Int. J. PancreatoL 9 Copyright 1991 by The Humana Press Inc. All rights of any nature whatsoever reserved. 0169-4197/91/9:087-091/$2.00
Growth Factors and Pancreatic Cancer Murray Korc Departments o f Medicine and Biological Chemistry, University o f California, lrvine, CA 92717
Summary Cultured human pancreatic cancer cells produce a number of growth factors, including transforming growth factor-~ (TGF-a). These cells also overexpress the epidermal growth factor (EGF) receptor and exhibit a parallel increase in EGF receptor mRNA levels. TGF-a, which binds to the EGF receptor, is more potent than EGF in enhancing the anchorage-independent growth of several pancreatic cancer cell lines, including T3M4 cells. In contrast, EGF is more efficient than TGF-a with respect to EGF receptor downregulation and tyrosine phosphorylation in T3M4 cells. Further, T3M4 cells recycle EGF, but markedly degrade TGF-a. It is suggested that the production of multiple growth factors, the overexpression of the EGF receptor, the recycling of EGF, and the attenuated ability of TGF-a to downregulate the EGF receptor combine to enhance the growth advantage of human pancreatic cancer cells~ Key Words: Epidermal growth factor receptor; transforming growth factor-a; pancreatic cancer. INTRODUCTION Carcinoma of the pancreas is a major cause of cancer death in the world. The factors that regulate pancreatic cancer cell proliferation and the reasons for the aggressiveness of this cancer are poorly understood. Recent work has established that several cultured human pancreatic cancer cell lines produce TGF-c~, transforming growth factor-~ (TGF-~), basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and the B chain of plateletderived growth factor (PDGF) (1-3). In addition, these cells overexpress the EGF receptor (4). In general, overexpression of the EGF receptor is associated with enhanced metastatic potential and tumor invasiveness (5). The observation that human pancreatic cancer cell lines produce a variety of growth-regulating peptides suggests that this may be an important mechanism whereby these cells achieve a growth advantage. The present article will focus on the findings from our laboratory concerning the potential role of the TGF-a:EGF receptor autocrine cycle in pancreatic cancer.
international Journal of Pancreatotogy
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Volume 9, 1991
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Korc
TRANSFORMING GROWTH FACTOR-c~
The EGF receptor binds EGF, TGF-a~ vaccinia virus growth factor, Shope fibroma virus growth factor, myxoma virus growth factor, and amphiregulin (6). These growth factors share only a 30-35070 amino acid sequence homology. However, they possess six cysteine residues in the same relative positions as EGF. Therefore, the three-dimensional configuration of their receptor binding domain is believed to be very similar to that of EGF. TGF-c~ is the most extensively studied of the EGF-like molecules. To date, there is no evidence for the existence of a distinct TGF-o~ receptor. Therefore, the biological activities of TGF-~ are generally believed to be mediated via the EGF receptor (7). TGF-~ can exert both autocrine and paracrine effects, and is capable of acting in a paracrine manner prior to its release from the cell surface (8). Many cancer cell lines express large quantities of TGF-~ (9), and overexpression of TGF-c~ following transfection experiments results in cellular transformation (10). EGF and TGF-a often exert similar biological effects (11). However, TGF-~ exerts a greater stimulatory effect than EGF with respect to calcium mobilization from fetal rat bones (12), arterial blood flow in the dog (13), angiogenesis in the hamster cheek pouch model (14), wound healing (15), induction of cell ruffling (16), formation of keratinocyte megacolonies (17), and inhibition of RL95-2 human endometrial carcinoma cells growth (18). In primary lung carcinoma cells, TGF-a enhances cell growth, whereas EGF inhibits growth (19). TGF-ct may also contribute to chemical and oncogeneinduced transformation (20,21)o Taken together, these observations suggest that the production of TGF-c~ may represent an important mechanism whereby cancer cells obtain a growth advantage. THE EPIDERMAL GROWTH FACTOR RECEPTOR
