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At least 217 records · Page 12Linked to original sources
PubMed2000

Loss of IL-6 receptor expression in cervical carcinoma cells inhibits autocrine IL-6 stimulation: abrogation of constitutive monocyte chemoattractant protein-1 production.

IL-6 is synthesized in human papilloma virus (HPV)-transformed cervical carcinoma cell lines and is supposed to stimulate these cells in an autocrine manner. We studied IL-6 production and responsiveness in nonmalignant HPV-transformed keratinocytes and cervical carcinoma cells in detail. IL-6 was detected in cervical carcinomas in situ. Correspondingly, HPV-positive carcinoma cell lines expressed high IL-6 levels. However, these carcinoma cell lines showed low responsiveness to IL-6 as revealed by low constitutive STAT3 binding activity, which was not further enhanced by exogenous IL-6. In contrast, in vitro-transformed nonmalignant keratinocytes without endogenous IL-6 production strongly responded to exogenous IL-6 with activation of STAT3. STAT3 protein expression levels were comparable in both responsive and nonresponsive cell lines. Also, gp130, the upstream signal-transducing receptor subunit conveying IL-6 signals into the cell, was expressed in all tested cell lines. However, the IL-6 binding subunit gp80 was lost in the malignant cells. Addition of soluble gp80 was sufficient to restore IL-6 responsiveness in carcinoma cells as shown by enhanced activation of STAT3 binding activity. As a consequence of the restored IL-6 responsiveness, carcinoma cells strongly produced the chemokine monocyte chemoattractant protein-1 (MCP-1). Our data demonstrate that cervical carcinoma cells producing high amounts of IL-6 only weakly respond to IL-6 in an autocrine manner due to limited gp80 expression. While production of IL-6 might contribute to a local immunosuppressive effect, silencing an autocrine IL-6 response prevents constitutive production of the mononuclear cell-attracting chemokine MCP-1. Both mechanisms might help the tumor to escape the immune system.

Apoptosis↗
PubMed1999

Regulation of gelatinase B production in corneal cells is independent of autocrine IL-1alpha.

PURPOSE: The matrix metalloproteinase gelatinase B is synthesized by cells at the leading edge of the corneal epithelium migrating to heal a wound. Recent data from the authors' laboratory suggest that excessive synthesis contributes to repair defects. The goal of the study reported here was to investigate mechanisms controlling gelatinase B production by corneal epithelial cells. METHODS: Freshly isolated cultures of corneal epithelial cells and early passage stromal fibroblasts from rabbit were used for these studies. RESULTS: In a previous study, it was found that the cytokine interleukin (IL)-1alpha is released into the culture medium of corneal epithelial cells more efficiently when they are plated at low density with limited cell-cell contact than when plated at high density. In this study, we show that production of gelatinase B by these cells is similarly affected by cell plating density. However, it is further demonstrated that these two events are not dependent on one another but occur in parallel: IL-1alpha does not regulate gelatinase B production (synthesis), nor was there evidence that any other secreted autocrine cytokine acts as mediator. Instead, our data suggest that gelatinase B production is downregulated directly by high cell density and indicate a connection to the level of protein kinase C activity. Nevertheless, the anticancer agent suramin, which blocks collagenase synthesis by interfering with autocrine cytokine-receptor interactions, still inhibits synthesis of gelatinase B. CONCLUSIONS: Unlike collagenase synthesis by corneal stromal fibroblasts, production (synthesis) of gelatinase B does not appear to be controlled by secreted autocrine cytokines but can still be inhibited by suramin. Suramin may make an effective therapeutic agent for controlling pathologic overproduction of gelatinase B in corneal ulcers.

