Growth Factors in the Intestinal Tract




Abstract


Gastrointestinal (GI) tissues express a multitude of growth factors, broadly defined as naturally occurring polypeptides that elicit cellular growth, proliferation, or differentiation following binding to surface membrane receptors. In the GI tract, growth factors perform functions at all stages of life, and play critical roles in development, maintenance, repair and regeneration, pro- and anticancer functions, and immune cell regulation. In this chapter, we discuss the basic physiological processes by which growth factors operate in GI tissue and the signaling underlying their specific roles in health and disease. We review several families of growth factors that have well-defined and significant roles in the GI tract [epidermal growth factor (EGF), transforming growth factor beta (TGF-β), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF)] and briefly discuss several other families with emerging roles.




Keywords

Growth factors, EGF, HGF, TGF, IGF, FGF, Intestinal development, Intestinal repair, Intestinal inflammation, Colon cancer

 




Acknowledgments


The authors would like to thank the contributions of authors of previous editions of this chapter to the development of this text: John A. Barnard and Kirk M. McHugh (4th ed.), and John F. Kuemmerle (5th ed.).




3.1


Introduction


Gastrointestinal (GI) tissues express a multitude of growth factors, broadly defined as naturally occurring polypeptides that elicit cellular growth, proliferation, or differentiation following binding to surface membrane receptors. The growth factor field arguably took root in the 1950s and 1960s with the identification of a number of soluble biological activities necessary to drive cell division. Over subsequent decades, many additional molecules were identified by efforts to find mediators involved in the transformation of normal cells to tumor cells (which characteristically display rapid proliferation and enhanced survival). These early findings laid the groundwork for a wealth of subsequent studies identifying mechanisms of growth factor secretion, receptors, modes of signaling, downstream pathways, and additional ligands that cosignal within each family. In the GI tract, growth factors perform functions at all stages of life and play critical roles in development, maintenance, repair and regeneration, pro- and anticancer functions, and immune cell regulation. In this chapter, we review several families of growth factors that have well defined and significant roles in the GI tract: epidermal growth factor (EGF), transforming growth factor beta (TGF-β), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF). We will also briefly discuss several other families with less well defined but emerging roles in the GI tract. An overview of these growth factors, their principal receptors, and targets of actions are listed in Table 3.1 .



Table 3.1

Overview of Major Growth Factors, Receptors, and Targets













































































Growth Factor Family Receptors Ligands Target Cell Types
Epidermal growth factor EGFR/ErbB1 EGF, TGF-α, NRG1-4, HB-EGF, amphiregulin, betacellulin, epiregulin, epigen Epithelium
ErbB2 Endothelium
ErbB3 Immune
ErbB4
Transforming growth factor-β TβR-I TGF-β, BMP2-7, activin, inhibin, nodal Epithelium
TβR-II Endothelium
Immune
Insulin-like growth factor IGFR1 IGF1 Epithelium
IGFR2 IGF2 Endothelium
Hepatocyte growth factor c-Met HGF Epithelium
Coreceptors (CD44) Endothelium
Mesenchyme
Immune
Fibroblast growth factor FGFR1-4 FGF1, 2, 4, 7, 9, 10, 15/19, 18, 21, 20 (in cancer), 23 Epithelium
Coreceptors (α/β-klotho) Mesenchyme
Trefoil factor CXCR4 TFF1, TFF2, TFF3 Epithelium
Unidentified others Immune
Hedgehog Ptch1-2 Shh, Ihh, Dhh Epithelium
Immune


The naming convention of peptide growth factors typically has relied upon the molecule’s apparent function when initially discovered. While this seems straightforward, subsequent research has invariably identified additional and sometimes even contradictory roles for these peptides; a growth factor may elicit a wholly distinct function than what the name would suggest depending on tissue location and context of expression. For instance, EGF has pleiotropic actions in many tissues including but not limited to the epidermis, and some EGF family members can have seemingly “nongrowth” activities such as promoting apoptosis or regulating ion transport. Transforming growth factor (TGF)-β has roles outside of transformation of normal cells, including wound healing, differentiation, and fibrosis, and in many settings actually acts as a tumor suppressor. Furthermore, though TGF-β and TGF-α have names that would suggest close relatives, they in fact belong to entirely different families of growth factors—TGF-β is the prototypic member of a whole family (the TGF-β superfamily), while TGF-α is an EGF-like molecule. Thus, the reader is cautioned against drawing too many conclusions regarding a peptide’s function from its name.


Although other classes of proteins such as cytokines/chemokines and peptide hormones can stimulate cellular growth; in this chapter, we will focus strictly on the traditional peptide growth factors. Cytokines can impact cell growth as a secondary outcome but in general tend to be immunomodulatory in function. Hormones are generated in glandular tissue and are typically secreted into circulation thus allowing for long-range actions. In contrast, peptide growth factors are sourced from a variety of cell types and tissues and are typically categorized as having autocrine, paracrine, or juxtacrine actions ( Fig. 3.1 ). Cytokines, chemokines, hormones, and similar molecules are covered in other chapters.




Fig. 3.1


Growth factor signaling routes. Growth factors are secreted from numerous sources and signal at different targets throughout the GI tract. Their modes of signaling can be broadly categorized as: Exocrine, exogenously derived growth factors (such as those in breast milk) eliciting signaling on their target cells; autocrine/juxtacrine, a growth factor acting on its receptor within the same cell or same cell type locally; paracrine, a growth factor derived from one cell type that acts on another cell type (such as mesenchymally derived factors binding to receptors on epithelial cells); endocrine, growth factors generated in one part of the body that migrate long distances (typically through circulation) to act on their target cells. EP , epithelium; ME , mesenchyme; CS , circulatory system.


