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Ethan Dmitrovsky - One of the best experts on this subject based on the ideXlab platform.

  • overexpression of the epidermal growth factor receptor and its ligand transforming growth factor α is frequent in resectable non small cell lung cancer but does not predict tumor progression
    Clinical Cancer Research, 1997
    Co-Authors: Valerie W Rusch, David S Klimstra, Ennapadam Venkatraman, Peter W T Pisters, John Langenfeld, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) Alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-Alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-Alpha only in 10% (10 of 96), of both EGFR and TGF-Alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-Alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-Alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-Alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.

  • overexpression of the epidermal growth factor receptor and its ligand transforming growth factor Alpha is frequent in resectable non small cell lung cancer but does not predict tumor progression
    Clinical Cancer Research, 1997
    Co-Authors: Valerie W Rusch, David S Klimstra, Ennapadam Venkatraman, Peter W T Pisters, John Langenfeld, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) Alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-Alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-Alpha only in 10% (10 of 96), of both EGFR and TGF-Alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-Alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-Alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-Alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.

  • differential expression of the epidermal growth factor receptor and its ligands in primary non small cell lung cancers and adjacent benign lung
    Cancer Research, 1993
    Co-Authors: Valerie W Rusch, Carlos Cordoncardo, Jose Baselga, J Orazem, Muhammad B Zaman, Syed A Hoda, J Mcintosh, Jonathan M Kurie, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and one of its ligands, transforming growth factor Alpha (TGF-Alpha), are thought to function as a potential autocrine loop in non-small cell lung cancer (NSCLC). However, the expression pattern of EGFR and the TGF-Alpha-related ligands have not been fully characterized in primary NSCLC and adjacent benign lung tissue. For this reason, we comprehensively examined the coexpression and differential expression of EGFR and its ligands, TGF-Alpha, epidermal growth factor (EGF), and amphiregulin (AR), by Northern analysis, in paired samples of primary tumors and uninvolved lung. For those RNA species overexpressed in malignant lung, single cell expression patterns were studied by immunohistochemistry. Specimens were obtained from 57 consecutive patients who underwent resection of carefully staged resectable NSCLC and were followed prospectively. Most (112 of 114) tissue samples yielded high-quality RNA. EGFR was expressed in 82 of 88 (93%) tissue samples, while TGF-Alpha was expressed in 62 of 72 (86%) samples, and AR was expressed in 64 of 70 (92%) samples. EGF was unexpressed in total cellular RNA in both tumor and uninvolved lung. In a comparison of RNA expression patterns in tumors and uninvolved lung, overexpression of EGFR was found in 45% (22 of 44) of tumors, while overexpression of TGF-Alpha was seen in 61% (22 of 36) of tumors, and decreased expression of AR was seen in 63% (22 of 35) of tumors. Cell type and stage did not influence differential expression, indicating that this is a frequent event in primary NSCLC. Simultaneous overexpression of EGFR and TGF-Alpha was seen in only 38% of tumors. Simultaneous overexpression of EGFR and decreased expression of AR were seen in only 21% of tumors. Thus far, the differential expression of EGFR, TGF-Alpha, and AR does not correlate with either disease-free or overall survival. These findings indicate that histologically dissimilar tumors can express similar components of autocrine or paracrine growth factor loops. Differential expression of EGFR and its ligands in tumor specimens compared to uninvolved lung is a common event in NSCLC and may participate in tumor growth without necessarily influencing tumor progression or histology.

Valerie W Rusch - One of the best experts on this subject based on the ideXlab platform.

  • overexpression of the epidermal growth factor receptor and its ligand transforming growth factor α is frequent in resectable non small cell lung cancer but does not predict tumor progression
    Clinical Cancer Research, 1997
    Co-Authors: Valerie W Rusch, David S Klimstra, Ennapadam Venkatraman, Peter W T Pisters, John Langenfeld, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) Alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-Alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-Alpha only in 10% (10 of 96), of both EGFR and TGF-Alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-Alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-Alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-Alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.

  • overexpression of the epidermal growth factor receptor and its ligand transforming growth factor Alpha is frequent in resectable non small cell lung cancer but does not predict tumor progression
    Clinical Cancer Research, 1997
    Co-Authors: Valerie W Rusch, David S Klimstra, Ennapadam Venkatraman, Peter W T Pisters, John Langenfeld, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) Alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-Alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-Alpha only in 10% (10 of 96), of both EGFR and TGF-Alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-Alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-Alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-Alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.

