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Peptide growth factors in the intestine

Dignass, Axel U.a; Sturm, Andreasb

European Journal of Gastroenterology & Hepatology: July 2001 - Volume 13 - Issue 7 - p 763-770
Review in Depth

A continuously increasing number of regulatory peptides has been demonstrated to be expressed in the intestine and to modulate several functional properties of various intestinal cell populations, including the intestinal epithelium and lamina propria cell populations. These regulatory peptides include members of the epidermal growth factor (EGF) family, the transforming growth factor beta (TGF-β) family, the insulin-like growth factor (IGF) family, the fibroblast growth factor (FGF) family, the trefoil factor (TFF) family, the colony-stimulating factor (CSF) family, and a few other seemingly unrelated regulatory peptides, such as hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and various interleukins, interferons and tumour necrosis factor-related proteins. In addition to the well-known effects on cell proliferation, these regulatory peptide factors regulate several other functional properties of epithelial and other cell populations, such as differentiation, migration, and extracellular matrix deposition and degradation. This review is designed not to discuss all the identified factors in detail but to highlight some of the basic principles of growth factor action in the intestine. It focuses mainly on classical growth factors rather than interleukins and interferons.

Departments of Medicine, Divisions of Hepatology and Gastroenterology, aCharité-Campus Virchow Clinic, Berlin and bUniversity of Essen, Germany

Correspondence to Axel Dignass, Charité Medical School – Virchow Clinic, Department of Medicine, Division of Hepatology and Gastroenterology, Augustenburger Platz 1, D13353 Berlin, Germany Tel: +49 30 450 553022; fax: +49 30 450 553902; e-mail: axel.dignass@charite.de

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Introduction

Peptide growth factors are usually characterized by a relatively low molecular weight of less than 25 kDa. Generally, they exert their effects through binding to specific high-affinity cell-surface receptors present on their respective target cells [1–3]. In contrast to classical peptide hormones, peptide growth factors tend to act locally on adjacent cells (paracrine or juxtacrine action), or on the same cell that has expressed the peptide factor (autocrine action) [2,4,5]. The terminology of regulatory peptides is often confusing and arbitrary. The term ‘cytokine’ is increasingly used to describe various regulatory peptides that can be identified as regulatory peptides, peptide growth factors, interleukins, interferons and colony-stimulating or haematopoietic stem cell factors [5].

Although the full variety of peptide factors that play a role in the control of the intestinal epithelium and non-epithelial compartment of the intestine has not been defined, there is increasing appreciation of the diversity of these factors and the importance of several specific peptides produced within the intestine. An increasing number of peptide growth factor genes have been identified, and some have been fully sequenced, cloned and synthesized. Several distinct peptide families are now recognized to modulate different cell functions of intestinal cell populations, including cell proliferation and differentiation. The identification and characterization of numerous peptide growth factors has led to the recognition of a network of interrelated factors within the intestine. The constituents of this network generally possess multiple functional properties and exhibit pleiotropism in their cellular sources and targets (Table 1). As a result, this network is highly redundant in several dimensions [6,7]. First, each cell type appears to produce more than one peptide growth factor. Second, each peptide growth factor may be produced by multiple different cell populations within the intestinal tract. Third, most or perhaps all cell populations seem to express receptors specific for more than one growth factor. Fourth, receptors for a single growth factor may be present on multiple different cell types, thus a single growth factor can exert a spectrum of different functional effects within a circumscribed region of the intestinal tract. Fifth, functional effects of a certain growth factor may be modulated by the co-presence of other growth factors. Sixth, multiple structurally related members of a peptide growth factor family may interact with a single receptor (e.g. epidermal growth factor (EGF) family peptides). Seventh, growth factors may modulate their own expression and also that of other growth factors and their receptors on various cellular targets.

Table 1

Table 1

Peptide growth factors can be reasonably classified on the basis of structural homology and disparities into several discrete families (Table 2). They include the EGF family, the transforming growth factor beta (TGF-β) family, the insulin-like growth factor (IGF) family, the fibroblast growth factor (FGF) family, the colony-stimulating factor (CSF) or haematopoietic stem cell factor family, and the trefoil factor (TFF) family. In addition to the structural similarities between peptides within a family, members of a peptide family share a single receptor or a family of receptors, so that functionally they are partially or wholly interchangeable. In addition to these families, a small number of peptide growth factors, seemingly without structural similarities to other growth factors, have been identified within the gastrointestinal tract, including hepatocyte growth factor (HGF) or scatter factor, vascular endothelial cell growth factor (VEGF), and platelet-derived growth factor (PDGF).

Table 2

Table 2

Various members of these regulatory peptide families play an important role in the modulation of cell proliferation, cell differentiation, angiogenesis, inflammation, gastrointestinal defence mechanisms, and intestinal wound repair both in vitro and in vivo. Furthermore, they serve as important messengers between the intestinal mucosa and the enteric nervous and immune systems (Fig. 1). This review is designed to describe general properties of prototypic peptide growth factors that are likely to be important in the intestine, rather than to discuss all relevant growth factors in extensive detail. For a more detailed description of peptide growth factors, interested readers are referred to handbooks and reviews and the references therein [5,7–16].

Fig. 1

Fig. 1

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Epidermal growth factor/transforming growth factor alpha family

This family consists of at least eight different peptides, including EGF, transforming growth factor alpha (TGF-α), amphiregulin, heparin-binding epidermal growth factor (HB-EGF), betacellulin, pox virus growth factors (found in vaccinia, shope and myxoma viruses), cripto and heregulin. Members of the EGF family are defined by three properties: the ability to bind to the EGF receptor, the capacity to mimic the biological activities of EGF, and amino acid sequence similarity to EGF. The overall identity of sequences within all members of the EGF family is approximately 20% [17].