Growth factor signaling in the GI tract is tightly regulated, in part due to the varied sources and targets of these peptides. It is important to keep in mind the ligand source and receptor location to understand fully differences in signaling outcomes. Growth factors are produced in a variety of tissues and histological strata including the epithelium, the subepithelium, exogenous sources such as breastmilk, and anatomically distinct sources (i.e., luminal EGF secreted from salivary and Brunner’s glands ). In some instances, notably with TGF-β and IGF, the source of growth factor can also be from recruited immune cells. Signaling specificity is supported by restricted or differential receptor expression on different cell types, including epithelial cells, endothelial cells, mesenchyme/fibroblasts, smooth muscle cells, and immune cells, among others. Regulated induction or suppression of ligand and receptor levels (e.g., Refs. ) can alter the responses of specific cell types or the overall tissue as well. Substantial work on each family of molecules in the past half century has revealed specific signaling pathways and alterations in intracellular activity that are stimulated by these growth factors. As some of these signaling pathways and intracellular events are shared, it is important to keep in mind the source(s) of ligands as well as expression patterns of the target receptors in understanding the context-dependent roles and specific outcomes.


Signaling initiated by growth factors occurs through a sequence involving ligand release (or presentation of tethered ligand) and extracellular binding to receptor; recognition of this event is then transmitted to intracellular signals through a variety of methods (predominantly, but not exclusively, kinase activity). Generally, a number of ligands can act through the same receptor. This initially was interpreted as a functional redundancy, but in the past few decades, it has become clear that while there is substantial overlap between shared ligands, conformational and contextual (including spatial and kinetic) differences in responses also come into play that finely tune the output. Thus, availability of a panel of highly similar but not quite identical ligands allows for greater flexibility in control of cell behavior. A significant amount of effort has gone into clarifying these aspects of growth factors in the GI tract, resulting in an evolving understanding of the physiological roles of closely related growth factors, but to a large extent this aspect of the field is still in its infancy. The spatial distinctions, differences in expression, and compartmentalization of related growth factors that share common receptors should be kept in mind when interpreting how the growth factor may function in vivo. These differences and any known implications for physiological function will be discussed within each subsection.


The groundwork laid in understanding the activity and function of peptide growth factors in cell culture was instrumental for determining the role of many of these molecules in maintenance of tissue homeostasis. Furthermore, understanding their activity has allowed us to recognize cases where inappropriate gain- or loss-of-function is involved in the development of disease. At the same time, understanding the basic biology and biochemistry of these molecules has allowed for harnessing this knowledge to advance therapeutics and disease treatment. For instance, in mouse models, a number of growth factors are dispensable for normal homeostatic maintenance/tissue turnover but absolutely required for appropriate and efficient response to injury and inflammation. In other cases, overexpression or lack of expression of growth factor signaling can result in profound baseline GI disturbances, implicating specific factors in tissue homeostasis, and in several cases are associated with disease states such as cancer.




3.2


Epidermal Growth Factor (EGF) Family


3.2.1


Introduction


The EGF family is a large group of peptide growth factors that, through activating one or more of the ErbB receptor tyrosine kinases ( Fig. 3.2 ), influence cell proliferation, differentiation, migration, function, and survival in the GI tract. EGF, the prototypic member of this family, was initially described in 1962 as a protein in mouse submaxillary gland extracts that promoted premature eye opening and incisor eruption in newborn mice. Decades of subsequent study on this “tooth-lid factor” have demonstrated critical roles for EGF and its relatives in most cell types in the body. The EGF family has expanded to include additional peptides including TGF-α, heparin-binding EGF-like growth factor (HB-EGF), heregulins/neuregulins (HRG/NRG), amphiregulin (AR), betacellulin (BTC), epiregulin (EPR), and epigen (for review, see Refs. ). These molecules share substantial sequence homology and, with varying degrees of affinity, the same receptors. Thus, they evoke overlapping but not completely identical biological activities, with differential receptor binding providing a first layer of explanation for the differences.




Fig. 3.2


EGFR/ErbB family of receptor tyrosine kinases. EGF-like growth factors signal through four distinct ErbB growth factor receptors, EGFR/ErbB1-ErbB4. These receptors share a common structure of an extracellular domain that binds ligand and an intracellular domain containing a tyrosine kinase domain and docking sites (tyrosine residues) for intracellular signaling components. Signaling commonly relies on receptor dimerization (either homo- or heterodimers). ErbB2 is unique in that it binds no growth factor ligands and relies upon heterodimerization to signal. ErbB3 is distinct in that it has attenuated kinase activity and thus primarily signals in heterodimers as well. ErbB4 is distinct in that TACE/ɣ-secretase cleavage of the intracellular domain generates a receptor fragment capable of acting within the cell (4ICD).


Each EGF family member is synthesized as an integral membrane protein with functionally distinct cytoplasmic, transmembrane, and extracellular domains and typically harbor extracellular proteolytic cleavage sites for processing by distinct members of the “a disintegrin and metalloproteinase” (ADAM) family of sheddases ( Fig. 3.3 ). Following cleavage and processing, EGF-like peptides bind and activate EGFR, ErbB3, and ErbB4. A fourth receptor, ErbB2, is involved in transducing signals from these ligands but does not appear to bind them directly. The receptors were named ErbBs due to their close homology with the v-erbB oncogene encoded by the avian erythroblastosis virus. Alternatively, they are also known as human epidermal growth factor receptor 1-4 (HER1-4). The choice of naming of these receptors in the literature is largely a factor of historical convention within the field of study—for instance, the breast cancer field typically relies on using the HER naming strategy, whereas the GI field generally uses the EGFR/ErbB names. Regardless of the name, upon ligand binding, the receptors are typically stabilized in homodimers (two of the same receptor) or heterodimers (two different ErbBs), leading to increased tyrosine kinase activity, transphosphorylation of the kinase cytoplasmic domain, and presentation of tyrosine-phosphorylated docking sites for downstream signaling adapters and substrates.