Animals↗
PubMed2002

Cytoprotective antioxidant activity of serum albumin and autocrine catalase in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) cells are long lived in vivo but undergo spontaneous apoptosis when cultured in vitro. Intriguingly, CLL cells also appear to have a specific susceptibility to oxidative stress - a potent inducer of apoptosis. Here, we show that serum albumin can function as a cytoprotective antioxidant of potential relevance to circulating CLL cells, and that autocrine catalase - a hydrogen peroxide-inactivating enzyme that may be released extracellularly - can perform a similar role under the crowded conditions that prevail at sites of tissue involvement. Albumin lowered oxidative stress in cultured CLL cells and inhibited spontaneous and reactive oxidant-induced apoptosis. Maximal effects were observed at a concentration of 10 mg/ml - fourfold lower than that in plasma and twofold higher than that in standard culture medium containing 10% fetal calf serum. Oxidative stress and spontaneous apoptosis were also decreased by cell crowding and by conditioned medium (CM) from crowded CLL cells, indicating that these processes were subject to autocrine regulation. CLL cells were found to express catalase and release enzyme activity into the culture medium. Exogenous catalase decreased oxidative stress and spontaneous apoptosis, and the anti-apoptotic effect of CM from crowded CLL cells was abrogated by the specific catalase inhibitor, 3'-amino-1,2,4-triazole. Together, these data strongly implicate autocrine catalase as a cytoprotective antioxidant. Oxidative stress in CLL cells was greatly diminished by ruthenium red - an inhibitor of mitochondrial reactive oxidant production - and by the glutathione (GSH) precursor N-acetylcysteine, suggesting that the GSH peroxidase antioxidant system may be compromised by lack of available substrate. Our findings highlight the importance of endogenous reactive oxidants in regulating CLL-cell apoptosis, and help to explain why CLL cells survive for prolonged periods in vivo despite their vulnerability to oxidative stress and spontaneous apoptosis when cultured in vitro.

Acetylcysteine↗
PubMed1996

Autocrine motility factor receptor as a possible urine marker for transitional cell carcinoma of the bladder.

PURPOSE: To determine whether autocrine motility factor receptor (AMFR) is detectable in the urine of patients with transitional cell carcinoma (TCC) of the bladder. MATERIALS AND METHODS: We assayed the urine of 89 patients with bladder pathology and 28 normal controls for AMFR. A monoclonal antibody to AMFR was used. RESULTS: All patients with muscle-invasive TCC tested positive for AMFR. Autocrine motility factor receptor was detectable for 80% of superficial tumors, with a correlation between AMFR and tumor grade. Seventy-five percent of control urines tested negative. CONCLUSIONS: Autocrine motility factor receptor is detectable in the urine of patients with TCC. Long-term follow-up and refinements in the assay should define the marker's utility for detection and prognosis.

Adult↗
PubMed1998

Both autocrine and paracrine effects of transfected acidic fibroblast growth factor are involved in the estrogen-independent and antiestrogen-resistant growth of MCF-7 breast cancer cells.

To determine the extent to which autocrine effects of acidic fibroblast growth factor (FGF)-1 overexpression contribute to an increased malignant phenotype, FGF-1-transfected MCF-7 cells were retransfected with a FGF receptor (FGFR1) vector encoding a truncated dominant-negative receptor to inhibit autocrine FGF signal transduction. This transfection eliminated FGF signaling within the breast cancer cells without interfering with their ability to produce FGF-1, thereby allowing possible paracrine effects to still be observed in vivo. Truncated FGFR1 overexpression inhibited the acquired ability of FGF-1-overexpressing cells to form colonies in soft agar in estrogen-depleted or antiestrogen-containing medium. However, soft agar colony formation was still stimulated by estrogen treatment in cells expressing up to 6 x 10(5) truncated FGFR1 sites per cell. In vivo, truncated receptor expression severely inhibited the ability of the FGF-1-overexpressing cells to form tumors without estrogen in ovariectomized mice, indicating that the mitogenic effect of FGF-1 on the breast tumor cells was important in the estrogen-independent in vivo growth of these transfectants. However, rapid formation of large tumors was still observed in estrogen-supplemented mice injected with the truncated FGFR1-expressing cells, suggesting that the paracrine effects of FGF production could act in synergy with mitogenic effects mediated by estrogen. Truncated FGFR1-overexpressing cells also continued to form tumors in tamoxifen-treated mice, raising the possibility that the paracrine effects of FGF-1 expression may allow the partial agonist properties of this antiestrogen to be more readily observed. We conclude that autocrine effects of FGF-1 increase the ability of MCF-7 breast cancer cells to grow in vitro and in vivo under estrogen-depleted conditions but that paracrine effects of FGF-1 are also involved in the enhancement of tumor growth in estrogen-supplemented or tamoxifen-treated animals.