Members of the EGF family act via the stimulation of specific cell-surface receptors [17]. The EGF receptor (EGFR) is well characterized and possibly the most biologically important receptor for EGF family members. Nevertheless, additional receptors similar in structure have been identified and seem to bind some or all of the EGF family growth factors. They include the human EGF receptors 2 (HER-2) and 3 (HER-3). Although mRNA encoding HER-2 and HER-3 has been detected in normal and fetal gastrointestinal tissues, as well as in colon cancers, the relative physiological importance remains unclear. Most members of the EGF family can bind to the EGFR to effect cellular responses. In view of the ability of the EGFR to bind various peptide members of the EGF family, the physiological ligand acting on the EGFR at a given site cannot be predicted a priori. Thus, activities observed in a given experimental system following addition of one member of this peptide family (e.g. EGF) might reflect a physiological response actually induced by another family member in vivo (e.g. TGF-α). This is especially relevant in the gastrointestinal tract, where EGFRs are detected widely but EGF itself is expressed in only highly circumscribed distribution in contrast to the broad expression of TGF-α and perhaps other related peptides. Binding sites in the gastrointestinal tract appear equivalent in distribution when either EGF or TGF-α have been used as the ligand in a manner consistent with the assumption that they share a common receptor [18–23].

EGF and TGF-α are the prototype members of the EGF family. Within the gastrointestinal tract, EGF is produced in submaxillary glands and Brunner's glands in the duodenum [24]. Small amounts appear to be produced within the exocrine pancreas. EGF is also present in gastric juice and within the intestinal lumen as a result of secretion from salivary glands, the pancreas and Brunner's glands. It is presumed to exert trophic and biological properties within the gastrointestinal tract through interaction at the mucosal surface [23,25,26]. This assumption is supported by the demonstration of apparent EGF binding sites on the apical (brush border) surface of enterocytes [21,27]. However, other workers have reported the presence of EGFRs on basolateral surfaces [28].

EGF is a potent stimulator of cell proliferation in epithelial and non-epithelial cell types present throughout the gastrointestinal tract [17,29,30]. The widespread distribution of EGFRs, including many cells committed to terminal differentiation, suggests that EGF (or another member of the EGF family) has a range of actions beyond its mitogenic activity. EGF has been demonstrated to modulate the expression of enzymes involved in the production of polyamines, to up-regulate intestinal electrolyte and nutrient transport in the enterocyte, to stimulate expression of brush border enzymes, to attenuate intestinal damage, and to promote intestinal healing [31–34].

TGF-α has been identified as a product of many cell types, including most epithelial cells [17]. TGF-α mRNA and bioactive protein have been demonstrated directly in human and rodent stomach, small intestinal and colonic epithelium [21,35,36]. TGF-α appears to act through the same receptor as EGF. Important functional activities of TGF-α and EGF are summarized in Table 3. Because of its proliferative effects, it has been proposed that TGF-α may play an important role in the development of intestinal malignancies [37,38].

Table 3

Table 3

Amphiregulin presumably acts through the same mechanisms as the other members of the EGF family. Amphiregulin expression has been found in normal and neoplastic colonic mucosa, and growth stimulation through an autocrine mechanism by amphiregulin has been demonstrated in a colon carcinoma-derived cell line [39–41].

Heregulin seems to be expressed in several isoforms in stomach, liver, pancreas and small intestine [42]. Cripto has been found in a small proportion of normal colonic mucosal cells, but in a high percentage of primary and metastatic human colorectal cancers [42].

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Transforming growth factor beta family

The prototypic member of the TGF-β family is TGF-β1 [5,43,44]. Despite intracellular cleavage, the TGF-β1 dimer remains in a biological inactive complex with the two propeptide segments through non-covalent association, the so-called latent form. The physiological processes regulating the bioactivation of TGF-β from its latent state have not been finally characterized [45].

TGF-β1 has been found to bind to several specific cell-surface TGF-β receptors. The type-1 and type-2 receptors work in a cooperative fashion: ligand binding to the type-1 receptor facilitates activation of the associated type-2 receptor, which then activates the intracellular signalling machine via SMAD proteins [44,46–51].

The TGF-βs have a diverse range of biological effects, summarized in Table 4. In adults, three isoforms of TGF-β (TGF-β1−−3) may be detected in all gastrointestinal tract tissues and accessory organs [52]. Within the small intestine, TGF-β expression has been demonstrated in both lamina propria cells and the epithelium [53]. It is generally accepted that almost all expression of TGF-β is observed in epithelial cells of the intestine and only minor amounts within constituents of the mucosal immune system.

Table 4

Table 4

Many observations indicate a role for TGF-β in both inflammation and tissue repair [10,54,55]. This is also supported by targeted disruption of the TGF-β1 gene by ‘gene knock-out’ technology, which results in multifocal, mixed inflammatory cell infiltration, often with necrosis. Animals homozygous for the mutated TGF-β allele show no gross developmental abnormalities at birth and develop a severe, multifocal inflammatory disease that affects several organs including diffuse inflammation in the stomach and intestine. TGF-β deficiency resulted in severe pathology leading to death at about 20 days of age associated with dysfunction of the immune and inflammatory system, indicating its essential role as a potent regulator of the immune and inflammatory system. Increased expression of TGF-β was also demonstrated following acute epithelial injury in vivo, and in patients with active inflammatory bowel diseases, suggesting that TGF-β may play a role during periods of active inflammation regulating the activation and inactivation of immune and other cell populations present within the intestinal mucosa [38,53].