Fig. 3.3


Family of EGF-like ligands. EGF-like ligands are membrane-anchored upon generation. These ligands can signal either while membrane-bound in a juxtacrine manner, or more typically following metalloproteinase-dependent cleavage and release of extracellular signaling domains. Typical cleaved, secreted sizes are indicated (red text) . EGF , epidermal growth factor; TGF-α , transforming growth factor-α; HBEGF , heparin-binding epidermal growth factor-like growth factor; AR , amphiregulin; EPR , epiregulin; BTC , betacellulin; EP , epigen; NRG1-4 , neuregulins 1-4.


Signaling through ErbB/HER receptors is complex, allowing for fine regulation of cellular outcome. A common component of ligand-induced signaling that is recurrent in growth factor biology is receptor dimerization. Within the EGFR/ErbB family, the number of ligands (each with individual affinity profiles for the different receptors), combined with the number of potential receptor dimers, allows for substantial diversity in cellular outcomes. For example, ErbB3 has very low kinase activity, while ErbB2 has no known ligand and typically functions in heterodimers. Furthermore, each receptor has a distinct pattern of c-terminal docking sites for downstream signaling, and different ligands can preferentially stabilize different dimer combinations to elicit different cellular effects. Thus, while signaling through these receptors can clearly have profound effects on cell growth and wound repair in the gut, the family can be “reused” with slight variations to control other cellular functions such as ion transport and differentiation.


3.2.2


Epidermal Growth Factor (EGF)


The study of EGF over the past half century has been foundational for our modern day understanding of classical ligand-receptor activation and signaling paradigms within the field of molecular and cellular biology. The importance of this body of work was underscored in 1987 when the Nobel Prize was awarded to Stanley Cohen and Rita Levi-Montalcini for the discovery of EGF and nerve growth factor. In the GI tract, EGF is produced in multiple compartments including the salivary glands, intestine, stomach, esophagus, and accessory organs (pancreas and liver). EGF elicits its classical mitogenic effects by binding EGFR on the cell surface, leading to receptor dimerization and tyrosine kinase activity. It is mainly exclusive to EGFR homodimers and EGFR/ErbB2 heterodimers in terms of binding affinity, though low binding to ErbB2/4 dimers has also been reported. Heterodimer activity can be important as asymmetric dimers not only have a broader palette of intracellular docking sites but can also be “biased” toward different ligands and have different internalization-downregulation profiles after activation. Following receptor binding and dimerization, phosphorylation of specific c-terminal tyrosine residues activates signals through a wide array of pathways including ERK MAPK, p38 MAPK, JNK, and PI 3-kinase, resulting in numerous context-dependent cellular outcomes including altered DNA synthesis, intracellular calcium influx, glycolysis, and selective regulation of gene and protein expression.


Sources of secreted EGF in the GI tract include the submaxillary glands and the Brunner’s glands of the duodenum. Both of these sources result in luminal secretion. This is important to note because EGFR is expressed predominantly on the basolateral surface of the intestinal epithelium. Thus, utilizing the luminal pool of EGF requires that the ligand somehow cross the barrier. This originally led to the hypothesis that EGF is a luminal surveillance factor, poised to react to injured mucosa (where the barrier is naturally broken) by stimulating cellular proliferation, migration, and repair. In adults, transepithelial migration of EGF does not readily occur; therefore, luminal EGF is primarily available to pass the barrier when it is breached to promote epithelial wound repair as well as interact with other cells expressing EGFR such as immune cells. Alternatively, there is some evidence for EGFR redistribution to the apical face of enterocytes after injury. However, EGF can also be induced in subepithelial myofibroblasts, and it is released by the Paneth cells near the small intestinal crypt base. This may establish a gradient of available EGF along the crypt-villus (crypt-surface mucosa in the colon) axis in homeostatic turnover, which is then disrupted by injury. Furthermore, the expression of EGF in ulcer associated epithelial cell lineages suggests it can be produced locally throughout the intestine in response to chronic damage. Interestingly, another route through which EGF can access the GI tract in early life is through breast-feeding, as mother’s milk has been shown to be a major source. This suggests EGF has a role in development and maintenance of the intestinal epithelium in this sensitive early period of life, consistent with pig models of development in which weaning-associated villus atrophy can be prevented, and growth curves enhanced, by supplying EGF.


Among other functions in the intestinal epithelium, EGF stimulates cell migration and restitution, increases proliferation, delays intestinal cell shedding, and modulates nutrient and ion transport. EGF infusion or administration results in elevated epithelial cell proliferation, increased small intestinal villi size, and increased intestinal diameter. Additionally, it has been shown to have important roles in the regulation of the intestinal stem cell niche. This role of EGF in maintaining the stem cell niche is highlighted by its requirement in cultures of self-organizing 3D cultures of intestinal mini-guts, known as enteroids, and gastric organoids.


The pleiotropic responses to EGF signaling are of course tightly regulated, both at the cellular and tissue levels. At the most basic level, EGFR activation at the cell surface triggers receptor endocytosis and either recycling or destruction of the receptor depending on strength and duration of signal (for review, see Ref. ); interruption of the internalization-ubiquitinylation-degradation sequence can have profound effects on cellular growth. Additional physiologic feedback loops on ligand expression and availability present another level of control. For example, in the stomach, EGF is digested by gastric acid to less active forms, while EGF also serves to inhibit gastric acid secretion. In the intestine, EGF can induce other ErbB ligands and can itself be negatively regulated by inflammatory cytokines. Multiple reciprocal feedback mechanisms allow for fine tuning of the signaling response and attendant proliferation, wound healing, and other homeostatic activities.


Many examples of enhanced EGF expression or signaling have been demonstrated following an insult to the GI mucosa or in context of disease. In general, these studies identify induction as a cytoprotective response contributing to restoration of health and homeostasis. In rat studies, intraperitoneal injection of EGF (which would have basolateral access to EGFR) conferred protection of the small intestinal mucosa against methotrexate-induced injury. In liver, following partial hepatectomy and in cirrhosis, EGF expression is induced and important for hepatic regeneration. In chronic intestinal inflammation, EGF expression is elevated in the ulcer associated cell lineages, which may contribute to epithelial restitution and repair. Under pathological conditions, EGF has been shown to attenuate intestinal damage and enhance mucosal healing. Animal model results showing that EGFR gain- or loss-of-function are protective or sensitizing to intestinal injury, respectively, strongly support a role for EGF in driving resolution of colitis. In fact, in a limited clinical trial with mild-to-moderate ulcerative colitis patients, the Playford group demonstrated an impressive 83% response rate, including enhanced mucosal healing, to EGF when given as an adjunct to mesalamine.


