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Matias A Avila - One of the best experts on this subject based on the ideXlab platform.

  • BASIC-LIVER, PANCREAS, AND BILIARY TRACT Amphiregulin: An Early Trigger of Liver Regeneration in Mice
    2020
    Co-Authors: Carmen Berasain, Josefa Castillo, Elena Erroba, David C Lee, Jesus Prieto, Elena R García-trevijano, Matias A Avila
    Abstract:

    See editorial on page 504. Background & Aims: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of Amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. Methods: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of Amphiregulin were studied in isolated hepatocytes. The in vivo role of Amphiregulin in liver regeneration after partial hepatectomy was analyzed in Amphiregulin-null mice. Results: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1␤ and prostaglandin E 2 , but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor ␣. We show that Amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, Amphiregulin-null mice display impaired proliferative responses after partial liver resection. Conclusions: Our findings indicate that Amphiregulin is an earlyresponse growth factor that may contribute to the initial phases of liver regeneration

  • Amphiregulin a new growth factor in hepatocarcinogenesis
    Cancer Letters, 2007
    Co-Authors: Carmen Berasain, Josefa Castillo, Jesus Prieto, M J Perugorria, Matias A Avila
    Abstract:

    Amphiregulin (AR) is a member of the epidermal growth factor family and a ligand of the epidermal growth factor receptor (EGFR). As other ligands of the EGFR, AR is synthesized as a precursor that is shed from the plasma membrane by metalloproteases. Hyperactive autocrine loops involving AR production have been described in a variety of tumors, and this growth factor is thought to play a non-redundant role in cancer development. AR expression is not detected in the normal liver, however it is readily induced during acute liver injury and behaves as a potent pro-regenerative and survival factor. Increased AR expression is also detected in human chronic liver injury (liver cirrhosis), which is considered a pre-neoplastic condition. Recent evidences suggest that AR can play a unique role in liver tumorigenesis and in the maintenance of the neoplastic phenotype of hepatocarcinoma cells. In this review, we summarize some aspects of AR patho-biology and the rationale behind its definition as a novel target in hepatocarcinoma therapy.

  • novel role for Amphiregulin in protection from liver injury
    Journal of Biological Chemistry, 2005
    Co-Authors: Carmen Berasain, Elena R Garciatrevijano, Josefa Castillo, Elena Erroba, Jesus Prieto, Monica Santamaria, Matias A Avila
    Abstract:

    Abstract Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor α, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and Amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that Amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.

  • Amphiregulin an early trigger of liver regeneration in mice
    Gastroenterology, 2005
    Co-Authors: Carmen Berasain, Elena R Garciatrevijano, Josefa Castillo, Elena Erroba, David C Lee, Jesus Prieto, Matias A Avila
    Abstract:

    Background & Aims: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of Amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. Methods: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of Amphiregulin were studied in isolated hepatocytes. The in vivo role of Amphiregulin in liver regeneration after partial hepatectomy was analyzed in Amphiregulin-null mice. Results: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1β and prostaglandin E2, but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor α. We show that Amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, Amphiregulin-null mice display impaired proliferative responses after partial liver resection. Conclusions: Our findings indicate that Amphiregulin is an early-response growth factor that may contribute to the initial phases of liver regeneration.

Carmen Berasain - One of the best experts on this subject based on the ideXlab platform.

  • BASIC-LIVER, PANCREAS, AND BILIARY TRACT Amphiregulin: An Early Trigger of Liver Regeneration in Mice
    2020
    Co-Authors: Carmen Berasain, Josefa Castillo, Elena Erroba, David C Lee, Jesus Prieto, Elena R García-trevijano, Matias A Avila
    Abstract:

    See editorial on page 504. Background & Aims: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of Amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. Methods: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of Amphiregulin were studied in isolated hepatocytes. The in vivo role of Amphiregulin in liver regeneration after partial hepatectomy was analyzed in Amphiregulin-null mice. Results: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1␤ and prostaglandin E 2 , but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor ␣. We show that Amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, Amphiregulin-null mice display impaired proliferative responses after partial liver resection. Conclusions: Our findings indicate that Amphiregulin is an earlyresponse growth factor that may contribute to the initial phases of liver regeneration

  • Amphiregulin a new growth factor in hepatocarcinogenesis
    Cancer Letters, 2007
    Co-Authors: Carmen Berasain, Josefa Castillo, Jesus Prieto, M J Perugorria, Matias A Avila
    Abstract:

    Amphiregulin (AR) is a member of the epidermal growth factor family and a ligand of the epidermal growth factor receptor (EGFR). As other ligands of the EGFR, AR is synthesized as a precursor that is shed from the plasma membrane by metalloproteases. Hyperactive autocrine loops involving AR production have been described in a variety of tumors, and this growth factor is thought to play a non-redundant role in cancer development. AR expression is not detected in the normal liver, however it is readily induced during acute liver injury and behaves as a potent pro-regenerative and survival factor. Increased AR expression is also detected in human chronic liver injury (liver cirrhosis), which is considered a pre-neoplastic condition. Recent evidences suggest that AR can play a unique role in liver tumorigenesis and in the maintenance of the neoplastic phenotype of hepatocarcinoma cells. In this review, we summarize some aspects of AR patho-biology and the rationale behind its definition as a novel target in hepatocarcinoma therapy.