  • differential expression of the epidermal growth factor receptor and its ligands in primary non small cell lung cancers and adjacent benign lung
    Cancer Research, 1993
    Co-Authors: Valerie W Rusch, Carlos Cordoncardo, Jose Baselga, J Orazem, Muhammad B Zaman, Syed A Hoda, J Mcintosh, Jonathan M Kurie, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and one of its ligands, transforming growth factor Alpha (TGF-Alpha), are thought to function as a potential autocrine loop in non-small cell lung cancer (NSCLC). However, the expression pattern of EGFR and the TGF-Alpha-related ligands have not been fully characterized in primary NSCLC and adjacent benign lung tissue. For this reason, we comprehensively examined the coexpression and differential expression of EGFR and its ligands, TGF-Alpha, epidermal growth factor (EGF), and amphiregulin (AR), by Northern analysis, in paired samples of primary tumors and uninvolved lung. For those RNA species overexpressed in malignant lung, single cell expression patterns were studied by immunohistochemistry. Specimens were obtained from 57 consecutive patients who underwent resection of carefully staged resectable NSCLC and were followed prospectively. Most (112 of 114) tissue samples yielded high-quality RNA. EGFR was expressed in 82 of 88 (93%) tissue samples, while TGF-Alpha was expressed in 62 of 72 (86%) samples, and AR was expressed in 64 of 70 (92%) samples. EGF was unexpressed in total cellular RNA in both tumor and uninvolved lung. In a comparison of RNA expression patterns in tumors and uninvolved lung, overexpression of EGFR was found in 45% (22 of 44) of tumors, while overexpression of TGF-Alpha was seen in 61% (22 of 36) of tumors, and decreased expression of AR was seen in 63% (22 of 35) of tumors. Cell type and stage did not influence differential expression, indicating that this is a frequent event in primary NSCLC. Simultaneous overexpression of EGFR and TGF-Alpha was seen in only 38% of tumors. Simultaneous overexpression of EGFR and decreased expression of AR were seen in only 21% of tumors. Thus far, the differential expression of EGFR, TGF-Alpha, and AR does not correlate with either disease-free or overall survival. These findings indicate that histologically dissimilar tumors can express similar components of autocrine or paracrine growth factor loops. Differential expression of EGFR and its ligands in tumor specimens compared to uninvolved lung is a common event in NSCLC and may participate in tumor growth without necessarily influencing tumor progression or histology.

Robert J Coffey - One of the best experts on this subject based on the ideXlab platform.

  • synergistic interaction of the neu proto oncogene product and transforming growth factor Alpha in the mammary epithelium of transgenic mice
    Molecular and Cellular Biology, 1996
    Co-Authors: William J Muller, Robert D. Cardiff, C L Arteaga, Senthil K Muthuswamy, Peter M Siegel, Marc A Webster, K S Meise, S A Halter, Robert J Coffey
    Abstract:

    Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-Alpha) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-Alpha, we examined whether coexpression of TGF-Alpha and Neu in mammary epithelium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring either a mouse mammary tumor virus/TGF-Alpha or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-Alpha and neu in the mammary epithelium. Female mice coexpressing TGF-Alpha and neu developed multifocal mammary tumors which arose after a significantly shorter latency period than either parental strain alone. The development of these mammary tumors was correlated with the tyrosine phosphorylation of Neu and the recruitment of c-Src to the Neu complex. Immunoprecipitation and immunoblot analyses with EGFR- and Neu-specific antisera, however, failed to detect physical complexes of these two receptors. Taken together, these observations suggest that Neu and TGF-Alpha cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.