In addition to studies of adult disease, work with administration to neonatal rodent pups has suggested that proper EGF signaling may be important in the prevention of neonatal intestinal inflammatory disease, such as necrotizing enterocolitis (NEC). Animals receiving EGF are protected from the formula feed-hypoxia model of NEC. This is presumably through suppressing epithelial apoptosis and encouraging rapid and efficient healing of epithelial damage, though secondary actions by other environmental factors such as bile acid pools may also contribute. These findings are also supported by some limited NEC work in human trials and have led to the hypothesis that lack of this growth factor (normally available in expressed breast milk ) may contribute to the increased NEC risk associated with formula feeding. Altogether, there is a substantial body of evidence suggesting that EGF could be useful therapeutically for promoting mucosal repair.


Despite the potential demonstrated in preclinical work, concerns over possible tumorigenic effects have limited exploration of EGF as a therapeutic agent (for discussion, see Ref. ). While EGF can drive wound repair and recovery of homeostasis, unregulated signaling through its receptor EGFR also plays a role in GI neoplasias. ErbB receptor tyrosine kinases have shown some promise as therapeutic targets in a variety of epithelial cancers including in colon. Altered EGF expression has been described in a number of tumors including pancreatic, esophageal, gastric, hepatic, and colorectal cancers. Furthermore, the potential for EGF to contribute to GI neoplasia has been suggested by mouse models, for example, the development of hepatocellular neoplasia in transgenic mice that overexpress secretable EGF. However, it should be noted that mutation, amplification, or forced overexpression represent radically different mechanisms than activation of the endogenous receptor with its normal ligand, even if the ligand is given therapeutically (acutely, instead of constitutive overexpression). Studies with mice deficient in EGFR signaling indicate that endogenous signaling actually acts as a tumor suppressor in some circumstances. As with many other regulatory peptides, EGF-driven signaling likely sits in a “Goldilocks” zone, with either excessive or insufficient activity leading to disease.


Loss-of-function studies suggest a functional redundancy for EGF exists in the intestinal tract. For example, administration of exogenous peptide is trophic for the GI tract and protects against intestinal injury, whereas EGF knockout mice have neither an overt intestinal phenotype nor exaggerated sensitivity to acute DSS colitis (though chronic colitis has not been well-described in this context). In contrast, the EGFR wav5 mutation, which encodes a receptor with very low activity, does predispose to and worsen colitis. This apparent contradiction is generally thought to be the result of ligand redundancy and/or compensation, though it is also clear from cell culture studies that individual ligands elicit distinct molecular and cellular responses. In fact, to achieve a histologically notable phenotype (in this case, spontaneous duodenal ulceration) in the absence of additional challenge (e.g., nonsteroidal antiinflammatory drug-mediated injury, cytokine injection), Troyer and colleagues deleted three different ligands —EGF, amphiregulin, and TGF-α. It is unclear whether the effects of this triple deletion are exactly equivalent to total loss of EGFR/ErbB1 signaling in the epithelium, as whole body knockout of the receptor is lethal in early life, though the GI tract is definitely perturbed in EGFR −/− pups. Furthermore, data from conditional knockout mice have not yet been reported. Overall, however, targeting ErbB receptors directly tends to have a greater physiological impact than deletion of limited sets of ligands.


Another complication with interpreting the results from ligand knockouts is recent data showing differential involvement for EGF signaling in different cell types; for example, while it is clear that EGFR activation in epithelial cells is protective, in macrophages it can promote inflammatory responses and contribute to colitis, as EGFR deletion from cells of the myeloid lineage (including macrophages) reduced disease in the murine DSS model. Similarly, in Helicobacter -induced gastritis, lack of macrophage-specific EGFR resulted in decreased gastric inflammation, though this was accompanied by increased bacterial load. These results demonstrate a role for EGF signaling in GI physiology and disease beyond its traditional role as a mitogenic factor. Further studies of the cell type-specific effects of EGF (and other ligands), and comparisons between the role of endogenous (and thus physiologically localized) versus exogenous, therapeutic application are warranted.


3.2.3


Transforming Growth Factor-Alpha (TGF-α)


Next to EGF, the most extensively studied EGF-family ligand in the GI tract is TGF-α. This molecule was initially discovered in the 1980s in screens designed to uncover factors involved in transformation of normal cells to malignant cells. In particular, these efforts were meant to identify factors that could be produced by the cells themselves that have self-regulating autocrine activity. These screens using assays of growth in soft agar as a measure of tumorigenicity identified TGF-α and TGF-β as cooperative drivers of transformation. As noted above, despite their names TGF-α shares sequence homology with EGF rather than TGF-β, competes with EGF for binding sites, and shares many biological activities of EGF owing in part to its affinity and signaling through the same receptor, EGFR.


TGF-α is readily expressed in the GI tract in fetal and adult stages and found as early as 10 weeks into gestation in humans that persists throughout life. Animal studies also suggest that GI expression of TGF-α may decrease with age. Expression is detectable in most epithelial cells of the GI tract at low levels including stomach, esophagus, small, and large intestines. In the stomach, levels are highest in parietal cells. In the esophagus and intestine, it is predominantly found in differentiated epithelial cell populations. In a similar manner to EGF and other growth factors, TGF-α is proteolytically cleaved from its membrane-bound proprotein by ADAM metalloprotease sheddases into the active form.


