M). The model predicts local capture of a lower affinity autocrine ligand to be less efficient when the ligand production rate is small relative to receptor appearance rate. Our experimental data confirm this prediction, demonstrating that cells can use ligand/receptor binding affinity to regulate ligand spatial distribution when autocrine ligand production is limiting for receptor signaling.

Animals↗
PubMed2002

[Effect of Salvia miltiorrhiza on autocrining growth factor by fibroblasts cultured in vitro].

OBJECTIVE: To investigate the mechanism of overhealing alleviation by salvia miltiorrhiza (SM) in wound healing. METHODS: Fibroblasts were cultured in vitro, and SM was applied with different concentrations (40, 80, 160 and 320 micrograms/ml) and time(the 1st, 2nd, 3rd, 4th and 5th days) to influence their autocrine. The levels of transforming growth factor-beta 1 (TGF-beta 1) and epidermal growth factor (EGF) were determined by ELIAS and radioimmunoassay respectively. RESULTS: The SM could inhibit autocrine of TGF-beta 1 by fibroblasts (P < 0.05). However, it did not affect autocrine of EGF (P > 0.05). CONCLUSION: The above results indicate that SM reduces overhealing by inhibiting the autocrine of TGF-beta 1 selectively.

Cell Division↗
PubMed1989

Tumor necrosis factor mediates autocrine growth inhibition in a chronic leukemia.

Autocrine production of growth factors may contribute to the rapid and fatal proliferation of acute hematologic malignancies. We have investigated whether the more controlled growth of less aggressive malignancies such as chronic myeloid leukemia (CML) may be associated with autocrine production of growth inhibitory factors. TNF inhibits the growth of both normal and leukemic hemopoietic progenitor cells. We find that exogenous TNF reduces the viability and DNA synthesis of purified myeloid cells from patients with CML and inhibits myeloid colony formation by patient progenitor cells. However, unlike progenitor cells from normal donors, patient myeloid progenitor cells also constitutively express mRNA for TNF and secrete functional TNF protein in culture. This endogenous TNF impedes the growth of CML cells because anti-TNF mAb shown to neutralize bioactive human TNF increases CML cell DNA synthesis whereas non-neutralizing anti-TNF mAb has no effect. Production of TNF by CML cells is not associated with production of lymphotoxin (TNF-beta), IL-1 or IL-6. TNF-mediated autocrine growth inhibition may contribute to the maintenance of the stable, chronic phase of this disease and similar mechanisms may operate in other malignancies to limit tumor proliferation. Competition between autocrine growth promoting and inhibiting factors may underlie the observed differences in biologic behavior between acute and chronic malignancies.

Antibodies, Monoclonal↗
PubMed1994

Evidence for internal autocrine regulation of growth in acute myeloblastic leukemia cells.

Blast cells from 70% of patients with acute myeloid leukemia (AML) show some evidence of in vitro autonomous growth, which appears to be related to the autocrine secretion of growth factors, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF). In the majority of cases, the growth factors appear to be involved in classical extracellular autocrine or paracrine loops with neutralizing antibodies to the relevant cytokine inhibiting growth. In a minority, however, antibodies do not inhibit growth despite evidence of secretion of the cytokine. There is evidence for intracellular autocrine loops in murine leukemic cell lines. In this study, we wished to investigate for the presence of such intracellular loops involving GM-CSF in AML blast cells. Blast cells from 11 patients with AML were cultured in the presence of either neutralizing GM-CSF antibody or an antisense oligonucleotide directed against GM-CSF. We also studied the effect of the oligonucleotide on the autonomous growth of cells whose production of GM-CSF had been apparently abolished by either interleukin-1 receptor antagonist (IL-1Ra) or following blast cell purification using the CD34 antigen. The autonomous growth of the blast cells from nine of the 11 patients was inhibited by the antisense oligonucleotide (but not by the control sense oligonucleotide). However, only six of the nine were inhibited by the anti-GM-CSF antibody. Similarly, in one patient whose CD34 purified blast cells continued to show a high degree of autonomous growth but did not produce detectable GM-CSF, growth was inhibited by the antisense oligonucleotide but not by antibody, while in another patient whose cells were inhibited by IL-1Ra with, again, loss of detectable GM-CSF, growth could be further inhibited by the addition of the oligonucleotide but not the antibody. These studies provide evidence that intracellular autocrine loops involving GM-CSF are involved in the autonomous growth of some AML blast cells.

Antibodies↗
PubMedDate not supplied

Autocrine and paracrine roles for growth factors in melanoma.

Distinct biologic and histopathological features characterizing each stage of tumor progression toward a more aggressive phenotype have been defined in the human melanocytic cell system. One of the most significant aspects accompanying melanoma progression is the acquisition of growth autonomy and the expression of multiple growth factors and receptors by tumor cells but not by normal melanocytes. Among the growth factors produced by melanoma cells, bFGF, TGF-alpha, TGF-beta, PDGF A and B chains, MGSA, and interleukins have been extensively characterized. The complex signaling networks mediated by these melanoma-derived factors are responsible for the autocrine growth stimulation of melanoma cells and for paracrine actions of growth factors in the generation of a microenvironment favorable for tumor survival and invasion. bFGF is the best characterized candidate for autocrine stimulation in melanoma cells. In addition, bFGF and other growth factors not apparently involved in autocrine loops have been shown to activate neighboring stromal cells and to participate in angiogenesis, fibrous stroma formation, activation of proteolytic enzymes produced by normal cells, promotion of adhesive interactions between tumor cells and extracellular matrix and endothelium, and suppression of local immunity. Experimental models that can account for the complex interactions between normal and tumor cells are needed to further explore the roles of autocrine and paracrine actions of growth factors and their receptors in melanoma development and progression.