Other TGF-β family peptides, such as activin A, and their respective receptors, Act I and Act II, have recently been demonstrated to be expressed within the intestine and to modulate intestinal epithelial cell function [56–58].

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Insulin-like growth factor family

IGF I and IGF II are expressed in diverse sites, including the gastrointestinal tract, with intrinsic biological activities in these tissues. The IGFs mediate their biological activities through interactions with at least three cell surface receptors. Both type-I and type-II IGF receptors and IGF I and IGF II are expressed in the gastrointestinal epithelium. IGF bioactivity is modulated by several IGF binding proteins. IGF peptides have been demonstrated to stimulate proliferation of epithelial and non-epithelial cells, to promote intestinal wound healing, to exert trophic effects within the intestine, and to promote tumour growth through autocrine mechanisms [29,59–64]. There is evidence that IGF I may be important in the development of fibrosis in Crohn's disease [65].

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Fibroblast growth factor family

The FGFs are a family of related 16–18-kDa proteins controlling normal growth and differentiation of mesenchymal, epithelial and neuroectodermal cell types [66]. FGF-1, or acidic FGF (aFGF), and FGF-2, or basic FGF (bFGF), are the best-characterized members of the FGF family. Although only limited data are available on the expression and biological activities of FGFs and their receptors in the gastrointestinal tract, several reports have described the presence of FGF family peptides and FGF receptors in the intestine [67–72]. Recent evidence supports the assumption that FGFs might serve as autocrine growth factors and stimulate intestinal epithelial cell proliferation [69,73–75]. In addition, aFGF and bFGF promoted intestinal epithelial restitution through a TGF-β-dependent pathway in vitro [73,76]. FGF-18, a novel member of the FGF family, stimulates proliferation in a number of tissues, most notably the liver and small intestine [77].

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Trefoil factor family

The TFF peptides are a family of proteins expressed in a region-selective pattern throughout the gastrointestinal tract. TFF peptides are characterized by a highly conserved motif designated a ‘P’ or trefoil domain that consists of six cysteine residues that are believed to result in the formation of three intrachain loops [78–81]. Members of the TFF family include TFF1 (formerly pS2), TFF2 (formerly spasmolytic polypeptide, SP), and TFF3 (previously intestinal trefoil factor, ITF). TFF1 was first identified in human breast carcinoma cell lines and is usually expressed in the stomach, Brunner's glands, and large-intestinal goblet cells near the surface. TFF2 is expressed in the fundus and antrum of the stomach, and the Brunner's gland acini and distal ducts of the small intestine. TFF3 is absent in the stomach, but is expressed in goblet cells in the small and large intestine and in Brunner's gland acini and ducts in the small intestine. TFF1 is expressed in a wide variety of human carcinomas, and TFF1 knock-out mice exhibit severe hyperplasia and dysplasia of antrum cells, indicating that TFF1 may be a specific tumour suppressor gene for the stomach [82]. TFF2 mRNA levels increase within 30 min after mucosal injury induced in the rat stomach, and administration of exogenous TFF2 protects against ethanol-induced gastric injury [83]. TFF peptides play an important role in the repair and healing of the gastrointestinal tract [84–86]. Mashimo et al. [85] showed that TFF3 knock-out mice have impaired mucosal healing properties. Interestingly, TFF peptides stimulate epithelial repair through TGF-β-independent pathways. Recent studies suggest that modulation of repair mechanisms by TFF peptides may be mediated by modulation of E-cadherin/catenin complex function [87,88]. In addition to the important effects on intestinal wound-healing mechanisms, TFF3 may also function as an inhibitory factor for the growth of colonic neoplasms [89].

Although the receptors for TFF peptides have not been identified definitely, it is assumed that TFF peptides that are secreted onto the luminal surface of the gastrointestinal epithelium may act at the luminal site of the epithelium through mechanisms distinct from those that act at the basolateral site of the epithelium.

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Colony-stimulating factors

The CSFs comprise a family of acidic glycoproteins characterized by their ability to induce the formation of distinct haematopoietic cell lineages that play an important role in haematopoiesis. Key members of this family are the stem cell growth factors interleukin 3 (IL-3, multi-CSF), GM-CSF, M-CSF (CSF-1) and G-CSF. Although the sites of action of these peptides seem to be predominantly the blood-forming tissues, they may be produced at a variety of different sites, including the intestine. Constituents of the lamina propria, predominantly macrophages/monocytes, have been found to produce each of these critical stem cell factors. There is some evidence that intraepithelial lymphocytes might proliferate in response to IL-3, but in general the presumptive targets of these peptides produced in the intestine are in the bone marrow [90]. Enhanced expression of GM-CSF, and to a lesser extent M-CSF, has been documented in lamina propria in association with inflammatory bowel disease [91]. It is speculated that CSFs serve to integrate the recruitment of inflammatory cells from the bone marrow with their utilization in inflammatory processes of the intestine.

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Hepatocyte growth factor

HGF, also identified as scatter factor, has been recognized to be the natural ligand of the Met-protooncogene [92]. Recent studies have demonstrated the expression of both Met/HGF receptor mRNA and protein in a broad range of tissues, including stomach, small intestine and colon [93]. Few data are available on the biological activities of HGF in the small and large intestine, but it is likely that HGF may play a role in the growth and morphogenesis of the gastrointestinal tract and in its remodelling following injury [94–99].