Animals↗
PubMed1998

Coexpression of parathyroid hormone-related protein and its receptor in breast carcinoma: a potential autocrine effector system.

Parathyroid hormone-related protein (PTHrP), the pathogenic factor in most cases of humoral hypercalcemia of malignancy, is also expressed by many normal tissues. Its diverse biologic activities in these tissues are mediated by the PTH/PTHrP receptor through autocrine and paracrine mechanisms. Recent data suggest that PTHrP and its receptor might also influence the growth and metastatic spread of some cancers through similar local actions. Accordingly, immunohistochemical studies using murine monoclonal antibodies to detect coexpression of PTHrP and the PTH/PTHrP receptor were performed on 52 invasive breast carcinomas to assess the existence of this potential autocrine effector system. All of the 52 invasive breast carcinomas expressed reactivity for PTHrP, and 50 (96%) of these tumors also expressed reactivity for the receptor. Although additional investigations are necessary for evaluation of the role of PTHrP and PTH/PTHrP receptor in tumor pathogenesis, our current study demonstrates the presence of this potential autocrine effector system in the great majority of invasive breast carcinomas.

Adult↗
PubMed1998

G-CSF production in human bladder cancer and its ability to promote autocrine growth: a review.

A variety of non-hematopoietic malignant tumors have been demonstrated to secrete granulocyte colony-stimulating factor (G-CSF) in amounts large enough to cause a significant systemic hematopoietic effect. Meanwhile, bladder cancer cells have been shown to secrete a variety of biological factors with no direct relation to urothelial cell origin. G-CSF produced by non-hematopoietic malignant cells in particular has been reported to be capable of inducing a leukemoid reaction in the host through intense stimulation of leukocyte production. This is most frequently associated with aggressive tumor cell growth and a poor clinical outcome. On the other hand, receptors for G-CSF have also been found on the cell surfaces of several non-hematopoietic cell types. These observations lead naturally to the tempting speculation that simultaneous acquisition of the ligand promotion and its receptor expression by a malignant tumor may provide a strong autocrine growth advantage. However, the role of autocrine growth factors in malignancy is even less clear, although it is undoubtedly important. In this review, G-CSF and tumor cell growth, particularly of human transitional cell carcinomas of the bladder, are discussed, and autocrine growth of human solid tumors is also summarized.

Autocrine Communication↗
PubMed1997

Autocrine activation of the IL-3/GM-CSF/IL-5 signaling pathway in leukemic cells.

The AML14.3D10 human myeloid leukemic cell line expresses receptors for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-5 (IL-5), but not IL-3. We have found that this cell line produces GM-CSF in amounts up to 113 pg/ml in culture supernatants. Deprivation of endogenous GM-CSF by addition of neutralizing anti-GM-CSF antibody strongly inhibits proliferation of the cells, suggesting a GM-CSF autocrine growth mechanism. To examine whether endogenously produced GM-CSF activates intracellular GM-CSF/IL-3/IL-5-related signal transduction pathways, we performed antiphosphotyrosine immunoblotting of cell lysates of AML14.3D10 cells before and after deprivation of endogenous GM-CSF. We found constitutive tyrosine-phosphorylation of a number of proteins in AML14.3D10 that could not be detectably increased by the addition of exogenous GM-CSF, IL-3, or IL-5. However, GM-CSF-deprived cells demonstrated a marked increase in phosphorylation of proteins of identical molecular mass following addition of GM-CSF and IL-5, but not IL-3, consistent with the receptor expression of the cells and the known use of the same signaling pathways by the three cytokines. This suggests that AML14.3D10 cells use endogenously produced GM-CSF to activate signal transduction pathways, interfering with activation by exogenous cytokine until the endogenous stimulation is removed. We then assessed the activation of the beta-subunit common to the GM-CSF/IL-3/IL-5 receptors (beta c), JAK2 and p53/56 lyn, known to be involved in the common signaling pathways of the three cytokines. We found that phosphorylation of beta c and JAK2 in response to GM-CSF and IL-5 could be markedly enhanced by depriving cells of endogenous GM-CSF. Constitutive hyperphosphorylation of lyn was found in AML14.3D10 cells, and no further activation of lyn in response to cytokine was demonstrable in GM-CSF-deprived cells, suggesting that lyn is activated in this cell line by a mechanism other than GM-CSF. These studies represent the first demonstration of autocrine activation of intracellular cytokine signaling pathways by malignant hematopoietic cells. Because the addition of anti-GM-CSF to cell cultures improved responsiveness of intracellular signal transducing molecules to exogenous GM-CSF and IL-5, it can be inferred that endogenously produced GM-CSF exerts its effects by secretion and binding to surface GM-CSF receptors, although an intracellular component to signaling cannot be excluded. These observations provide further information regarding an autocrine contribution to leukemic cell growth, and establish a new model for study of these events.