  • novel role for Amphiregulin in protection from liver injury
    Journal of Biological Chemistry, 2005
    Co-Authors: Carmen Berasain, Elena R Garciatrevijano, Josefa Castillo, Elena Erroba, Jesus Prieto, Monica Santamaria, Matias A Avila
    Abstract:

    Abstract Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor α, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and Amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that Amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.

  • Amphiregulin an early trigger of liver regeneration in mice
    Gastroenterology, 2005
    Co-Authors: Carmen Berasain, Elena R Garciatrevijano, Josefa Castillo, Elena Erroba, David C Lee, Jesus Prieto, Matias A Avila
    Abstract:

    Background & Aims: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of Amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. Methods: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of Amphiregulin were studied in isolated hepatocytes. The in vivo role of Amphiregulin in liver regeneration after partial hepatectomy was analyzed in Amphiregulin-null mice. Results: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1β and prostaglandin E2, but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor α. We show that Amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, Amphiregulin-null mice display impaired proliferative responses after partial liver resection. Conclusions: Our findings indicate that Amphiregulin is an early-response growth factor that may contribute to the initial phases of liver regeneration.

Amandine Hurbin - One of the best experts on this subject based on the ideXlab platform.

  • The multiple roles of Amphiregulin in human cancer.
    Biochimica et Biophysica Acta - Molecular Cell Research, 2011
    Co-Authors: Benoit Busser, Jean-luc Coll, Lucie Sancey, Elisabeth Brambilla, Amandine Hurbin
    Abstract:

    Amphiregulin (AREG) is one of the ligands of the epidermal growth factor receptor (EGFR). AREG plays a central role in mammary gland development and branching morphogenesis in organs and is expressed both in physiological and in cancerous tissues. Various studies have highlighted the functional role of AREG in several aspects of tumorigenesis, including self-sufficiency in generating growth signals, limitless replicative potential, tissue invasion and metastasis, angiogenesis, and resistance to apoptosis. The oncogenic activity of AREG has already been described in the most common human epithelial malignancies, such as lung, breast, colorectal, ovary and prostate carcinomas, as well as in some hematological and mesenchymal cancers. Furthermore, AREG is also involved in resistance to several cancer treatments. In this review, we describe the various roles of AREG in oncogenesis and discuss its translational potential, such as the development of anti-AREG treatments, based on AREG activity. In the last decade, independent groups have reported successful but sometimes contradictory results in relation to the potential of AREG to serve as a prognostic and/or predictive marker for oncology, especially with regard to anti-EGFR therapies. Thus, we also discuss the potential usefulness of using AREG as a therapeutic target and validated biomarker for predicting cancer outcomes or treatment efficacy.

  • inhibition of apoptosis by Amphiregulin via an insulin like growth factor 1 receptor dependent pathway in non small cell lung cancer cell lines
    Annals of the New York Academy of Sciences, 2003
    Co-Authors: Amandine Hurbin, Laurence Dubrez, Jean-luc Coll, Marie-christine Favrot
    Abstract:

    The reciprocal activation of Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) pathways has been shown to induce inhibition of serum deprivation apoptosis in non-small cell lung cancer (NSCLC) cell lines H358 and H322. We demonstrated that AR activated the IGF1 receptor (IGF1-R), which in turn induced the secretion of AR and IGF1. Transactivation of the IGF1-R by AR is independent of its binding to EGFR. Thus, AR can inhibit apoptosis in NSCLC cells through an IGF1-R-dependent pathway.

  • Inhibition of Apoptosis by Amphiregulin via an Insulin-like Growth Factor-1 Receptor-dependent Pathway in Non-small Cell Lung Cancer Cell Lines
    Journal of Biological Chemistry, 2002
    Co-Authors: Amandine Hurbin, Laurence Dubrez, Jean-luc Coll, Marie-christine Favrot
    Abstract:

    Several abnormalities in the insulin-like growth factor -1 (IGF1) and erbB receptors pathways stimulate the growth and survival of lung cancer cells, but their mechanisms of action and cooperation are poorly understood. In this report, we have identified a new mechanism of apoptosis inhibition by Amphiregulin through an IGF1-dependent survival pathway in non-small cell lung cancer (NSCLC) cells: Amphiregulin activates the IGF1 receptor that in turn induces the secretion of am-phiregulin and IGF1. In the absence of serum, the NSCLC cell line H358 resists apoptosis and secretes factors protecting the NSCLC cell line H322 from serum deprivation apoptosis. IGF1 receptor inhibitor AG1024 as well as epidermal growth factor receptor inhibitors AG556 and ZD1839 restore apoptosis in H322 cells cultured in H358-conditioned medium. Accordingly, the an-ti-apoptotic activity of H358-conditioned medium is completely abolished after incubation with anti-amphi-regulin neutralizing antibody and only partially with anti-IGF1 neutralizing antibody. H358-conditioned medium and Amphiregulin induce IGF1 receptor phospho-rylation in H322 cells, which is prevented by anti-amphi-regulin neutralizing antibody but not by AG556 or ZD1839. H358 cells secrete a high level of Amphiregulin that, in combination with IGF1, prevents serum deprivation apoptosis. Finally, IGF1 receptor inhibitor blocks Amphiregulin and IGF1 release by H358 cells.

Daniel J Tschumperlin - One of the best experts on this subject based on the ideXlab platform.

  • lysophosphatidic acid stimulates egf family ectodomain shedding and paracrine signaling from human lung fibroblasts
    2012
    Co-Authors: Tetsuya Shiomi, Francis Boudreault, Nurcicek Padem, Shigeki Higashiyama, Daniel J Tschumperlin
    Abstract:

    Lysophospatidic acid (LPA) is a bioactive lipid mediator implicated in tissue repair and wound healing. It mediates diverse functional effects in fibroblasts, including proliferation, migration and contraction, but less is known about its ability to evoke paracrine signaling to other cell types involved in wound healing. We hypothesized that human pulmonary fibroblasts stimulated by LPA would exhibit ectodomain shedding of EGFR ligands that signal to lung epithelial cells. To test this hypothesis, we used alkaline phosphatase (AP) -tagged EGF receptor (EGFR) ligand plasmids transfected into CCL-151 lung fibroblasts, and ELISAs to detect shedding of native ligands. LPA induced shedding of transfected AP-tagged HB-EGF, Amphiregulin and TGFalpha;non-transfected fibroblasts shed Amphiregulin and HB-EGF under baseline conditions, and increased shedding of HB-EGF in response to LPA.. Treatment of fibroblasts with LPA (10 μM) resulted in elevated phosphorylation of ERK1/2 (3.3 ± 0.04 fold induction at 5 minutes), enhanced expression of mRNA for c-fos (59 ± 7.9-fold at 30 minutes), HB-EGF (28 ± 4.7-fold at 4 hours) and Amphiregulin (5.7 ± 1.8-fold at 4 hours), and enhanced proliferation at 96 hours. However, none of these fibroblast responses to LPA required ectodomain shedding or EGFR activity. To test the ability of LPA to stimulate paracrine signaling from fibroblasts, we transferred conditioned medium from LPA stimulated- CCL-151 cells, and found enhanced EGFR and ERK1/2 phosphorylation in reporter A549 cells in excess of what could be accounted for by transferred LPA alone. About one-third of th response (37%, P < 0.05) was attributable to EGFR activation. These data demonstrate that LPA mediates EGF-family ectodomain shedding, resulting in enhanced paracrine signaling from lung fibroblasts to epithelial cells.

  • Lysophosphatidic acid stimulates epidermal growth factor-family ectodomain shedding and paracrine signaling from human lung fibroblasts
    Wound Repair and Regeneration, 2011
    Co-Authors: Tetsuya Shiomi, Francis Boudreault, Nurcicek Padem, Shigeki Higashiyama, Jeffrey M. Drazen, Daniel J Tschumperlin
    Abstract:

    : Lysophospatidic acid (LPA) is a bioactive lipid mediator implicated in tissue repair and wound healing. It mediates diverse functional effects in fibroblasts, including proliferation, migration and contraction, but less is known about its ability to evoke paracrine signaling to other cell types involved in wound healing. We hypothesized that human pulmonary fibroblasts stimulated by LPA would exhibit ectodomain shedding of epidermal growth factor receptor (EGFR) ligands that signal to lung epithelial cells. To test this hypothesis, we used alkaline phosphatase-tagged EGFR ligand plasmids transfected into lung fibroblasts, and enzyme-linked immunosorbent assays to detect shedding of native ligands. LPA induced shedding of alkaline phosphatase-tagged heparin-binding epidermal growth factor (HB-EGF), Amphiregulin, and transforming growth factor-a; non-transfected fibroblasts shed Amphiregulin and HBEGF under baseline conditions, and increased shedding of HB-EGF in response to LPA. Treatment of fibroblasts with LPA resulted in elevated phosphorylation of extracellular signal-regulated kinase 1/2, enhanced expression of mRNA for c-fos, HB-EGF and Amphiregulin, and enhanced proliferation at 96 hours. However, none of these fibroblast responses to LPA required ectodomain shedding or EGFR activity. To test the ability of LPA to stimulate paracrine signaling from fibroblasts, we transferred conditioned medium from LPA-stimulated cells, and found enhanced EGFR and extracellular signal-regulated kinase 1/2 phosphorylation in reporter A549 cells in excess of what could be accounted for by transferred LPA alone. These data show that LPA mediates EGF-family ectodomain shedding, resulting in enhanced paracrine signaling from lung fibroblasts to epithelial cells.