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Acknowledgements

Part of the work that was performed in the authors’ laboratories was supported by grants from the Deutsche Forschungsgemeinschaft (Di 477/3-1 and Di 477/3-4) and research support from the University of Essen and Charité Medical School to AD.

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References

• Of special interest

•• Of outstanding interest

1. Green AR. Peptide regulatory factors: multifunctional mediators of cellular growth and differentiation. Lancet 1989; i: 705–707.
2. •Sporn MB, Roberts AB. Autocrine secretion – 10 years later. Ann Intern Med 1992; 117: 408–414. Excellent overview about the basic characteristics of regulatory peptides and their mechanisms to modulate various cell functions.
3. •Nathan C, Sporn M. Cytokines in context. J Cell Biol 1991; 113: 981–986. Good description and definition of the cytokine network. This review illustrates the complex interactions of cytokines within a complex network of regulatory peptides, extracellular matrix factors, cell–cell contacts, and other modulatory factors.
4. Sporn MB, Roberts AB. Transforming growth factor-β: recent progress and new challenges. J Cell Biol 1992; 119: 1017–1021.
5. ••Sporn MB, Roberts AB. Peptide Growth Factors and Their Receptors I and II. New York: Springer-Verlag; 1991. Although a little outdated, this book provides an excellent overview of regulatory peptides, with extensive descriptions of all relevant growth factor families and their most important representatives. A must for anybody who is interested in the numerous, and constantly increasing number of cytokines and their biological effects.
6. Babyatsky MW, Podolsky DK. Growth and differentiation in the GI tract. In: Textbook of Gastroenterology. Yamada T, Alpers DH, Owyang C, Powell DW, Silverstein FE (editors). New York: Lippincott; 1991. pp. 475–501.
7. Dignass AU, Podolsky DK. Growth factors in inflammatory bowel disease. In: Cytokines in Inflammatory Bowel Disease. Fiocchi C (editor). Austin: R.G. Landes; 1996. pp. 137–155.
8. ••Podolsky DK. Mechanisms of regulatory peptide action in the gastrointestinal tract: trefoil peptides. J Gastroenterol 2000; 35 (suppl 12) : 69–74. Excellent overview that summarizes the current knowledge on TFFs and their modulatory effects within the gastrointestinal tract.
9. •Beck PL, Podolsky DK. Growth factors in inflammatory bowel disease. Inflamm Bowel Dis 1999; 5: 44–60. Extensive and systematic review of the role of growth factors in inflammatory bowel disease.
10. •Jones MK, Tomikawa M, Mohajer B, Tarnawski AS. Gastrointestinal mucosal regeneration: role of growth factors. Front Biosci 1999; 4: D303–309. Review that summarizes the effects of growth factors on gastrointestinal repair mechanisms in a systematic fashion.
11. Murphy MS. Growth factors and the gastrointestinal tract. Nutrition 1998; 14: 771–774.
12. Alison MR, Sarraf CE. The role of growth factors in gastrointestinal cell proliferation. Cell Biol Int 1994; 18: 1–10.
13. Baldwin GS, Whitehead RH. Gut hormones, growth and malignancy. Baillieres Clin Endocrinol Metab 1994; 8: 185–214.
14. Podolsky DK. Healing the epithelium: solving the problem from two sides. J Gastroenterol 1997; 32: 122–126.
15. ••Wilson AJ, Gibson PR. Epithelial migration in the colon: filling in the gaps. Clin Sci (Colch) 1997; 93: 97–108. Excellent and systematic overview of the current status of epithelial restitution (migration), with a special focus on the modulation of epithelial migration by growth factors.
16. Rogler G, Andus T. Cytokines in inflammatory bowel disease. World J Surg 1998; 22: 382–389.
17. Carpenter G, Wahl MI. The epidermal growth factor family. In: Peptides, Growth Factors and their Receptors I. Sporn MB, Roberts AB (editors). New York: Springer-Verlag; 1991. pp. 69–171. Although a little outdated, this review provides important information about EGF family peptides and may serve as a valuable source to anyone who wants to get an overview about the structural and functional properties of EGF family peptides.
18. Menard D, Pothier P. Radioautographic localization of epidermal growth factor receptors in human fetal gut. Gastroenterology 1991; 101: 640–649.
19. Koyama SY, Podolsky DK. Differential expression of transforming growth factors alpha and beta in rat intestinal epithelial cells. J Clin Invest 1989; 83: 1768–1773.
20. Malecka-Panas E, Kordek R, Biernat W, Tureaud J, Liberski PP, Majumdar AP. Differential activation of total and EGF receptor (EGF-R) tyrosine kinase (tyr-k) in the rectal mucosa in patients with adenomatous polyps, ulcerative colitis and colon cancer. Hepatogastroenterology 1997; 44: 435–440.
21. Montaner B, Asbert M, Perez-Tomas R. Immunolocalization of transforming growth factor-alpha and epidermal growth factor receptor in the rat gastroduodenal area. Dig Dis Sci 1999; 44: 1408–1416.
22. Tarnawski AS, Jones MK. The role of epidermal growth factor (EGF) and its receptor in mucosal protection, adaptation to injury, and ulcer healing: involvement of EGF-R signal transduction pathways. J Clin Gastroenterol 1998; 27 (suppl 1) : 12–20.
23. Wong WM, Wright NA. Epidermal growth factor, epidermal growth factor receptors, intestinal growth, and adaptation. J Parenter Enteral Nutr 1999; 23: S83–88.