Antibodies↗
PubMed1996

Bombesin may stimulate proliferation of human pancreatic cancer cells through an autocrine pathway.

Bombesin is trophic to normal pancreas and acinar cell adenocarcinoma, but its effects on ductal cell tumors are undetermined. The autocrine growth effects of bombesin on well-differentiated (HPAF, CD11) and poorly differentiated (CD18, PANC-1) human ductal pancreatic cancer cell lines were investigated. Receptor binding of labeled bombesin was measured in a whole-cell microplate assay. Bombesin production was measured by radioimmunoassay. Proliferative responses were quantified using the MTT assay. Messenger RNA for bombesin and its receptor were identified by primer extension analysis. A single class of high-affinity binding sites was detected on HPAF and CD18 cells. Similar affinities and high receptor densities were found on the 2 cell lines. Bombesin was secreted by all 4 cell lines during 24-hr culture in serum-free media, and its recovery was enhanced in the presence of protease inhibitors. Primer extension analysis demonstrated the presence of mRNA for both bombesin and its receptor in HPAF, CD18, CD11 and PANC-1 cells, even though no functional receptor was found in the latter 2 lines. Bombesin significantly stimulated the proliferation of HPAF and CD18 cells. This trophic effect was inhibited by the specific bombesin antagonist RC-3095. Bombesin may act as an autocrine growth factor in some human pancreatic cancer cell lines. Furthermore, other cell lines transcribe mRNA for bombesin receptors but have no functional bombesin receptors, suggesting a genetic or post-translational change in the receptor for these cells. Bombesin may be involved as a growth factor in the development of pancreatic ductal adenocarcinoma in humans. This possible autocrine growth pathway may provide an avenue for therapeutic intervention in this malignant disease.

Bombesin↗
PubMed1998

Autocrine motility factor and the extracellular matrix. I. Coordinate regulation of melanoma cell adhesion, spreading and migration involves focal contact reorganization.

Cellular interactions with the extracellular matrix are complex and are involved in numerous biological processes. These interactions may be modulated by cytokines such as tumor cell autocrine motility factor, a secreted molecule that regulates cellular growth and migration by a receptor-mediated pathway. In this report we provide evidence suggesting that high- and low-metastatic K1735 melanoma cells coordinate their attachment, spreading and migratory responses to autocrine motility factor and the extracellular substratum through alterations in focal adhesion plaque architecture that are dependent on both inherent cellular metastatic phenotype and the composition of the supporting matrix. Thus, since activation of the autocrine motility factor receptor has previously been shown to enhance the experimental metastasis of the high- but not the low-metastatic K1735 cells, differences in melanoma cell malignancy in this system may be due in part to a coordinated interplay between cytokine-mediated responses and extracellular matrix-directed regulation of cellular adhesion, spreading and motility.

Animals↗
PubMed1998

Autocrine motility factor and the extracellular matrix. II. Degradation or remodeling of substratum components directs the motile response of tumor cells.