The EGF receptor is a 170-kdalton protein that is encoded by a gene that is located on the short arm of chromosome 7 (22,23). The extracellutar portion of the receptor is cysteine rich, and contains the ligand binding region that binds EGF and TGF-a, whereas the intraceUular domain contains the kinase region that catalyzes the autophosphorylation process (24,25). Tyrosine phosphorylation of the receptor is essential for its mitogenic effects (26). The receptor exhibits a strong sequence homology with the protein product of the avian erythroblastosis virus v-erb B oncogene (27), and its overexpression during transfection experiments induces the transformed phenotype (28)~ THE ROLE OF THE EGF RECEPTOR IN H U M A N PANCREATIC CANCER
Human pancreatic cancer cells overexpress the EGF receptor (4). The reasons for this overexpression are not known. However, these cells exhibit increased levels of EGF receptor mRNA (4). Some of these cell lines also exhibit structural and/or numerical alterations of chromosome 7, without a measurable increase in the number of EGF receptor gene copies (4). These
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observations suggest that the production a n d / o r half-life of EGF receptor m R N A may be increased in these cells. In most cell types, EGF is internalized and rapidly degraded (29). However, EGF is not readily degraded in h u m a n pancreatic carcinoma cells (30,31). In the case of PANC-I and T3M~ cells, there is recycling of the ligand between the intracellular and extracellular compartments (30,31). This p h e n o m e n o n may allow for one EGF molecule to induce the degradation of numerous EGF receptors and for the local accumulation of EGF within the tumor milieu. By contrast, TGF-c~ is extensively degraded in these cells (31). There are several additional differences between EGF and TGF-c~ in human pancreatic carcinoma cells. Thus, TGF-c~ is 10- to 100-fold more potent than EGF at enhancing the anchorage-independent growth of T3M4 cells (1). Further, EGF markedly decreases the half-life of the EGF receptor in these cells, thereby greatly decreasing their ability to bind EGF (31). In contrast, the effects of TGF-c~ on these functions in T3M4 cells are considerably smaller (31). These differences are associated with an attenuated ability of TGF-~ to induce tyrosine phosphorylation of the EGF receptor by comparison with EGF (32), which may spare the EGF receptor from excessive autocrine degradation. However, in the same cell line, EGF and TGF-c~ are equipotent with respect to TGF-c~ autoinduction (33). Taken together, these findings indicate that EGF and TGF-~ can exert both similar and different biological effects after binding to the same receptor. It is our hypothesis that TGF-c~ participates in the autocrine regulation of the growth of pancreatic cancer cells. In support of this hypothesis, these cells express large amounts of TGF-c~ m R N A (1,2) and release detectable levels of TGF-c~ protein into the medium (1). ~25I-labeled TGF-c~ binds and is internalized in these cells (1). Further, antiTGF-c~ monoclonal antibodies inhibit the growth in soft agar of PANC-I human pancreatic carcinoma cells (33). The importance of TGF-c~ in the regulation of pancreatic growth is also underscored by studies with transgenic mice in which production of TGF-o~ leads to acinar cell proliferation and pseudoductular acinar metaplasia (34,35)~
ACKNOWLEDGMENT This study was supported by Public Health Service Grant CA-40162 awarded by the National Cancer Institute.
REFERENCES 1 Smith J J, Derynck R, Korc M. Production of transforming growth factor c~ in human pancreatic cancer cells: evidence for a superagonist autocrine cycle. Proc. Natl. Acad. Sci. USA 1987; 84: 7567-7570. 2 Ohmura E, Okada M, Onoda N, Kamiya Y, Murakami H, Tsushima T, Shizume K. Insulin-like growth factor I and transforming growth factor c~as autocrine growth factors in human pancreatic cancer cell growth. Cancer Res. 1990; 50: 103-107. 3 Beauchamp RD, Lyons RM, Yang EY, Coffey RJ Jr., Moses HL. Expression of and response to growth regulatory peptides by two human pancreatic carcinoma cell lines. Pancreas 1990; 5: 369-380.