24. Konturek JW, Bielanski W, Konturek SJ. Distribution and release of epidermal growth factor in man. Gut 1989; 30: 1194–1200.
25. Challacombe DN, Wheeler EE. Trophic action of epidermal growth factor on human duodenal mucosa cultured in vitro. Gut 1991; 32: 991–993.
26. Reeves JR, Richards RC, Cooke T. The effects of intracolonic EGF on mucosal growth and experimental carcinogenesis. Br J Cancer 1991; 63: 223–226.
27. Thompson JF. Specific receptors for epidermal growth factor in rat intestinal microvillus membranes. Am J Physiol 1988; 254: G429–435.
28. Scheving LA, Shiurba RA, Nguyen TD. Epidermal growth factor receptor of the intestinal enterocyte localization to the laterobasal but not brush border membrane. J Biol Chem 1989; 264: 1735–1741.
29. Kurokowa M, Lynch K, Podolsky DK. Effects of growth factors on an intestinal epithelial cell line: transforming growth factor beta inhibits proliferation and stimulates differentiation. Biochem Biophys Res Commun 1987; 142: 775–782.
30. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem 1990; 265: 7709–7712.
31. Fitzpatrick LR, Wang P, Johnson LR. Effect of epidermal growth on polyamine-synthesizing enzymes in rat enterocytes. Am J Physiol 1987; 252: G209–214.
32. Opleta-Madsen K, Hardin J, Gall DG. Epidermal growth factor upregulates intestinal electrolyte and nutrient transport. Am J Physiol 1991; 260: G807–814.
33. Riegler M, Sedivy R, Sogukoglu T, Cosentini E, Bischof G, Teleky B. et al. Epidermal growth factor promotes rapid response to epithelial injury in rabbit duodenum in vitro. Gastroenterology 1996; 111: 28–36.
34. •Dignass AU, Podolsky DK. Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor beta. Gastroenterology 1993; 105: 1323–1332. Demonstrates that several cytokines that are expressed within the intestinal mucosa enhance epithelial restitution, the initial step of epithelial repair following superficial injury, through a TGF-β-dependent mechanism, highlighting the central role of TGF-β in the maintenance of intestinal epithelial homeostasis.
35. Malden LT, Novack U, Burgess AW. Expression of transforming growth factor α messenger RNA in the normal and neoplastic gastro-intestinal tract. Int J Cancer 1989; 43: 380–384.
36. Thomas DM, Nasim MM, Gullick WJ. Immunoreactivity of transforming growth factor α in the normal adult gastrointestinal tract. Gut 1992; 33: 628–631.
37. Cai YC, Jiang Z, Vittimberga F, Xu X, Savas L, Woda B. et al. Expression of transforming growth factor-alpha and epidermal growth factor receptor in gastrointestinal stromal tumours. Virchows Arch 1999; 435: 112–115.
38. •Babyatsky MW, Rossiter G, Podolsky DK. Expression of transforming growth factor α and β in colonic mucosa in inflammatory bowel disease. Gastroenterology 1996; 110: 975–984. Demonstrates increased expression of TGF-β in areas with active inflammation in both ulcerative colitis and Crohn's disease patients, and enhanced expression of TGF-α in quiescent mucosa of ulcerative colitis patients with long-standing ulcerative colitis, indicating that these peptides may play an important role in intestinal repair and development of neoplasia in patients with inflammatory bowel disease.
39. De Angelis E, Grassi M, Gullick WJ, Johnson GR, Rossi GB, Tempesta A. et al. Expression of cripto and amphiregulin in colon mucosa from high risk colon cancer families. Int J Oncol 1999; 14: 437–440.
40. Johnson GR, Saeki T, Gordon AW, Shoyab M, Salomon DS, Stromberg K. Autocrine action of amphiregulin in a colon carcinoma cell line and immunocytochemical localization of amphiregulin in human colon. J Cell Biol 1992; 118: 741–751.
41. Saeki T, Stromberg K, Qi CF, Gullick WJ, Tahara E, Normanno N. et al. Differential immunohistochemical detection of amphiregulin and cripto in human normal colon and colorectal tumors. Cancer Res 1992; 52: 3467–3473.
42. Ciardiello F, Kim N, Saeki T. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Proc Nat Acad Sci USA 1991; 88: 7792–7796.
43. ••Massague J. The transforming growth factor β family. Annu Rev Cell Biol 1990; 6: 597–641. Although a little outdated, this review provides important information about TGF-β family peptides and may serve as a valuable source to anyone who wants to get an overview of the structural and functional properties of TGF-β family peptides.
44. ••Massague J. Receptors for the TGF-β family. Cell 1992; 69: 1067–1070. Although a little outdated, this review provides extensive information about TGF-β family receptors and may serve as a valuable source to anyone who wants to get an overview of TGF-β family peptide signalling.
45. Lyons RM, Gentry LE, Purchio AF. Mechanism of activation of latent recombinant transforming growth factor β1 by plasmin. J Cell Biol 1990; 110: 1361–1367.
46. Chen R-H, Ebner R, Derynck R. Inactivation of the type II receptor reveals two receptor pathways for the diverse TGFβ activities. Science 1993; 260: 1335–1338.
47. Lopez-Casillas F, Cheifetz S, Doody J. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGFβ receptor system. Cell 1991; 67: 785–795.
48. ••Massague J. TFG-beta signal transduction. Annu Rev Biochem 1998; 67: 753–791. Up-to-date summary about TGF-β signalling mechanisms and characterization of signal transduction pathways.