At first glance, substantial redundancy between TGF-α and EGF might be expected, and indeed in a number of tissues, the mature TGF-α plays similar roles to EGF in terms of cellular proliferation and differentiation. However, these molecules display clear differences in regulation of expression, localization/compartmentalization, EGFR binding, and biochemical effects on the receptor. For instance, EGF is secreted from distinct sites of the GI tract, whereas TGF-α is more broadly expressed, thus segregating the effects of these two growth factors based on location. TGF-α tends to be available primarily basolaterally, whereas the major portion of EGF seems to be apical. Furthermore, TGF-α and EGF bind EGFR with different kinetics ; this contributes to different profiles of downstream effector binding as well as different endocytic trafficking of ligand- receptor complexes leading to either EGFR recycling or destruction.


In vivo studies have shown that active TGF-α has trophic effects on the GI epithelium and stimulates epithelial growth, enhanced restitution, and cellular proliferation. It is important to note that TGF-α is sorted largely to the basolateral compartment. As its receptor, EGFR is also basolaterally located, it has been suggested that in contrast to EGF juxtacrine or paracrine TGF-α activity may be important for homeostatic regulation of the GI tract. Highlighting this difference in compartmentalization, TGF-α administered enterally shows no significant effects on proliferation, demonstrating a lack of functional redundancy between EGF and TGF-α in this tissue. Alternatively, TGF-α administered parenterally results in stimulation of GI growth and cell proliferation. Furthermore, TGF-α overexpressing mice show hyperplastic gastric mucosa. Knockout mice for this ligand or animals transgenically overexpressing it display increased susceptibility to, or protection from, DSS colitis, respectively. Thus, TGF-α is clearly an essential part of the injury response in the intestine.


As with EGF, TGF-α also plays a role in hepatocyte growth and liver regeneration. In the partial hepatectomy model, TGF-α is induced in liver and circulation and correlates with increased DNA synthesis in the regenerating liver. Interestingly, TGF-α is not required for regeneration as mice deficient in this ligand are still able to exhibit hepatocyte proliferation. This suggests EGF or other EGFR-signaling molecules compensate and restore liver mass in these settings. It is interesting to note, however, that TGF-α overexpressing animals have increased liver mass and elevated DNA synthesis and hepatocyte proliferation, demonstrating the significant effect of TGF-α on liver growth.


TGF-α also has a variety of nonmitogenic roles in the GI tract. Like EGF, it limits gastric acid secretion, but is also rendered less active by gastric acid in the stomach demonstrating a regulatory loop in its activity. TGF-α has also been shown to modulate ion and nutrient transport, stimulate mucin secretion, and mesenteric and mucosal blood flow and promote smooth muscle contraction. Together, these roles appear to promote tissue maintenance and repair following GI injury.


Not surprisingly in light of how TGF-α was discovered, this ligand is deregulated in many GI cancers, including esophagus, stomach, and colon. Several lines of evidence suggest the overexpression of TGF-α is associated with severity of tumorigenicity. For instance, TGF-α expression positively correlates with tumor severity and is expressed in serum in the case of GI tumors, including gastric, pancreatic, and colon. Furthermore, activation of the TGF-α receptor, EGFR, is increased in GI cancer opening the field for therapeutic intervention using several FDA-approved EGFR inhibitors that could act in part by limiting the action of TGF-α (gefitinib, erlotinib, cetuximab, panitumumab, and lapitinib). Efforts to identify patients who would be most responsive to specific treatments or chemotherapeutic agents are still underway.


3.2.4


Neuregulin (NRG)


NRG growth factors (also known as heregulins, HRG) are a subclass of EGF-like molecules that were initially identified in the 1990s in screens for ErbB3 and ErbB4 ligands. Since this time, the study of NRGs has expanded dramatically, and roles for this family of growth factors have been identified in cardiac development, neuronal function, metabolism, epithelial cell development and survival, and immune cell activation. The NRGs harbor mitogenic roles including growth, differentiation, and survival of epithelial, glial, and muscle cells in vitro.


Mammals harbor four neuregulin genes (NRG1-4). NRG transcripts are readily detected in the liver, stomach, small intestine, and colon. Substantial splice variation as well as multiple transcriptional start sites per gene allow for production of a wide array of distinct molecules, including for example up to 15 different NRG1 peptides and 4 or more NRG4s. The functional significance of the different variants of each gene product have, for the most part, not yet been explored. The most widely studied ligand, NRG1β (a.k.a. HRG1β), is expressed throughout the GI tract including esophagus, stomach, intestine, and colon. Aside from a few recent papers on NRG4, most of what is known about neuregulins in the gut is based on work with NRG1β. It should also be noted that the majority of functional studies, especially in cell culture or administration to animals, have used soluble extracellular domain peptides (i.e., the “business end” of the molecule). Thus, many of these findings will be cross-applicable not only to a number of different isoforms but also leave out entirely the impact of regulatory effects on cleavage/secretion or potential juxtacrine signaling from tethered ligand.


The majority of NRGs are synthesized as preproteins inserted in the plasma membrane, thus requiring proteolytic cleavage by ADAM sheddases. Notable exceptions include the B-type variants of NRG4, which are missing the transmembrane domain and appear to be expressed in the cytoplasm, with as-yet unknown function. Since the 1990s, experimental evidence has uncovered the affinity of the shed ligands for each of their various ErbB receptors. NRG1 and NRG2 bind and activate both ErbB3 and ErbB4 (with some splice variant-driven specificity between α and β variants preferring ErbB3 and ErbB4, respectively), while NRG3 and NRG4 exclusively bind ErbB4, at least in cell culture experiments.


Functionally, NRGs and their receptors in the intestine have been shown to have roles in cytoprotection, regulation of chloride secretion, development of the enteric nervous system, and epithelial secretory cell differentiation. NRG4, in particular, has antiapoptotic effects on the intestinal epithelium ; on the other hand, it can elicit cellular death responses in other cell types such as inflammatory macrophages. The ability to kill inflammatory macrophages while protecting the intestinal epithelium from cytokine-induced apoptosis is the likely explanation for the protective effects of NRG4 in colitis models. Additionally, ErbB4 (the NRG4 receptor) has been associated with hypoxia signaling and can stabilize hypoxia-induced factor-1α, which tends to be protective in the gut. ErbB4 stabilization of hypoxia-induced factor-1α was associated with altered regulation of cellular metabolism, which together with studies showing NRG4 has a protective effect versus obesity-associated inflammation suggests a likely role for NRGs in the link between hypoxia and metabolism, which may be very important in the gut.