International Journal o f Pancreatotogy
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Korc
90 4
5 6 7 8 9 I0 11 12 13 14 15 16 17 18 19 20 21 22
Korc M, Meltzer P, Trent J. Enhanced expression of epidermal growth factor receptor correlates with alterations of chromosome 7 in human pancreatic cancer. Proco Natl. Acad. Sci. USA 1986; 83: 5141-5144. Neal D, Bennett M, Hall R, Marsh C, Abel P, Sainsbury J, Harris A. Epidermal growth factor receptors in human bladder cancer: comparison of invasive and superficial tumours. Lancet 1985; 1: 366-368. Soyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 1988; 243: 1074-t077. Massague J. Epidermal growth factor-like transforming growth factor II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells. J. Biolo Chem. 1983; 258: 13614-13620. Brachmann R, Lindquist PB, Nagashima M, Kohr W, Lipari T, Napier M, Derynck R. Transmembrane TGF-c~precursors activate EGF/TGF-a receptors. Cell 1989; 56: 691-700. Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringman TS, Berger WH. Synthesis of messenger RNAs for transforming growth factors a and/3 and the epidermal growth factor receptor by human tumors. Cancer Res. 1987; 47: 707-712. Rosenthal A, Lindquist PB, Bringman TS, Goeddel DV, Derynck R. Expression in rat fibroblasts of a human transforming growth factor-c~ cDNA results in transformation. Cell 1986; 46: 301-309. Rhodes JA, Tam JP, Finke U, Sannders M, Bernanke J, Silen W, Murphy RA. Transforming growth factor a inhibits secretion of gastric acid. Proc. Natl. Acad. Sci. USA 1986; 83: 3844-3846. Ibbotson KJ, Harrod J, Gowen M, D'Souza S, Smith DD, Winkler ME, Derynck R, Mundy GR. Human recombinant transforming growth factor a stimulates bone resorption and inhibits formation in vitro. Proc. Natl. Acad. Sci. USA 1986; 83: 2228-2232. Ga BS, Hotlenberg MD, MacCannelt KL, Lederis K, Winkler ME, Derynck R. Distinct vascular actions of epidermal growth factor-urogastrone and transforming growth factor-or. J. Phar. Exp. Ther. 1987; 242: 331-337. Schreiber AB, Winkler ME, Derynck R. Transforming growth factor-a: a more potent angiogenic mediator than epidermal growth factor. Science 1986; 232: t250-1253. Schultz GS, White M, Mitchell R, Brown G, Lynch J, Twardzik DR, Todaro GJ. Epithelial wound healing enhanced by transforming growth factor-a and vaccinia growth factor. Science 1987; 235: 350-352. Myrdal SE, Twardzik DR, Auersperg N. Cell-mediated co-action of transforming growth factors: incubation of type/3 with normal rat kidney cells produces a soluble activity that prolongs the ruffling response to type a. J. Cell Biol. 1986; 102: 1230-1234. Barrandon Y, Green H. Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-a and epidermal growth factor. Cell 1987; 50: 1131-1137. Korc M, Haussler CA, Trookman NS. Divergent effects of epidermal growth factor and transforming growth factors on a human endometrial carcinoma cell line. Cancer Res. 1987; 47: 4909-4914. Siegfried, JM. Detection of human lung epithelial cell growth factors produced by a lung carcinoma cell line: use in culture of primary solid lung tumors. Cancer Res. 1987; 47: 2903-2910. Wong DTW, Gallager GT, Gertz R, Chang ALC, Shklar G. Transforming growth factor a in chemically transformed hamster oral keratinocytes. Cancer Res. 1988; 48:3130-3134. Dickson RB, Kasid A, Huff KK, Bates SE, Knabbe C, Bronzert D, Getmann EP, Lippman ME. Activation of growth factor secretion in tumorigenic states of breast cancer induced by 17/3-estradiol and v-Ha-ras oncogene. Proc. Natl. Acad. Sci. USA 1987; 84: 837-841. Ullrich A, Coussens L, Hayflick JS, Dull T J, Gray A, Tam AW, Lee J, Yarden Y, Liverman TA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD, Seeburg PH. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in .4.431 epidermoid carcinoma cells. Nature (London) 1984; 309: 418-425.