  • Extracellular matrix regulates whey acidic protein gene expression by suppression of TGF-Alpha in mouse mammary epithelial cells: studies in culture and in transgenic mice.
    The Journal of cell biology, 1995
    Co-Authors: Claudia Qiao Lin, Robert J Coffey, Peter J. Dempsey, Mina J. Bissell
    Abstract:

    Whey acidic protein (WAP) is an abundant rodent milk protein. Its expression in mouse mammary epithelial cell cultures was previously found to require the formation of an extracellular matrix (ECM)-induced three-dimensional alveolar structure. In the absence of such structures, cells were shown to secrete diffusible factors leading to suppression of WAP expression. We demonstrate here that (a) TGF-Alpha production and secretion by mammary cells is downregulated by the basement membrane-dependent alveolar structure, and (b) compared with beta-casein, WAP expression is preferentially inhibited both in culture and in transgenic mice when TGF-Alpha is added or overexpressed. Thus, (c) the enhanced TGF-Alpha production when cells are not in three-dimensional structures largely accounts for the WAP-inhibitory activity found in the conditioned medium. Since this activity can be abolished by incubating the conditioned medium with a function blocking antibody to TGF-Alpha. The data suggest that ECM upregulates WAP by downregulating TGF-Alpha production. We also propose that changes in TGF-Alpha activity during mouse gestation and lactation could contribute to the pattern of temporal expression of WAP in the gland. These results provide a clear example of cooperation among lactogenic hormones, ECM, and locally acting growth factors in regulation of tissue-specific gene expression.

  • cause of failure of lactation in mouse mammary tumor virus human transforming growth factor Alpha transgenic mice
    Experimental Biology and Medicine, 1994
    Co-Authors: S Sakai, Robert J Coffey, M Mizuno, Toshio Harigaya, Kazutoshi Yamamoto, Takao Mori, Hiroshi Nagasawa
    Abstract:

    Transgenic female mice bearing human transforming growth factor-Alpha (TGF Alpha) cDNA under the control of the mouse mammary tumor virus enhancer/promoter became pregnant but failed lactation. TGF Alpha mRNA was detected in the mammary glands of these mice by the reverse transcriptase-polymerase chain reaction. By the use of collagenase-dissociated mammary epithelial cells, the binding of prolactin to its receptor was determined before and after parturition. At the end of pregnancy, the binding in TGF Alpha transgenic (TGF Alpha [+]) mice was small and its amount was comparable to that in the TGF Alpha negative (TGF Alpha [-]) mice. On the day of parturition, prolactin binding in TGF Alpha (+) mice increased approximately 1.9-fold (insignificant), while that in TGF Alpha (-) mice elevated over 5.3-fold (P < 0.01). The binding sites per cell were also higher in TGF Alpha (-)mice. Radioimmunoassay of prolactin suggested that in TGF Alpha (+) mice the low level of prolactin binding after parturition was not due to masking effect of serum prolactin. Among six TGF Alpha (+) mice assayed, one mother with the highest prolactin binding activity (3.7-fold increase) initiated lactation, but the others did not. As there was little difference between groups in the growth and synthesis in the mammary glands, it was concluded that the failure of lactation in TGF Alpha (+) mice is principally due to the lack of elevation of mammary prolactin receptor after parturition. At present, the role of TGF Alpha in this process is obscure; however, TGF Alpha was revealed not to interfere with the binding of prolactin to the receptor.

  • transforming growth factor Alpha TGF Alpha concentrations increase in regenerating rat liver evidence for a delayed accumulation of mature TGF Alpha
    Endocrinology, 1993
    Co-Authors: William E Russell, Peter J. Dempsey, Silvio Sitaric, A J Peck, Robert J Coffey
    Abstract:

    Changes in the concentration of transforming growth factor-Alpha (TGF Alpha) protein were measured in regenerating liver. TGF Alpha stimulates both DNA and protein synthesis in various liver-derived cells, and its mRNA levels increase in liver after partial hepatectomy (PH), suggesting that it may be an important autocrine regulator of liver regeneration. Using a sheep antiserum raised against mature rat TGF Alpha, we developed a sensitive TGF Alpha RIA. TGF Alpha was extracted from livers in a detergent-containing buffer with protease inhibitors. Liver extracts, to a volume of 10 microliters/tube, produced a displacement curve of [125I]TGF Alpha that was parallel to the pure standard. The TGF Alpha content of normal liver was 57.04 +/- 26.25 pg/mg protein, 5.24 +/- 2.61 ng/mg DNA, and 10.33 +/- 4.47 ng/g liver (n = 5; mean +/- SD). Between 13-17 h after operation, TGF Alpha concentrations in the livers of PH animals increased over those in sham-operated (SH) controls (P < 0.05) and remained twice those in SH controls for more than 96 h, returning to control values by 8 days. In unoperated liver, gel chromatography showed all TGF Alpha immunoactivity to be in fractions corresponding to known TGF Alpha precursors (15-30 kilodaltons). Mature 5.6-kilodalton TGF Alpha was not detected until 48 h after PH and was still present at 96 h. These data support a role for TGF Alpha in the response to PH in the rat. However, the presence of TGF Alpha precursors in normal liver, the short (< 4-h) interval between the increase in TGF Alpha concentrations and the onset of hepatocyte DNA synthesis, the sustained elevation of TGF Alpha levels after DNA synthesis has ceased, and the lack of detectable processing to the mature form until DNA synthesis has subsided all suggest that the membrane-anchored precursor and the mature forms of TGF Alpha may have different functions, cellular sources, or target cells in regenerating liver.