Dysregulation of NRG signaling has been linked to GI disease development. Whole-exome sequencing revealed that NRG1 is frequently mutated in IBD-associated colorectal cancer. Polymorphisms or deletions of this gene as well as of NRG3 are associated with Hirschsprung’s disease. NRG1 and 2 are both decreased in KRAS-mutant colon cancers. NRG1 and NRG4 expressions are suppressed in total parenteral nutrition-associated intestinal inflammation (where excessive intestinal epithelial apoptosis is observed), but can be rescued by EGF administration. NRG4 expression is decreased in human inflammatory bowel disease and rodent models of colitis. Interestingly, restoration of NRG4 ameliorates disease parameters in several animal models of colitis, suggesting harnessing neuregulin signaling may be a beneficial therapeutic target in the GI tract.


3.2.5


Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF)


Heparin-binding epidermal growth factor-like (HB-EGF) growth factor was initially identified as a mitogenic factor present in the conditioned media of a tumor macrophage cell line. Its expression is induced by TNF and oxidative stress, among other proliferative stimuli. Like other EGF-related peptides, HB-EGF is synthesized as a transmembrane protein and proteolytically cleaved by ADAM sheddases to generate its mature, active soluble form. The dominant activities of HB-EGF are stimulating cell proliferation, survival, and cell motility. HB-EGF binds EGFR and ErbB4 to induce phosphorylation. Limited evidence exists supporting different functions of HB-EGF between these two receptors. For example, in cells expressing ErbB4 but not EGFR, the effect of this ligand is chemotactic as opposed to proliferative.


HB-EGF has been identified in gastric parietal cells, but its intrinsic expression elsewhere in the GI tract under homeostatic conditions is low. Exogenous sources of HB-EGF include recruited macrophages and breast milk. In the intestine, HB-EGF is rapidly induced in response to acute injury, where it has been shown to protect against hypoxic injury and may play a role in wound healing. In intestinal, kidney, and liver epithelial cells, enforced expression of or treatment with HB-EGF prevents cell death in response to apoptotic stimuli (such as TNF), demonstrating its role as an epithelial survival factor. These findings suggest growth factor signaling elicited by a recruited cell type or source (i.e., macrophages, breast milk) may be an important role in the protection of GI epithelium following damage. In this regard, HB-EGF has been studied fairly extensively for activity against NEC. Exogenous HB-EGF treatment is effective in preventing incidence and severity of formula feed/hypoxia-induced NEC in rat pups, as is overexpression in transgenic mice ; conversely, knockout animals were more susceptible to experimental NEC. Protection with HB-EGF is accompanied by improved barrier function, reduced epithelial apoptosis, and a reduction in damage to intestinal microcirculation. Interestingly, HB-EGF also altered the balance of macrophage polarization in the gut to a more repair-directed (so-called “M2” population) phenotype in this model, suggesting that similar to NRG4 and EGF, HB-EGF has important effects on the innate immune cells during inflammation, though each ligand seems to have a very different mechanism of action in these cells.


3.2.6


Other EGF-Like Growth Factors: Amphiregulin, Betacellulin, Epiregulin, Epigen


Amphiregulin (AR) was first described in 1988, and is named for its ability to stimulate or inhibit cell growth depending on the cell type under study. AR is expressed in the GI tract in normal and neoplastic cells and binds exclusively to EGFR. At baseline, it is expressed at low levels, primarily in the small intestinal epithelium and surface epithelium of the colon. Levels in both the epithelium and the mesenchyme increase in inflammatory bowel disease and colon cancers. Studies have shown AR stimulates epithelial cell growth and may promote tumorigenesis via an autocrine loop ; it may also be packaged in exosomes and stimulate tumor growth through this mechanism. In vivo studies of AR-null mice show no obvious baseline defects in the GI tract without additional challenge, supporting a normal physiological role primarily involving response to injury or inflammation rather than homeostatic turnover.


Similar to amphiregulin, epiregulin (EPR) can have either stimulatory or inhibitory effects on the growth of cells depending on context. This ligand, first described in 1995, is produced both by stromal fibroblasts and epithelial cells, and like AR is induced by challenge. EPR appears to be important for repair, as deletion results in increased susceptibility to DSS-induced colitis. However, EPR knockouts show no overt developmental defects, suggesting this ligand is also more important in response to injury than homeostasis. It is dispensable for intestinal tumorigenesis, but can contribute to tumor growth and to expansion of Lgr5 + stem cells during regeneration and carcinogenesis.


Betacellulin (BTC) was first identified in 1993 from a mouse insulinoma cell line and appears to be expressed in pancreas and throughout the epithelium of the small intestine and colon. It is also a component of expressed milk, at least in cows. Relative to EGF, it signals through distinct patterns of EGFR phosphorylation suggesting distinct signaling outcomes. In fact, a recent analysis clustering EGFR ligands based on recruitment (and timing) of downstream effectors grouped EGF, amphiregulin, and EPR together, with BTC, TGFα, and epigen forming a second cluster and HB-EGF standing unique. Furthermore, like HB-EGF BTC can bind ErbB4 as well as EGFR, adding additional complexity to its potential function. BTC stimulates crypt cell proliferation and increases intestinal size, dependent on EGFR signaling, in mice, and may have antiapoptotic effects on intestinal epithelial cells. Furthermore, in a transgenic overexpression system, BTC promoted tumor development (multiplicity) in Apc min mice. The explicit role for this ligand in normal physiology or whether it is required for intestinal tumorigenesis remains unclear.