49. ••Kretzschmar M, Massague J. SMADs: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev 1998; 8: 103–111. Excellent summary of the rapidly expanding understanding of the major regulatory network of SMAD proteins and their role in TGF-β signalling.
50. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E. et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J 1997; 16: 5353–5362.
51. Persson U, Souchelnytskyi S, Franzen P, Miyazono K, ten Dijke P, Heldin CH. Transforming growth factor (TGF-beta)-specific signaling by chimeric TGF-beta type II receptor with intracellular domain of activin type IIB receptor. J Biol Chem 1997; 272: 21 187–21 194.
52. Barnard JA, Warwick GJ, Gold L. Localizations of TGFβ isoforms in the normal small intestine and colon. Gastroenterology 1993; 105: 67–73.
53. Dignass AU, Stow JL, Babyatsky MW. Acute epithelial injury in the rat small intestine in vivo is associated with expanded expression of transforming growth factor alpha and beta. Gut 1996; 38: 687–693.
54. •Wahl SM. Transforming growth factor beta (TGFβ) in inflammation: a cause and a cure. J Clin Immunol 1992; 12: 61–74. Good review about the potential role of TGF-β in inflammation, which highlights potential beneficial and deleterious effects of TGF-β.
55. Border WA, Ruoslathi E. Transforming growth factor β1 in disease: the dark side of tissue repair. J Clin Invest 1992; 90: 1–7.
56. Hubner G, Brauchle M, Gregor M, Werner S. Activin A: a novel player and inflammatory marker in inflammatory bowel disease? Lab Invest 1997; 77: 311–318.
57. Dignass AU, Schulte KM, Jung S, Harder-d'Heureuse J, Wiedenmann B. Activin A modulates intestinal epithelial cell function in vitro. Gastroenterology 2000; 118 (4): A823.A823.
58. Sonoyama K, Rutatip S, Kasai T. Gene expression of activin, activin receptors, and follistatin in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2000; 278: G89–97.
59. Chen K, Nezu R, Wasa M, Sando K, Kamata S, Takagi Y, Okada A. Insulin-like growth factor-1 modulation of intestinal epithelial cell restitution. J Parenter Enteral Nutr 1999; 23: S89–92.
60. •Howarth GS, Xian CJ, Read LC. Insulin-like growth factor-I partially attenuates colonic damage in rats with experimental colitis induced by oral dextran sulphate sodium. Scand J Gastroenterol 1998; 33: 180–190. Interesting study that provides evidence that IGF I plays a potential role in modulating intestinal injury in vivo.
61. ••Rechler MM, Nissley SP. Insulin-like growth factors. In: Peptide Growth Factors and Their Receptors I. Sporn MB, Roberts AB (editors). New York: Springer-Verlag; 1991. pp. 263–367. Although a little outdated, this review provides extensive information about IGF family peptides and may serve as a valuable source to anyone who wants to get an overview of the structural and functional properties of IGF family peptides.
62. Thompson MA, Cox AJ, Whitehead RH, Jonas HA. Autocrine regulation of human tumor cell proliferation by insulin-like growth factor II: an in vitro model. Endocrinology 1990; 126: 3033–3042.
63. Young GP, Taranto TM, Jonas HA. Insulin-like growth factor and the developing and mature rat small intestine: receptors and biological actions. Digestion 1990; 46: 240–252.
64. •Lund PK, Zimmermann EM. Insulin-like growth factors and inflammatory bowel disease. Baillieres Clin Gastroenterol 1996; 10: 83–96. Summarizes the important role of IGF peptides in inflammatory bowel diseases.
65. Zimmermann EM, Sartor RB, McCall RD, Pardo M, Bender D, Lund PK. Insulin-like growth factor I and interleukin 1β messenger RNA in a rat model of granulomatous enterocolitis and hepatitis. Gastroenterology 1993; 105: 399–409.
66. ••Baird A, Böhlen P. Fibroblast growth factors. In: Peptide Growth Factors and Their Receptors I. Sporn MB, Roberts AB (editors). New York: Springer-Verlag; 1991. pp. 369–418. Although a little outdated, this review provides an extensive overview of FGF peptides and may serve as a valuable source to anyone who wants to get an overview of the structural and functional properties of FGF peptides.
67. Ernst H, Muller M, Paulus A, Hahn EG, Ell C. Immunohistochemical localization of basic fibroblast growth factor in the normal adult gastrointestinal tract. Eur J Gastroenterol Hepatol 1994; 6: 559–564.
68. New BA, Yeoman LC. Identification of basic growth factor sensitivity and receptor and ligand expression in human colon tumor cell lines. J Cell Physiol 1992; 150: 320–326.
69. Nice EC, Fabri L, Whitehead RH, James R, Simpson RJ, Burgess AW. The major colonic cell mitogen extractable from colonic mucosa is an N-terminally extended form of basic fibroblast growth factor. J Biol Chem 1991; 22: 14 425–14 430.
70. Ohtani H, Nakamura S, Watanabe Y, Mizoi T, Saku T, Nagura H. Immunocytochemical localization of basic fibroblast growth factor in carcinomas and inflammatory lesions of the human digestive tract. Lab Invest 1993; 68: 520–527.
71. Cordon-Cardo C, Vlodavsky I, Haimovitz-Friedman A, Hicklin D, Fuks Z. Expression of basic fibroblast growth factor in normal human tissues. Lab Invest 1990; 63: 832–840.
72. El Hariry I, Pignatelli M, Lemoine N. Fibroblast growth factor 1 and fibroblast growth factor 2 immunoreactivity in gastrointestinal tumours. J Pathol 1997; 181: 39–45.