Chemokine CXCL1↗
PubMed1995

B-lineage lymphoid blast crisis in juvenile chronic myelogenous leukemia: II. Interleukin-1-mediated autocrine growth regulation of the lymphoblasts.

A pre-B acute lymphoblastic leukemia (ALL) cell line with monosomy 7 was established from a child with juvenile chronic myelogenous leukemia (JCML) in lymphoid blast crisis. Analysis of the growth properties of the cell line, termed 'W1' showed an interleukin-1 (IL-1) mediated autocrine pattern of cell proliferation with the following features: W1 colony growth without added growth factor was density-dependent and colony growth was augmented with serum-free autologous cell culture supernatant; exogenous IL-1 beta had a growth-promoting effect on W1 colony numbers when cells were seeded at low density; W1 cells constitutively expressed mRNA for IL-1 beta, and high levels of IL-1 beta were measured in W1 cell lysates; anti-IL-1 beta antibodies as well as IL-1 receptor antagonist markedly suppressed W1 colony growth when either was added to cultures of cells seeded without growth factors at low density; anti-GM-CSF antibodies and anti-IL-3 antibodies had no inhibitory effect on W1 colony growth. Whereas W1 colony growth was also augmented by adding IL-3, IL-4, IL-6, IL-7, GM-CSF, Steel factor and erythropoietin individually to the cultures, W1 cells did not constitutively express mRNA for any of these cytokines. W1 colony growth was markedly suppressed by exogenous TNF-alpha which contrasts sharply with the autocrine growth promoting effect of TNF-alpha on myelomonocytic elements of JCML in 'chronic' phase. The inhibitory effect of TNF-alpha on W1 cells was not due to downregulation of IL-1 production. The IL-1-dependent growth of W1 cells appeared to be unique because none of five other pre-B lineage ALL cell lines established as controls showed an autocrine growth loop via IL-1. W1 cells provide a valuable opportunity to examine the relationship of monosomy 7, B-lineage acute lymphoblastic leukemia, aberrant genetic expression of cytokines and their receptors, and IL-1 mediated autocrine cell growth in cancer.

B-Lymphocytes↗
PubMed1995

Differential dependence of the tumorigenicity of chemically transformed rat liver epithelial cells on autocrine production of transforming growth factor alpha.

The tumorigenic phenotype in rat liver epithelial cells overexpressing c-myc may depend on a transforming growth factor (TGF)-alpha/epidermal growth factor receptor autocrine loop (L. W. Lee et al., Cancer Res., 51: 5238-5244, 1991). In the present study, we have used constitutive sense and antisense TGF-alpha expression vectors to modify TGF-alpha production in carcinogen-transformed clonal derivatives of a rat liver epithelial cell line, WB-F344, that variably express c-myc, endogenous TGF-alpha, and tumorigenicity. Transgene-mediated TGF-alpha protein production was elevated 2- to 9-fold in derivatives of a low c-myc-expressing transformed cell line, GN4, and 35-fold in a derivative of a high c-myc-expressing cell line, GN6. Although the GN4- and GN6-derived cell lines expressed functional EGF receptor and steady-state c-myc mRNA levels that were comparable to their respective parental cell lines, increased TGF-alpha expression did not increase the tumorigenicity of the derivatives relative to the parental cell lines. Similarly, in vitro growth characteristics of the GN4- and GN6-derived cell lines were not markedly altered by increased autocrine TGF-alpha production. Additionally, GN4, GN6, and their derivatives were, for the most part, unresponsive to exogenously applied TGF-alpha in vitro. In contrast, antisense TGF-alpha RNA expression significantly suppressed endogenous TGF-alpha production in a high c-myc-expressing, high TGF-alpha-expressing, highly tumorigenic clonal line, GP9; this suppression resulted in lowered steady-state c-myc levels and attenuated in vitro growth. Antisense-mediated suppression of all of these in vitro phenotypes in GP9 was reversed by exogenous TGF-alpha. The latency of tumor formation by the antisense derivative of cell line GP9 was significantly lengthened (> 3-fold) relative to the time required for tumor formation by its parental cell line. These results demonstrate that a TGF-alpha/epidermal growth factor receptor autocrine loop may be necessary for exaggerated in vitro and in vivo growth of some transformed rat liver epithelial cells (e.g., GP9); however, the autocrine loop is not generally sufficient to support tumorigenicity, even in transformed clonal lines expressing elevated levels of c-myc.

Actins↗
PubMed1993

An autocrine model for cell- and matrix-associated fibroblast growth factor.

While the prototypic fibroblast growth factors (FGFs) are known to have important roles in the stimulation of cell proliferation and angiogenesis, their lack of a conventional secretory signal peptide sequence has presented a challenge to our understanding of the mechanisms by which they are released from cells and subsequently engaged at cell-membrane-localized receptors. The autocrine and paracrine function of polypeptide growth factors has frequently involved the delivery of a large, transmembrane precursor molecule to the cell surface and its subsequent proteolytic release. Through the use of chimeric growth factors, and enhanced proteolytic release of cell-associated populations of growth factor precursors, it has been established that cell-associated growth factor populations can exhibit autocrine and paracrine activity. This commentary will draw upon the potential role of cell- and matrix-associated FGF populations to develop a model for the release of prototypic FGFs from low-affinity sites on the cell surface, or from extracellular matrix, to high-affinity, cellular receptors. It is proposed that cell- and matrix-associated FGF may exhibit autocrine function and provide the capacity to be regulated in a variety of normal and transformed cell systems. It is also proposed that growth factor delivery mechanisms involving cell- and matrix-associated ligand populations represent a specialized form of regulated delivery. This specialized delivery mechanism may confer autocrine advantages upon a variety of growth factor family gene products.

Animals↗