  • epidermal growth factor receptor ligands regulate keratin 8 expression in keratinocytes and transforming growth factor Alpha mediates the induction of keratin 8 by the v rasha oncogene
    Cell Growth & Differentiation, 1993
    Co-Authors: Christina Cheng, Robert J Coffey, Peter J. Dempsey, Tamar Tennenbaum, Stuart H Yuspa, Andrzej A Dlugosz
    Abstract:

    Cytokeratins 8 and 18 (Endo A and B) are among the earliest expressed embryonic genes and the major components of the cytoskeleton in simple epithelia of the adult. Recent data indicate that these cytokeratins are aberrantly expressed in several epithelial tumor types and that expression in cultured mouse keratinocytes is linked to activation of the rasHa oncogene. Furthermore, up-regulation of K8/K18 in keratinocytes is associated with reciprocal suppression of K1. We now show that the aberrant expression of K8 and K18 and suppression of K1 in cultured keratinocytes transduced with the v-rasHa gene are mediated by a factor secreted into the culture medium. Furthermore, transforming growth factor Alpha (TGF-Alpha) and epidermal growth factor elicit an identical pattern of K8/K18 expression and K1 suppression in normal keratinocytes. The factor in medium from v-rasHa keratinocytes is TGF-Alpha, as a specific blocking antibody for rat and mouse TGF-Alpha prevents the expression of K8 and restores expression of K1. The tyrosine kinase inhibitor genistein also prevents K8 induction in v-rasHa keratinocytes and in normal keratinocytes treated with TGF-Alpha- or v-rasHa-conditioned medium. However, simply stimulating proliferation of keratinocytes by cholera toxin does not result in expression of K8 or suppression of K1. Finally, tumor grafts from neoplastic epidermal cells overexpressing TGF-Alpha via retroviral transduction of human TGF-Alpha complementary DNA in vitro show coordinate expression of K8 and human TGF-Alpha. These studies indicate that K8 expression in keratinocytes, and derivative neoplastic cells, in vivo and in vitro is regulated by epidermal growth factor receptor ligands. Since the expression of cytokines and K8/K18 in early embryogenesis is often coincident, cytokines may be the physiological mediators of K8/K18 expression in embryonic cells.

Peter W T Pisters - One of the best experts on this subject based on the ideXlab platform.

  • overexpression of the epidermal growth factor receptor and its ligand transforming growth factor α is frequent in resectable non small cell lung cancer but does not predict tumor progression
    Clinical Cancer Research, 1997
    Co-Authors: Valerie W Rusch, David S Klimstra, Ennapadam Venkatraman, Peter W T Pisters, John Langenfeld, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) Alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-Alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-Alpha only in 10% (10 of 96), of both EGFR and TGF-Alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-Alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-Alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-Alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.

  • overexpression of the epidermal growth factor receptor and its ligand transforming growth factor Alpha is frequent in resectable non small cell lung cancer but does not predict tumor progression
    Clinical Cancer Research, 1997
    Co-Authors: Valerie W Rusch, David S Klimstra, Ennapadam Venkatraman, Peter W T Pisters, John Langenfeld, Ethan Dmitrovsky
    Abstract:

    The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) Alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-Alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-Alpha only in 10% (10 of 96), of both EGFR and TGF-Alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-Alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-Alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-Alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.

Jennifer H Dorrington - One of the best experts on this subject based on the ideXlab platform.