The intestinal function for epigen, the most recently identified ligand in this group has not to date been reported. EPGN expression in the small bowel and colon is supported by online datasets in the Gene Expression Omnibus ( https://www-ncbi-nlm-nih-gov.easyaccess2.lib.cuhk.edu.hk/geo/ ). Thus, it likely has as-yet-undescribed roles in intestinal physiology.


All or nearly all of the ligands that bind ErbB family receptor tyrosine kinases are represented in the GI tract. While there appears to be substantial overlap in the function of these ligands, detailed analyses have demonstrated both shared and distinct roles in GI physiology. In-depth studies focused on understanding the individual regulation, biochemistry, and function of these ligands have the potential to uncover new approaches to leveraging signaling driven by these ligands for clinical use in GI disorders.




3.3


Transforming Growth Factor-Beta (TGF-β) Family


3.3.1


Introduction


As previously mentioned, TGFβ was initially isolated during a screen in the early 1980s for factors that transform normal cells. It was known at the time that malignant cells grew without requirement for the same level of exogenous growth factors as normal cells, and thus uncovering what endogenous growth factors maintained their growth (potentially through an autocrine loop) was of high interest. Treatment of normal fibroblastic cells suspended in soft agar with conditioned media from transformed mouse fibroblasts stimulated growth of these colonies, and extensive work went into characterizing factors in the transformed cell media. These early screens (which also identified TGF-α) implicated TGF-β as a secreted cell-transforming factor. TGF-β has since evolved into the prototype molecule of a new superfamily with pleotropic effects, including tumor suppression . Other members of the TGF-β superfamily now include bone morphogenic proteins (BMPs), activins and inhibins, nodal, and others. Early studies showing high TGF-β concentration within mitochondria of liver and cardiac muscle suggested that it may directly regulate cell metabolism to control mitogenesis. Significant early work in the 1990s revealed a role of TGF-β signaling in many areas of GI development and homeostasis.


TGF β-related peptides are synthesized as precursor propeptides and processed to release biologically active protein. Canonical signaling occurs through heterodimeric receptors, each of which is made up of a type I and a type II TGF-β receptor (TβR) peptides ( Fig. 3.4 ). TGF-β binding to TβRII allows stabilization of a complex with TβRI and phosphorylation of TβRI by TβRII. TβRI subsequently phosphorylates SMAD (mammalian homologs of Drosophila mothers against decapentaplegic and Caenorhabditis elegans SMA) proteins (most notably SMAD2 and 3), which then form multiple SMAD complexes, accumulate in the nucleus, and regulate transcription.




Fig. 3.4


TGF-β signaling. TGF-β binds to TGFβR complex and initiates Smad protein activation to mediate the downstream signaling effects within the cell.


3.3.2


Transforming Growth Factor-Beta (TGF-β)


Three genes expressing canonical TGF-β isoforms have been described, named TGF-β1-3. In the gut, TGF-β expression has been well characterized in the small and large intestine within the lamina propria and epithelial cells. Although other members are present, TGF-β1 is the most broadly studied ligand in the GI tract to date. It should be noted that while the studies forming the basis of much of our mechanistic understanding have not yet fully explored the differences between TGF-β1, 2, and 3, there is evidence (like with ErbB ligands) for variation in affinity, timing, and so on, that likely drives biological diversity. These ligands, much like the EGF-like peptides, likely have overlapping but not identical GI functions within the superfamily. Additional detailed studies are needed to understand the functional differences between these molecules.


The receptors for TGF-β superfamily ligands have been shown to work in a coordinated manner, essentially in heterodimers of two classes of peptides. Ligand binding to TβRI results in activation of TβRII, leading to intracellular SMAD signaling, although SMAD-independent signaling as a result of TGF-β has also been shown. Receptor expression in the GI tract largely mirrors that of the ligands, with some variance in studies, largely supporting the thought that TGF-β acts along an autocrine or paracrine feedback loop.


A number of studies have demonstrated that signaling through TGF-β in the GI epithelium results in inhibition of cell growth through SMAD, whereas p38 signaling can elicit apoptosis and epithelial-to-mesenchymal transition. Growth inhibition by TGF-β involves cell cycle arrest in G1 phase and prevention of S-phase entry. Furthermore, in the GI tract, TGF-β can induce epithelial cell apoptosis and has been shown to function as a tumor suppressor. At first glance, this may seem at odds with the ligand’s original identification as a growth factor for transformed cells. In this regard, it is important to note that different studies support the role of TGF-β as either a tumor suppressor or a tumor promoter depending on context in the GI tract. In some cases, increased expression is seen as a marker of colorectal cancer severity and recurrence, and multiple colon carcinoma lines exhibit growth in response to stimulation with TGF-β. These altered outcomes are likely dependent on the specific genetic and microenvironment detail of a given tumor. TGF-β/SMAD signaling can also play important roles in regulation of the intestinal stem cell niche.


Under pathophysiological conditions, TGF-β stimulates wound healing at concentrations lower than required for growth arrest, and expression is upregulated in wound healing. Expression is increased by acute epithelial injury in the GI mucosa in patients with active inflammatory bowel diseases, suggesting this is a compensatory response to resolve disease. However, in contrast and making this observation more complex, impaired TGF-β signaling has been observed in some active IBD patients. In vivo studies show that the loss of TGF-β signaling renders mice more susceptible to chemically induced colitis.


Our understanding of the function of TGF-β has been greatly advanced through the use of genetic inactivation mouse models. TGF-β1 knockout mice that do not die in embryonic stages display aggressive inflammatory cell infiltration in the stomach and intestine, and tissue necrosis, which was an early indicator that TGF-β played important roles in tissue maintenance and had novel actions on inflammatory cells and immune homeostasis. These mice typically die by 20 days of age. Interestingly, this inflammation was not prevented by housing in germ-free environments, suggesting the microbiota is not precipitating this immune response. TGF-β2 and TGF-β3 knockout mice do not have obvious abnormalities in GI development, reinforcing the notion that TGF-β1 is the primary driver of GI outcomes.