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27 28 29 30 31 32 33 34 35
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Shimizu N, Kondo I, Gamon S, Behzadian M, Shimizu Yo Genetic analysis of hyperproduction of epidermal growth factor receptors in human epidermoid carcinoma A431 cells. Somatic Cell Molec. Genet. 1984; 10: 45-53. Honegger AM, Dull T J, Felder S, Van Obberghen E, Bellot F, Szapary D, Schmidt A, Ullrich A, Schlessinger J. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell 1987; 51:19%209. Margolis B, Bellot F, Honegger AM, Ultrich A, Schlessinger J, Zilberstein A. Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor. Mol. Cell. Biol. 1990; 10: 435-441. Honegger AM, Szapary D, Schmidt A, Lyall R, Van Obberghen E, Dull T J, UUrich A, Schlessinger J. A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol. Cell. Biol. 1987; 7: 4568-4571o Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfietd MD. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature (London) 1984; 307: 521-527. VeluT J, Bequinot L, Vass WC, Willingham WC, Merlino GT, Pastan I, Lowry DR. Epidermal growth factor-dependent transformation by a human EGF receptor proto-oncogene. Science 1987; 238: 1408-1410. Soderquist AM, Carpenter G. Biosynthesis and metabolic degradation of receptors for epidermal growth factor. J. Membrane Biol. 1986; 90: 97-105. Korc M, Magun B. Recycling of epidermal growth factor in a human pancreatic carcinoma cell line. Proc. Natl. Acad. Sci. USA 1985; 82: 6172-6175. Korc M, Finman JE. Attenuated processing of epidermal growth factor in the face of marked degradation of transforming growth factor alpha. J. Biol. Chem. 1989; 264: 14990-14999. Korc M, Shah G, Barff J. High-affinity binding sites for transforming growth factor alpha: evidence for variant epidermal growth factor receptor. Clinical Res. 1990; 38: 530A. Glinsmann-Gibson BJ, Korc M. Regulation of transforming growth factor-alpha mRNA expression in T3M4 human pancreatic carcinoma cells. Pancreas 1991; 6: 142-149. Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC. Overexpression of TGFc~ in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 1990; 61:1121-1t35. Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT. TGF-c~ overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 1990; 61: 1137-1146.
International Journal o f Panereatology
Volume g, 1991
Growth Factors and Pancreatic Cancer Murray Korc Departments o f Medicine and Biological Chemistry, University o f California, lrvine, CA 92717
Summary Cultured human pancreatic cancer cells produce a number of growth factors, including transforming growth factor-~ (TGF-a). These cells also overexpress the epidermal growth factor (EGF) receptor and exhibit a parallel increase in EGF receptor mRNA levels. TGF-a, which binds to the EGF receptor, is more potent than EGF in enhancing the anchorage-independent growth of several pancreatic cancer cell lines, including T3M4 cells. In contrast, EGF is more efficient than TGF-a with respect to EGF receptor downregulation and tyrosine phosphorylation in T3M4 cells. Further, T3M4 cells recycle EGF, but markedly degrade TGF-a. It is suggested that the production of multiple growth factors, the overexpression of the EGF receptor, the recycling of EGF, and the attenuated ability of TGF-a to downregulate the EGF receptor combine to enhance the growth advantage of human pancreatic cancer cells~ Key Words: Epidermal growth factor receptor; transforming growth factor-a; pancreatic cancer. INTRODUCTION Carcinoma of the pancreas is a major cause of cancer death in the world. The factors that regulate pancreatic cancer cell proliferation and the reasons for the aggressiveness of this cancer are poorly understood. Recent work has established that several cultured human pancreatic cancer cell lines produce TGF-c~, transforming growth factor-~ (TGF-~), basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), and the B chain of plateletderived growth factor (PDGF) (1-3). In addition, these cells overexpress the EGF receptor (4). In general, overexpression of the EGF receptor is associated with enhanced metastatic potential and tumor invasiveness (5). The observation that human pancreatic cancer cell lines produce a variety of growth-regulating peptides suggests that this may be an important mechanism whereby these cells achieve a growth advantage. The present article will focus on the findings from our laboratory concerning the potential role of the TGF-a:EGF receptor autocrine cycle in pancreatic cancer.