  • bronchial epithelial compression regulates epidermal growth factor receptor family ligand expression in an autocrine manner
    American Journal of Respiratory Cell and Molecular Biology, 2005
    Co-Authors: Eric K Chu, Jeffrey M. Drazen, John S Foley, Jason Cheng, Anita S Patel, Daniel J Tschumperlin
    Abstract:

    The epidermal growth factor receptor (EGFR), an important signaling pathway in airway biology, is stimulated by compressive stress applied to human airway epithelial cells. Although the EGFR ligand, heparin-binding epidermal growth factor-like growth factor (HB-EGF), is known to be released as a result of this stimulation, whether compressive stress enhances expression of other EGFR ligands, and the duration of mechanical compression required to initiate this response, is not known. Human airway epithelial cells were exposed to compressive stress, and expression of four EGFR ligands was examined by quantitative PCR. Cells were exposed to: (1) continuous compressive stress over 8 h, (2) compression with and without EGFR inhibitor (AG1478), or (3) time-limited compression (3.75, 7.5, 15, 30, and 60 min). Compressive stress produced a sustained upregulation of the EGFR ligands HB-EGF, epiregulin, and Amphiregulin, but not transforming growth factor-alpha. Inhibition with AG1478 demonstrated that expression of HB-EGF, epiregulin, and Amphiregulin is dependent on the signaling via the EGFR. Immunostaining for epiregulin protein demonstrated increased expression with compression and attenuation with EGFR inhibition. The response of all three EGFR ligands persisted long after the mechanical stimulus was removed. Taken together, these data suggest the possibility of a mechanically activated EGFR autocrine feedback loop involving selected EGFR ligands.

Marie-christine Favrot - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of apoptosis by Amphiregulin via an insulin like growth factor 1 receptor dependent pathway in non small cell lung cancer cell lines
    Annals of the New York Academy of Sciences, 2003
    Co-Authors: Amandine Hurbin, Laurence Dubrez, Jean-luc Coll, Marie-christine Favrot
    Abstract:

    The reciprocal activation of Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) pathways has been shown to induce inhibition of serum deprivation apoptosis in non-small cell lung cancer (NSCLC) cell lines H358 and H322. We demonstrated that AR activated the IGF1 receptor (IGF1-R), which in turn induced the secretion of AR and IGF1. Transactivation of the IGF1-R by AR is independent of its binding to EGFR. Thus, AR can inhibit apoptosis in NSCLC cells through an IGF1-R-dependent pathway.

  • Inhibition of Apoptosis by Amphiregulin via an Insulin-like Growth Factor-1 Receptor-dependent Pathway in Non-small Cell Lung Cancer Cell Lines
    Journal of Biological Chemistry, 2002
    Co-Authors: Amandine Hurbin, Laurence Dubrez, Jean-luc Coll, Marie-christine Favrot
    Abstract:

    Several abnormalities in the insulin-like growth factor -1 (IGF1) and erbB receptors pathways stimulate the growth and survival of lung cancer cells, but their mechanisms of action and cooperation are poorly understood. In this report, we have identified a new mechanism of apoptosis inhibition by Amphiregulin through an IGF1-dependent survival pathway in non-small cell lung cancer (NSCLC) cells: Amphiregulin activates the IGF1 receptor that in turn induces the secretion of am-phiregulin and IGF1. In the absence of serum, the NSCLC cell line H358 resists apoptosis and secretes factors protecting the NSCLC cell line H322 from serum deprivation apoptosis. IGF1 receptor inhibitor AG1024 as well as epidermal growth factor receptor inhibitors AG556 and ZD1839 restore apoptosis in H322 cells cultured in H358-conditioned medium. Accordingly, the an-ti-apoptotic activity of H358-conditioned medium is completely abolished after incubation with anti-amphi-regulin neutralizing antibody and only partially with anti-IGF1 neutralizing antibody. H358-conditioned medium and Amphiregulin induce IGF1 receptor phospho-rylation in H322 cells, which is prevented by anti-amphi-regulin neutralizing antibody but not by AG556 or ZD1839. H358 cells secrete a high level of Amphiregulin that, in combination with IGF1, prevents serum deprivation apoptosis. Finally, IGF1 receptor inhibitor blocks Amphiregulin and IGF1 release by H358 cells.