  • induction of apoptosis in thecal interstitial cells action of transforming growth factor TGF Alpha plus TGF beta on bcl 2 and interleukin 1 beta converting enzyme
    Journal of Endocrinology, 1998
    Co-Authors: A Foghi, K J Teerds, H Van Der Donk, N C Moore, Jennifer H Dorrington
    Abstract:

    Follicular atresia is characterized by the initial rapid loss of granulosa cells by apoptosis, followed by the loss of thecal cells at a slower rate. We have previously shown that treatment of subconfluent cultures of thecal/interstitial cells (T/I) with transforming growth factor (TGF) Alpha plus TGF beta caused chromatin condensation and internucleosomal fragmentation characteristic of apoptosis, whereas in the presence of either TGF Alpha or TGF beta alone the cells remained healthy. In this study we have examined the effect of TGF Alpha and TGF beta alone and in combination on the levels of mRNA encoding bcl-2 and interleukin-1 beta-converting enzyme (ICE) in T/I cells using a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay. Bcl-2, a cell survival gene, has been implicated in regulating the balance between cell proliferation and cell death in physiological processes. ICE, the homolog of the C. elegans cell death gene, ced-3, is also involved in apoptotic signal transduction. The levels of mRNA encoding specific PCR products for bcl-2 (430 bp) and ICE (453 bp) were amplified from T/I cell cDNA. Untreated T/I cells and TGF Alpha- or TGF beta-treated cells contained comparable levels of bcl-2 mRNA. Treatment of T/I cells with TGF Alpha plus TGF beta significantly decreased the levels of bcl-2 mRNA expression. TGF Alpha plus TGF beta caused a significant decrease in bcl-2 mRNA levels within 3 h of treatment of T/I cells, followed by a progressive decline to 10% of control levels after 24 h of treatment. In contrast, in control T/I cells, the levels of ICE mRNA were low. TGF Alpha plus TGF beta caused a progressive increase in ICE mRNA, reaching levels 2- and 3-fold higher than control cells after 5 and 7 h respectively. DNA analysis showed that DNA fragmentation, indicative of apoptosis, occurred after 10 h of treatment with TGF Alpha plus TGF beta. These studies demonstrated that treatment of T/I cells with TGF Alpha plus TGF beta influenced gene expression of bcl-2 and ICE prior to the time at which DNA fragmentation was observed. We propose that the gene products of bcl-2 and ICE are involved in the apoptotic signal transduction pathway induced by TGF Alpha plus TGF beta in T/I cells.

  • induction of apoptosis in rat thecal interstitial cells by transforming growth factor α plus transforming growth factor β in vitro
    Journal of Endocrinology, 1997
    Co-Authors: A Foghi, K J Teerds, H Van Der Donk, Jennifer H Dorrington
    Abstract:

    In each estrous cycle dominant follicles are selected from a growing pool to develop to the preovulatory stage and to ovulate. Those follicles that do not ovulate must be eliminated in order to maintain the constant mass and homeostasis of the ovary. Granulosa cells are lost by apoptosis at the onset of follicular atresia, whereas apoptotic thecal cells are identified at later stages of atresia. Since transforming growth factor (TGF) Alpha and TGF beta 1 have been implicated in the regulation of thecal cell physiology we have localized these growth factors by immunohistochemistry in sections of ovaries from 25-day-old rats, an age at which the ovary exhibits a wave of atresia of preantral follicles. Thecal cells contained TGF Alpha and TGF beta 1 throughout the entire process of follicular atresia. To determine if these growth factors could influence thecal cell death, thecal/interstitial cells were isolated from 25-day-old rats, and maintained in culture with growth factors. Subconfluent cultures treated with TGF Alpha or TGF beta 1 alone remained healthy whereas in the presence of both TGF Alpha and TGF beta 1 there was light microscopical evidence of rounding up of cells and detachment from the monolayer. Chromatin condensation and internucleosomal fragmentation, characteristic of apoptosis, were observed by nucleic acid staining and fluorescence microscopy of thecal/interstitial cells treated with TGF Alpha plus TGF beta 1. Further evidence that these cells were undergoing apoptosis came from DNA analysis and the demonstration of DNA laddering. This response of thecal/interstitial cells to TGF Alpha plus TGF beta 1 was density dependent; confluent cultures were protected from the induction of apoptosis under these conditions. We conclude that thecal cells are eliminated from atretic follicles by the active and strictly regulated process of involving the combined actions of TGF Alpha and TGF beta 1.