international Journal of Pancreatotogy
87
Volume 9, 1991
88
Korc
TRANSFORMING GROWTH FACTOR-c~
The EGF receptor binds EGF, TGF-a~ vaccinia virus growth factor, Shope fibroma virus growth factor, myxoma virus growth factor, and amphiregulin (6). These growth factors share only a 30-35070 amino acid sequence homology. However, they possess six cysteine residues in the same relative positions as EGF. Therefore, the three-dimensional configuration of their receptor binding domain is believed to be very similar to that of EGF. TGF-c~ is the most extensively studied of the EGF-like molecules. To date, there is no evidence for the existence of a distinct TGF-o~ receptor. Therefore, the biological activities of TGF-~ are generally believed to be mediated via the EGF receptor (7). TGF-~ can exert both autocrine and paracrine effects, and is capable of acting in a paracrine manner prior to its release from the cell surface (8). Many cancer cell lines express large quantities of TGF-~ (9), and overexpression of TGF-c~ following transfection experiments results in cellular transformation (10). EGF and TGF-a often exert similar biological effects (11). However, TGF-~ exerts a greater stimulatory effect than EGF with respect to calcium mobilization from fetal rat bones (12), arterial blood flow in the dog (13), angiogenesis in the hamster cheek pouch model (14), wound healing (15), induction of cell ruffling (16), formation of keratinocyte megacolonies (17), and inhibition of RL95-2 human endometrial carcinoma cells growth (18). In primary lung carcinoma cells, TGF-a enhances cell growth, whereas EGF inhibits growth (19). TGF-ct may also contribute to chemical and oncogeneinduced transformation (20,21)o Taken together, these observations suggest that the production of TGF-c~ may represent an important mechanism whereby cancer cells obtain a growth advantage. THE EPIDERMAL GROWTH FACTOR RECEPTOR
The EGF receptor is a 170-kdalton protein that is encoded by a gene that is located on the short arm of chromosome 7 (22,23). The extracellutar portion of the receptor is cysteine rich, and contains the ligand binding region that binds EGF and TGF-a, whereas the intraceUular domain contains the kinase region that catalyzes the autophosphorylation process (24,25). Tyrosine phosphorylation of the receptor is essential for its mitogenic effects (26). The receptor exhibits a strong sequence homology with the protein product of the avian erythroblastosis virus v-erb B oncogene (27), and its overexpression during transfection experiments induces the transformed phenotype (28)~ THE ROLE OF THE EGF RECEPTOR IN H U M A N PANCREATIC CANCER
Human pancreatic cancer cells overexpress the EGF receptor (4). The reasons for this overexpression are not known. However, these cells exhibit increased levels of EGF receptor mRNA (4). Some of these cell lines also exhibit structural and/or numerical alterations of chromosome 7, without a measurable increase in the number of EGF receptor gene copies (4). These
International Journal of Pancreatology
Volume 9, 1991
Growth Factors
89
observations suggest that the production a n d / o r half-life of EGF receptor m R N A may be increased in these cells. In most cell types, EGF is internalized and rapidly degraded (29). However, EGF is not readily degraded in h u m a n pancreatic carcinoma cells (30,31). In the case of PANC-I and T3M~ cells, there is recycling of the ligand between the intracellular and extracellular compartments (30,31). This p h e n o m e n o n may allow for one EGF molecule to induce the degradation of numerous EGF receptors and for the local accumulation of EGF within the tumor milieu. By contrast, TGF-c~ is extensively degraded in these cells (31). There are several additional differences between EGF and TGF-c~ in human pancreatic carcinoma cells. Thus, TGF-c~ is 10- to 100-fold more potent than EGF at enhancing the anchorage-independent growth of T3M4 cells (1). Further, EGF markedly decreases the half-life of the EGF receptor in these cells, thereby greatly decreasing their ability to bind EGF (31). In contrast, the effects of TGF-c~ on these functions in T3M4 cells are considerably smaller (31). These differences are associated with an attenuated ability of TGF-~ to induce tyrosine phosphorylation of the EGF receptor by comparison with EGF (32), which may spare the EGF receptor from excessive autocrine degradation. However, in the same cell line, EGF and TGF-c~ are equipotent with respect to TGF-c~ autoinduction (33). Taken together, these findings indicate that EGF and TGF-~ can exert both similar and different biological effects after binding to the same receptor. It is our hypothesis that TGF-c~ participates in the autocrine regulation of the growth of pancreatic cancer cells. In support of this hypothesis, these cells express large amounts of TGF-c~ m R N A (1,2) and release detectable levels of TGF-c~ protein into the medium (1). ~25I-labeled TGF-c~ binds and is internalized in these cells (1). Further, antiTGF-c~ monoclonal antibodies inhibit the growth in soft agar of PANC-I human pancreatic carcinoma cells (33). The importance of TGF-c~ in the regulation of pancreatic growth is also underscored by studies with transgenic mice in which production of TGF-o~ leads to acinar cell proliferation and pseudoductular acinar metaplasia (34,35)~
ACKNOWLEDGMENT This study was supported by Public Health Service Grant CA-40162 awarded by the National Cancer Institute.