73. Dignass AU, Tsunekawa S, Podolsky DK. Fibroblast growth factors modulate intestinal epithelial cell growth and migration. Gastroenterology 1994; 106: 1254–1262.
74. Housley RM, Morris CF, Boyle W, Ring B, Biltz R, Tarpley JE. et al. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. J Clin Invest 1994; 94: 1764–1777.
75. Matsuda K, Sakamoto C, Konda Y, Nakano O, Matozaki T, Nishisaki H. et al. Effects of growth factors and gut hormones on proliferation of primary cultured gastric mucous cells of guinea pig. J Gastroenterol 1996; 31: 498–504.
76. Paimela H, Goddard PJ, Carter K, Khakee R, McNeil PL, Ito S, Silen W. Restitution of frog gastric mucosa in vitro: effect of fibroblast growth factor. Gastroenterology 1993; 104: 1337–1345.
77. Hu MC, Qiu WR, Wang YP, Hill D, Ring BD, Scully S. et al. FGF-18, a novel member of the fibroblast growth factor family, stimulates hepatic and intestinal proliferation. Mol Cell Biol 1998; 18: 6063–6074.
78. Poulsom R. Trefoil peptides. Baillieres Clin Gastroenterol 1996; 10: 113–134.
79. ••Sands BE, Podolsky DK. The trefoil peptide family. Annu Rev Physiol 1996; 58: 253–273. Extensive overview of the structural, physicochemical and functional activities of TFF peptides and their expression in various tissues, including the gastrointestinal tract.
80. Wong WM, Poulsom R, Wright NA. Trefoil peptides. Gut 1999; 44: 890–895.
81. Thim L. Trefoil peptides: from structure to function. Cell Mol Life Sci 1997; 53: 888–903.
82. •Lefebvre O, Chenard M, Masson R, Linares J, Dierich A, LeMeur M. et al. Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. Science 1996; 274: 259–262. Demonstrates that TFF-I (pS2) is essential for normal differentiation of the antral and pyloric gastric mucosa, and may function as a gastric-specific tumour suppressor gene.
83. •Babyatsky MW, DeBeaumont M, Thim L, Podolsky DK. Oral trefoil peptides protect against ethanol- and indomethacin-induced gastric injury in rats. Gastroenterology 1996; 110: 489–497. Demonstrates that topical TFF peptides protect the gastric mucosa against ethanol- and indomethacin-induced gastric injuries. The authors conclude that these peptides contribute to surface mucosal defence.
84. •Dignass A, Lynch-Devaney K, Kindon H, Thim L, Podolsky DK. Trefoil peptides promote epithelial migration through a transforming growth factor beta-independent pathway. J Clin Invest 1994; 94: 376–383. Demonstrates that TFF-II and TFF-III do not modulate intestinal epithelial proliferation, but that they enhance epithelial restitution through TGF-β-independent mechanisms, indicating that TFF peptides may play an important role in intestinal wound repair.
85. ••Mashimo H, Wu DC, Podolsky DK, Fishman MC. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 1996; 274: 262–265. Demonstrates impaired repair mechanisms in ITF (TFF-III) knock-out mice providing evidence for the important role that TFF peptides may play in the maintenance of the intestinal epithelial barrier and intestinal repair in vivo.
86. •Playford RJ, Marchbank T, Goodlad RA, Chinery RA, Poulsom R, Hanby AM. Transgenic mice that overexpress the human trefoil peptide pS2 have an increased resistance to intestinal damage. Proc Natl Acad Sci USA 1996; 93: 2137–2142. Transgenic animal study that supports the hypothesis that TFF peptides are important in stimulating gastrointestinal repair.
87. Efstathiou JA, Noda M, Rowan A, Dixon C, Chinery R, Jawhari A. et al. Intestinal trefoil factor controls the expression of the adenomatous polyposis coli–catenin and the E-cadherin–catenin complexes in human colon carcinoma cells. Proc Natl Acad Sci USA 1998; 95: 3122–3127.
88. Liu D, el Hariry I, Karayiannakis AJ, Wilding J, Chinery R, Kmiot W. et al. Phosphorylation of beta-catenin and epidermal growth factor receptor by intestinal trefoil factor. Lab Invest 1997; 77: 557–563.
89. •Uchino H, Kataoka H, Itoh H, Hamasuna R, Koono M. Overexpression of intestinal trefoil factor in human colon carcinoma cells reduces cellular growth in vitro and in vivo. Gastroenterology 2000; 118: 60–69. Demonstrates that overexpression of ITF suppresses the growth of colon carcinoma cells providing evidence that ITF may function as an inhibitory factor for the growth of colonic neoplasm.
90. Dippold W, Meyer-zum-Büschenfelde KH. Proliferation of gastrointestinal carcinoma cells by T-lymphocyte factors interleukin-3 and granulocyte–macrophage colony-stimulating-factor. Immunol Res 1991; 10: 258–260.
91. Pullmann WES, Kobayashi M, Hapel AJ, Doe WF. Enhanced mucosal cytokine production in inflammatory bowel disease. Gastroenterology 1992; 102: 529–537.
92. Bottaro DP, Rubin JS, Faletto DL. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991; 251: 802–804.
93. DiRenzo MF, Narsimhan RP, Olivero M. Expression of the Met/HGF receptor in normal and neoplastic human tissue. Oncogene 1991; 6: 1997–2003.
94. Dignass AU, Lynch Devaney K, Podolsky DK. Hepatocyte growth factor/scatter factor modulates intestinal epithelial cell proliferation and migration. Biochem Biophys Res Commun 1994; 202: 701–709.
95. •Goke M, Kanai M, Podolsky DK. Intestinal fibroblasts regulate intestinal epithelial cell proliferation via hepatocyte growth factor. Am J Physiol 1998; 274: G809–818. Demonstrates that fibroblasts stimulate intestinal epithelial proliferation through a paracrine mechanism mediated predominantly by HGF.