Autocrine motility factor is a tumor-secreted cytokine which regulates cellular growth and motility by a receptor-mediated pathway. In the accompanying report (Part I of II), it was demonstrated that high (K1735-M1) and low (K1735-C1.11) metastatic murine melanoma cells display distinct adhesion and spreading characteristics which correlate with their differential spontaneous and stimulated migrations on the extracellular matrix components fibronectin, laminin and collagen IV. These parameters were further related to discrete profiles of focal adhesion plaque integrity and reorganization. Here we describe unique migration patterns observed in these murine melanoma cells which reflect differences in degradation and/or remodeling of the cellular substratum. These profiles of matrix interaction were influenced distinctly by autocrine motility factor and dictated by both substrate composition and cellular phenotype. Since activation of the autocrine motility factor receptor stimulates invasion of a reconstituted basement membrane and enhances experimental metastasis by high- but not low-metastatic K1735 cells, differences in the invasive phenotypes of these cells may be due in part to their differential responses to external stimuli coupled with internal propensities toward either matrix degradation and migration (high-metastatic cells) or matrix remodeling and stasis (low-metastatic cells).

Animals↗
PubMed1998

Phenotypic consequences of transforming growth factor beta1 gene ablation in murine embryonic fibroblasts: autocrine control of cell proliferation and extracellular matrix biosynthesis.

The profound effects of transforming growth factor beta1 (TGF-beta1) on the immune system, cardiogenesis, in yolk sac hematopoeisis and in differentiation of endothelium have been demonstrated by detailed analyses of TGF-beta1 knockout mice during embryogenesis. We have systematically examined the autocrine and paracrine roles of TGF-beta1 in cell proliferation and in its ability to modulate the gene expression of selected components of extracellular matrix (ECM) using embryonic fibroblasts from TGF-beta1 null mice (TGF-beta-1(-/-)). The rates of cell proliferation of embryonic fibroblasts from normal mice (TGF-beta1(+/+)) and TGF-beta1 null mice were compared by cell counting, by 3H thymidine incorporation, and by measuring the fraction of cells in the G1, S, and G2/M phases of the cell cycle by fluorescent activated cell sorting (FACS). Concurrently, the expression of pro-alpha1(I) collagen, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) was also quantified by hybridization of total mRNA from TGF-beta1(+/+) and TGF-beta1(-/-) embryonic fibroblasts. We report that TGF-beta1(-/-) cells proliferated at about twice the rate of TGF-beta1(+/+) cells. Further, TGF-beta1 null fibroblasts accumulated and synthesized lower constitutive levels of pro-alpha1(I) collagen, fibronectin, and PAI-1 mRNA. The quantitative differences in the rates of cell proliferation and ECM gene expression between TGF-beta1(+/-) and TGF-beta1(-/-) cells could be eliminated by treatment of TGF-beta1(+/+) cells with a neutralizing antibody of TGF-beta1. Thus, our results are consistent with the hypothesis that TGF-beta1 acts as a negative autocrine regulator of growth and a positive autocrine regulator of ECM biosynthesis in embryonic fibroblasts.

Animals↗
PubMed2000

Rhythmic autocrine activity in cultured insect epidermal cells.

It is now well established that ecdysteroids can be produced in insects in the absence of prothoracic glands. In this respect, it has been shown that cells in culture can produce ecdysteroids. Our aims were: (1) to determine whether ecdysteroid target cells of epidermal origin could also be the source of ecdysteroids; (2) to monitor more accurately the kinetics of ecdysteroid production; and (3) to check for possible relationships between this synthetic activity and dynamics of cell division. An insect cell line (IAL-PID2) established from imaginal discs of the Indian meal moth, Plodia interpunctella, with wild-type sensitivity to ecdysteroids was used in our study. Our results showed that the Plodia cell line exhibited autocrine activity. When division of IAL-PID2 cells was synchronized, a rhythmic production of ecdysteroids was observed. However, further experiments indicated that this rhythmicity could be cell autonomous. This led us to anticipate the existence of two cell subpopulations that would be able to produce ecdysteroids rhythmically, a minor one that would be cell cycle serum-independent population, and a major population that would need serum growth factors to proliferate and produce ecdysteroids. Qualitative study of the ecdysteroid content of the media clearly showed that ecdysone was the major immunoreactive product. Taken together, our findings clearly show that an insect cell line of epidermal origin is capable of rhythmic autocrine production of ecdysteroids. These results support the hypothesis that alternate sites for ecdysteroid production in vivo may exist and could play a role in local regulation of development. We now plan to determine the cellular basis of this rhythmic autocrine activity and to confirm the existence of growth factor-autonomous cells in the culture as well as the potent role played by ecdysteroids in the cross-talk between various cell subpopulations.