REFERENCES 1 Smith J J, Derynck R, Korc M. Production of transforming growth factor c~ in human pancreatic cancer cells: evidence for a superagonist autocrine cycle. Proc. Natl. Acad. Sci. USA 1987; 84: 7567-7570. 2 Ohmura E, Okada M, Onoda N, Kamiya Y, Murakami H, Tsushima T, Shizume K. Insulin-like growth factor I and transforming growth factor c~as autocrine growth factors in human pancreatic cancer cell growth. Cancer Res. 1990; 50: 103-107. 3 Beauchamp RD, Lyons RM, Yang EY, Coffey RJ Jr., Moses HL. Expression of and response to growth regulatory peptides by two human pancreatic carcinoma cell lines. Pancreas 1990; 5: 369-380.
International Journal o f Pancreatotogy
Volume 9, 1991
Korc
90 4
5 6 7 8 9 I0 11 12 13 14 15 16 17 18 19 20 21 22
Korc M, Meltzer P, Trent J. Enhanced expression of epidermal growth factor receptor correlates with alterations of chromosome 7 in human pancreatic cancer. Proco Natl. Acad. Sci. USA 1986; 83: 5141-5144. Neal D, Bennett M, Hall R, Marsh C, Abel P, Sainsbury J, Harris A. Epidermal growth factor receptors in human bladder cancer: comparison of invasive and superficial tumours. Lancet 1985; 1: 366-368. Soyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 1988; 243: 1074-t077. Massague J. Epidermal growth factor-like transforming growth factor II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells. J. Biolo Chem. 1983; 258: 13614-13620. Brachmann R, Lindquist PB, Nagashima M, Kohr W, Lipari T, Napier M, Derynck R. Transmembrane TGF-c~precursors activate EGF/TGF-a receptors. Cell 1989; 56: 691-700. Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringman TS, Berger WH. Synthesis of messenger RNAs for transforming growth factors a and/3 and the epidermal growth factor receptor by human tumors. Cancer Res. 1987; 47: 707-712. Rosenthal A, Lindquist PB, Bringman TS, Goeddel DV, Derynck R. Expression in rat fibroblasts of a human transforming growth factor-c~ cDNA results in transformation. Cell 1986; 46: 301-309. Rhodes JA, Tam JP, Finke U, Sannders M, Bernanke J, Silen W, Murphy RA. Transforming growth factor a inhibits secretion of gastric acid. Proc. Natl. Acad. Sci. USA 1986; 83: 3844-3846. Ibbotson KJ, Harrod J, Gowen M, D'Souza S, Smith DD, Winkler ME, Derynck R, Mundy GR. Human recombinant transforming growth factor a stimulates bone resorption and inhibits formation in vitro. Proc. Natl. Acad. Sci. USA 1986; 83: 2228-2232. Ga BS, Hotlenberg MD, MacCannelt KL, Lederis K, Winkler ME, Derynck R. Distinct vascular actions of epidermal growth factor-urogastrone and transforming growth factor-or. J. Phar. Exp. Ther. 1987; 242: 331-337. Schreiber AB, Winkler ME, Derynck R. Transforming growth factor-a: a more potent angiogenic mediator than epidermal growth factor. Science 1986; 232: t250-1253. Schultz GS, White M, Mitchell R, Brown G, Lynch J, Twardzik DR, Todaro GJ. Epithelial wound healing enhanced by transforming growth factor-a and vaccinia growth factor. Science 1987; 235: 350-352. Myrdal SE, Twardzik DR, Auersperg N. Cell-mediated co-action of transforming growth factors: incubation of type/3 with normal rat kidney cells produces a soluble activity that prolongs the ruffling response to type a. J. Cell Biol. 1986; 102: 1230-1234. Barrandon Y, Green H. Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-a and epidermal growth factor. Cell 1987; 50: 1131-1137. Korc M, Haussler CA, Trookman NS. Divergent effects of epidermal growth factor and transforming growth factors on a human endometrial carcinoma cell line. Cancer Res. 1987; 47: 4909-4914. Siegfried, JM. Detection of human lung epithelial cell growth factors produced by a lung carcinoma cell line: use in culture of primary solid lung tumors. Cancer Res. 1987; 47: 2903-2910. Wong DTW, Gallager GT, Gertz R, Chang ALC, Shklar G. Transforming growth factor a in chemically transformed hamster oral keratinocytes. Cancer Res. 1988; 48:3130-3134. Dickson RB, Kasid A, Huff KK, Bates SE, Knabbe C, Bronzert D, Getmann EP, Lippman ME. Activation of growth factor secretion in tumorigenic states of breast cancer induced by 17/3-estradiol and v-Ha-ras oncogene. Proc. Natl. Acad. Sci. USA 1987; 84: 837-841. Ullrich A, Coussens L, Hayflick JS, Dull T J, Gray A, Tam AW, Lee J, Yarden Y, Liverman TA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD, Seeburg PH. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in .4.431 epidermoid carcinoma cells. Nature (London) 1984; 309: 418-425.
International Journal o f Pancreatology
Volume 9, 1991
Growth Factors 23 24 25 26
27 28 29 30 31 32 33 34 35
91
Shimizu N, Kondo I, Gamon S, Behzadian M, Shimizu Yo Genetic analysis of hyperproduction of epidermal growth factor receptors in human epidermoid carcinoma A431 cells. Somatic Cell Molec. Genet. 1984; 10: 45-53. Honegger AM, Dull T J, Felder S, Van Obberghen E, Bellot F, Szapary D, Schmidt A, Ullrich A, Schlessinger J. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell 1987; 51:19%209. Margolis B, Bellot F, Honegger AM, Ultrich A, Schlessinger J, Zilberstein A. Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor. Mol. Cell. Biol. 1990; 10: 435-441. Honegger AM, Szapary D, Schmidt A, Lyall R, Van Obberghen E, Dull T J, UUrich A, Schlessinger J. A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol. Cell. Biol. 1987; 7: 4568-4571o Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfietd MD. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature (London) 1984; 307: 521-527. VeluT J, Bequinot L, Vass WC, Willingham WC, Merlino GT, Pastan I, Lowry DR. Epidermal growth factor-dependent transformation by a human EGF receptor proto-oncogene. Science 1987; 238: 1408-1410. Soderquist AM, Carpenter G. Biosynthesis and metabolic degradation of receptors for epidermal growth factor. J. Membrane Biol. 1986; 90: 97-105. Korc M, Magun B. Recycling of epidermal growth factor in a human pancreatic carcinoma cell line. Proc. Natl. Acad. Sci. USA 1985; 82: 6172-6175. Korc M, Finman JE. Attenuated processing of epidermal growth factor in the face of marked degradation of transforming growth factor alpha. J. Biol. Chem. 1989; 264: 14990-14999. Korc M, Shah G, Barff J. High-affinity binding sites for transforming growth factor alpha: evidence for variant epidermal growth factor receptor. Clinical Res. 1990; 38: 530A. Glinsmann-Gibson BJ, Korc M. Regulation of transforming growth factor-alpha mRNA expression in T3M4 human pancreatic carcinoma cells. Pancreas 1991; 6: 142-149. Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC. Overexpression of TGFc~ in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 1990; 61:1121-1t35. Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT. TGF-c~ overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 1990; 61: 1137-1146.
International Journal o f Panereatology
Volume g, 1991