96. Kinoshita Y, Nakata H, Hassan S, Asahara M, Kawanami C, Matsushima Y. et al. Gene expression of keratinocyte and hepatocyte growth factors during the healing of rat gastric mucosal lesions. Gastroenterology 1995; 109: 1068–1077.
97. Kong W, Yee LF, Mulvihill SJ. Hepatocyte growth factor stimulates fetal gastric epithelial cell growth in vitro. J Surg Res 1998; 78: 161–168.
98. •Takahashi M, Ota S, Shimada T, Hamada E, Kawabe T, Okudaira T. et al. Hepatocyte growth factor is the most potent endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary culture. J Clin Invest 1995; 95: 1994–2003. Suggests that HGF may be a potent endogenous promoter of gastric epithelial cell proliferation and migration, and may contribute to gastric mucosal repair through a paracrine mechanism.
99. Sturm A, Schulte C, Schatton R, Becker A, Cario E, Goebell H, Dignass AU. Transforming growth factor-beta and hepatocyte growth factor plasma levels in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000; 12: 445–450.
100. Sakamoto C, Matsuda K, Nakano O, Konda Y, Matozaki T, Nishisaki H, Kasuga M. EGF stimulates both cyclooxygenase activity and cell proliferation of cultured guinea pig gastric mucous cells. J Gastroenterol 1994; 29 (suppl 7) : 73–76.
    101. Coffey RJ, Goustin AJ, Soderquist AM. Transforming growth factors α and β expression in human colon cancer lines. Cancer Res 1987; 47: 4590–4594.
      102. Scheiman JM, Meise KS, Greenson JK, Coffey RJ. Transforming growth factor-alpha (TGF-alpha) levels in human proximal gastrointestinal epithelium. Effect of mucosal injury and acid inhibition. Dig Dis Sci 1997; 42: 333–341.
        103. Goodlad RA, Raja KB, Peters TJ. Effects of urogastrone-epidermal growth factor on intestinal brush border enzymes and mitotic activity. Gut 1991; 32: 994–998.
          104. Tahara E. Growth factors and oncogenes in human gastrointestinal carcinomas. J Cancer Res Clin Oncol 1990; 116: 121–131.
          105. Basson MD, Modlin JM, Madri JA. Human enterocyte (Caco-2) migration is modulated in vitro by extra-cellular matrix composition and epidermal growth factor. J Clin Invest 1992; 90: 15–23.
            106. Massague J. Transforming growth factor-α: a model for membrane anchored growth factors. J Biol Chem 1990; 265: 21 393–21 396.
              107. Barnard JA, Beauchamp RD, Coffey RJ, Moses HL. Regulation of intestinal epithelial cell growth by transforming growth factor type β. Proc Nat Acad Sci USA 1989; 86: 1578–1582.
                108. Suemori S, Ciacci C, Podolsky DK. Regulation of transforming growth factor expression in rat intestinal epithelial cell lines. J Clin Invest 1991; 87: 2216–2221.
                  109. Ciacci C, Lind SE, Podolsky DK. Transforming growth factor β regulation of migration in wounded rat intestinal epithelial monolayers. Gastroenterology 1993; 105: 93–101.
                    110. Goke M, Zuk A, Podolsky DK. Regulation and function of extracellular matrix intestinal epithelial restitution in vitro. Am J Physiol 1996; 271: G729–740.
                      111. McKaig BC, Makh SS, Hawkey CJ, Podolsky DK, Mahida YR. Normal human colonic subepithelial myofibroblasts enhance epithelial migration (restitution) via TGF-beta3. Am J Physiol 1999; 276: G1087–1093. Shows that human colonic subepithelial myofibroblasts secrete predominantly bioactive TGF-β3 and enhance restitution in wounded epithelial monolayers via a TGF-β-dependent pathway.
                        112. Cross D, Cambier JC. Transforming growth factor β1 has differential effects on B cell proliferation and activation antigen expression. J Immunol 1990; 144: 432–439.
                          113. Cross M, Dexter TM. Growth factors in development, transformation, and tumorigenesis. Cell 1991; 64: 271–280.
                            114. ••Neurath MF, Fuss I, Kelsall BL, Presky DH, Waegell W, Strober W. Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance. J Exp Med 1996; 183: 2605–2616. Suggests that TGF-β production can abrogate experimental granulomatous colitis, and that regulation of TGF-β levels may be relevant in the treatment of human inflammatory bowel disease.
                              115. Reibman J, Meixler S, Lee TC, Gold LI, Cronstein BN, Haines KA. et al. Transforming growth factor β1, a potent chemoattractant for human neutrophils, bypasses classic signal-transduction pathways. Proc Nat Acad Sci USA 1991; 88: 6805–6809.
                                116. Stallmach A, Schuppan D, Lazar D, Riese HH, Riecken E. Increased collagen type III synthesis by fibroblasts isolated from strictures of patients with Crohn's disease. Gastroenterology 1992; 102: 1920–1929.
                                  117. Graham MF, Bryson GR, Diegelmann RF. Transforming growth factor β1 selectively augments collagen synthesis by human intestinal smooth muscle cells. Gastroenterology 1990; 99: 447–453.
                                    Keywords:

                                    cytokine; epithelium; growth factor; intestine; regulatory peptide

                                    © 2001 Lippincott Williams & Wilkins, Inc.