Animals↗
PubMed1993

The CD2 and CD28 adhesion molecules induce long-term autocrine proliferation of CD4+ T cells.

In vitro human T lymphocyte activation requires two-signal triggering delivered by lectins, phorbol esters or antibodies directed against surface molecules. Stimulation of adhesion molecules by CD2 and/or CD28 antibodies defines alternative activation pathways. Activation by CD2 + CD28 monoclonal antibodies induces high-level, long-lasting and monocyte-independent proliferation of highly purified T cells. Limiting dilution cultures showed that CD28 in association with CD2 or CD3, without addition of exogenous cytokines, induced single-cell proliferation. CD2 + CD28 stimulation induced long-term interleukin (IL)-2-dependent autocrine proliferation of CD4+ T cell clones. We tried to elucidate this long-term proliferation by evaluating cytokine secretion and cytokine dependency. CD28 associated to CD3 or CD2 induced high levels of IL-2, tumor necrosis factor (TNF) and IL-4 secretion for 10 days, in contrast to CD3 alone which induced only TNF secretion. Cytokines of the monocytic lineage were also secreted, such as colony-stimulating factor-1, granulocyte-macrophage colony-stimulating factor or IL-1, the latter being more specific of CD2 + CD28 activation. Blocking antibodies confirmed the crucial role of IL-2 in CD2 + CD28 activation. Anti-IL-4, anti-IL-7 receptor or anti-TNF antibodies had no effect on proliferation. Stimulation with CD2 + CD28 induced long-term autocrine (at least for IL-2) proliferation for CD4+ T cells, with no evidence for the implication of another cytokine among those tested other than IL-2. This represents a model for long-term autocrine growth for non-leukemic cells.

Antigens, CD↗
PubMed1990

Serum changes the response of cultured Morris hepatoma 7777 cells to autocrine growth factors.

The addition of calf serum to culture medium alters the biological response of Morris hepatoma 7777 (MH) cells to autocrine growth factors isolated from conditioned medium of the investigated cells. Acetic acid (AA) extract obtained from conditioned medium of MH cells showed a change in anchorage-independent growth-regulatory activity from stimulation (serum-free) to inhibition (10% calf serum). Two protein fractions of apparent molecular weight 15 and 7.5 kDa isolated from AA-extract by Bio-Gel P-60 filtration also changed their growth-regulatory activity after supplementation of culture medium with calf serum. The contradictory effect of autocrine regulators estimated in soft agar using the 3H-thymidine (3H-TdR) incorporation test and colony formation assay gave generally comparable results, except in the case of the 15-kDa fraction. The most active 7.5-kDa fraction stimulated 3H-TdR incorporation and colony formation in serum-free medium up to about 300 and 500% respectively, while in the presence of 10% calf serum inhibition of about 20 and 50% has been observed. Our results suggest that the fraction contains an autocrine growth factor(s), whose activity is inverted in the presence of serum.

Animals↗
PubMed1992

des-(1-3)-IGF-I, an insulin-like growth factor analog used to mimic a potential IGF-II autocrine loop, promotes the differentiation of human colon-carcinoma cells.

HT29-D4 human colon-carcinoma cells have been shown to secrete insulin-like growth factor (IGF)-II and to simultaneously express type-I IGF receptors. However, the sequestration of IGF-II by several molecular forms of IGF-binding proteins (IGFBP) in the culture medium prevents the establishment of an operative IGF-II autocrine loop. IGFBPs secreted by HT29-D4 cells (HT29-D4 IGFBP) comprise isoforms of IGFBP-4 (25, 27 and 30 kDa) and 2 unidentified forms (34.5 and 32-34 kDa). This latter does not bind 125I-IGF-I. The net affinity of HT29-D4 IGFBP is about 12 times stronger for IGF-II (KD approx. 10(-10) M) than for IGF-I. All the HT29-D4 IGFBP molecular forms are unable to bind the N-terminally truncated IGF-I analog, des-(1-3)-IGF-I. In contrast, HT29-D4 cell-surface type-I IGF receptors bind IGF-I and des-(1-3)-IGF-I identically (KD approx. 5 x 10(-10) M). We have taken advantage of these particular binding properties to use des-(1-3)-IGF-I to mimic a potential IGF autocrine loop and to observe its biological consequences. Nanomolar concentrations of des-(1-3)-IGF-I induce HT29-D4 cells to develop into a differentiated phenotype, as judged by a substantial carcinoembryonic antigen release and the induction of numerous intercellular cysts with well-organized microvilli. In the same way, des-(1-3)-IGF-I early induces a slight inhibition of HT29-D4 cell proliferation. Based on these findings, we conclude that the type-I IGF receptor primarily controls the differentiation of these colonic cells, and that HT29-D4 cancer cells remain in an undifferentiated state because of their inability to use endogenous IGF-II as an autocrine regulatory factor.

Carcinoembryonic Antigen↗
PubMed1993

Demonstration of a TGF-alpha-EGF-receptor autocrine loop and c-myc protein over-expression in papillary thyroid carcinomas.

Autocrine growth stimulation has been identified in several types of human cancer. In the present study we wanted to establish whether autocrine stimulation of the epidermal-growth-factor receptor (EGF-r) by its ligand, transforming growth factor alpha (TGF-alpha) occurs in thyroid neoplasia. We examined 190 fresh, frozen thyroid tissue samples from 70 patients by immunohistochemistry with antibodies to EGF-r, TGF-alpha, c-erbB-2 and c-myc. EGF-r expression was detected in 17 out of 19 papillary carcinomas, TGF-alpha expression in 10, and c-erbB-2 expression in 15. No papillary carcinoma expressed TGF-alpha without also expressing EGF-r. Concomitant expression of EGF-r, TGF-alpha and c-erbB-2 was seen in 7 papillary carcinomas. No EGF-r, TGF-alpha or c-erbB-2 immunopositivity was found in normal-appearing thyroid tissue (25 cases), whereas a few of the non-neoplastic lesions (colloid goitres and diffuse hyperplasias) expressed either EGF-r or TGF-alpha. c-myc expression was detectable in all tissue samples, and expression was invariably nuclear. Increased expression was observed in 10 out of 19 papillary carcinomas, and 8 of these also co-expressed EGF-r and TGF-alpha. In situ hybridization confirmed the presence of TGF-alpha mRNA in tumour epithelium of TGF-alpha-immunopositive samples. The concomitant expression of EGF-r, TGF-alpha and TGF-alpha mRNA gives evidence for a TGF-alpha-EGF-r autocrine loop in thyroid papillary carcinomas. The increased c-myc expression may reflect the proliferative advantage of these tumours.

Carcinoma, Papillary↗
PubMed1992

Epidermal growth factor dependence and TGF alpha autocrine growth regulation in primary rat tracheal epithelial cells.

We have examined dependence of primary rat tracheal epithelial (RTE) on exogenous epidermal growth factor (EGF) and determined whether a TGF alpha autocrine pathway is operating in these cells. Primary RTE cells plated in serum free media (SFM) without EGF and bovine pituitary factor (BPE) show little proliferation compared to cultures propagated in media containing EGF/BPE (CSFM). Removal of EGF/BPE shortly after plating, however, results in significant proliferation, although plateau cell densities are reduced and cell morphology is significantly altered compared to cells propagated in CSFM. Addition of EGF and/or BPE to cultures propagated in SFM minus EGF/BPE restores maximum cell density. The concentration of TGF alpha peptide in media conditioned by cells propagated without EGF/BPE is lower than the concentration in the media of CSFM cultures. TGF alpha mRNA and protein levels are also significantly lower in cells late in culture compared to logarithmically growing cells regardless of the presence or absence of EGF/BPE. The proliferation of primary RTE cells propagated without EGF/BPE is inhibited by neutralizing TGF alpha antiserum and by a tyrphostin compound that blocks TGF alpha/EGF receptor tyrosine kinase activity. These results indicate that primary RTE cells utilize TGF alpha as an autocrine growth factor and that the autocrine pathway is regulated as a function of growth state of the cells. However, this pathway does not provide growth autonomy to primary RTE cells, since cultures remain dependent on exogenous EGF/BPE for sustained proliferation.

Animals↗