The profound impact of TGF-β isoform knockout on inflammation is likely directly due to its expression and role within cells of the immune system. Macrophages, T-cells, and B-cells all express TGF-β, which can regulate pro- and antiinflammatory functions of these cells. The elevated inflammation in TGF-β1 KO mice points to an antiinflammatory role for TGF-β in the stomach and intestine. This is in line with the finding that TGF-β has an inhibitory effect on T-cell inflammatory activities. However, in vitro, TGF-β stimulates neutrophil chemotaxis, and is known to have both stimulatory and inhibitory effects on B-cell IgA production depending on context. In human intestinal mast cells, TGF-β tightly inhibits and regulates their function. Together, these findings demonstrate that, in addition to regulating epithelial cell behavior, TGF-β family ligands exert effects on multiple recruited immune cell types.


3.3.3


Other TGF-β Family Ligands


Bone morphogenetic protein (BMP) was discovered in 1965 as a bone remodeling factor. The family of TGF-β-related BMPs is extensive, including 6 of the originally identified BMPs (BMP2-7 but not BMP1, which is a metalloproteinase) as well as a number of more recently identified peptides totaling more than 15 family members. These growth factors can act through the same SMAD-dependent mechanism as canonical TGF-β signaling, and have proven to be essential for development of the GI tract during embryogenesis. BMP signaling is activated in all levels of gut patterning at the mesoderm, ectoderm, and endoderm layers of the developing chick embryo and in murine gut development. Temporally regulated BMP signaling is necessary for gastric patterning. Furthermore, this family is implicated in the regulation of intestinal stem cell self-renewal, as demonstrated by (among other results) expansion of the stem cell niche in conditional Bmpr1a null mice and the requirement for the BMP inhibitor Noggin in maintenance of Lgr5 + cell-dependent enteroid cultures. Thus, this signaling pathway is likely important in repair mechanisms of the GI tract. BMP7 administration ameliorated experimental colitis in rats, although in contrast BMP inhibitors have been shown to improve inflammation and colitis-associated anemia in mice. Dysregulated BMP activity has also been associated with development of Barretťs esophagus and eosinophilic esophagitis. BMPs can inhibit colon cancer cell growth or induce apoptosis in vitro, and loss of BMPs has been reported coincident with adenoma-cancer transition in colorectal cancer patients. On the other hand, at least some evidence also suggests a gain of function role in promoting tumor progression. The mechanisms driving these seemingly contradictory responses (balance of different BMP ligands, receptor expression, permissive microenvironment, etc.) require more investigation, but like other growth factors, the response and involvement of BMPs in intestinal disease are likely complex and context dependent.


Activins and inhibins are closely related ligands, generated by joining (through disulfide bonds) different subunits in five different combinations (Activin A, Activin B, Activin AB, Inhibin A, and Inhibin B). They are expressed in a variety of different patterns in either the mesenchyme or epithelium throughout the GI tract. They exert opposing effects on mitogenesis and other cellular functions, despite sharing similar signaling through the SMAD pathway. Furthermore, individual activins/inhibins have region-specific effects; for example, Activin A inhibits growth of gastric epithelium while stimulating colonic epithelial growth. Some evidence suggests that activins are regulated in IBD with expression of, for example, the βA subunit correlating with degree of inflammation in patients and mouse models. There is also some evidence linking altered Activin A expression to colon cancer, though like many TGF-β superfamily ligands the question of whether it is a promoter or inhibitor or tumor growth is likely context dependent. Since activins and inhibins regulate the immune system as well as the epithelium, further study will be required to understand where they exert their key effects during GI homeostasis and disease.




3.4


Insulin-Like Growth Factor Family


3.4.1


Introduction


The IGF ligands, including IGF-1 and IGF-2, were initially identified in 1957 as factors that increased sulfanation into rat cartilage, though not as the names they are known by today. Later studies in the 1970s independently identified them as molecules present in human serum and with a similar structure to proinsulin. Subsequent work revealed that IGFs have a substantial impact on cell metabolism growth and cell survival in the digestive system.


3.4.2


Insulin-Like Growth Factor (IGF)


Unlike insulin, IGFs are not produced and stored exclusively in the β cells of the pancreas, but are synthesized and secreted by a number of cells in the body in a regulated manner. IGF-1 is produced in adults by the mesenchyme of the intestine, and potentially other regions, and is known to stimulate intestinal epithelial cell proliferation. Both IGF-1 and IGF-2 are secreted in the breast milk as another route of reaching the GI tract. IGF-2 is commonly considered the embryonic form of IGF, with substantially higher expression during development, and is associated in adults with pathologic states such as cancer.


Largely these factors exert their effects on the GI tract by stimulating epithelial cell proliferation and inhibiting apoptosis. They act through endocrine, paracrine, and autocrine routes, binding and activating the IGFR-1 and IGFR-2 receptor tyrosine kinases ( Fig. 3.5 ). IGF-1 binds with high affinity to IGFR-1 and significantly lower affinity to IGFR-2. IGF-2 binds both IGFR-1 and IGFR-2 with high affinity. The majority of GI effects of IGFs are mediated by IGFR-1. Ligation of an IGFR leads to autophosphorylation of the receptor and activation of intracellular pathways, including insulin receptor substrate-1 (IRS-1). IRS-1 subsequently activates a variety of pathways, especially Ras and PI3K. Additionally, IGFR-1 can stimulate the heterotrimeric G-protein, Gi2, which alters signaling through ERK1/2 MAPK.




Fig. 3.5


IGF signaling. IGF is released from cells of the GI tract and liver and binds to IGFR. IGF-I and IGF-II activities in the gastrointestinal tract are predominantly mediated by IGF-IR. IGF-IR signaling stimulates PI3K/Akt activity and the Ras/RAF MAPK signaling cascades leading to effects on cellular growth and proliferation.


Regulation of IGF signaling is accomplished through several mechanisms. IGF-binding proteins (IGFBP) 1-6 can either promote or inhibit IGF function depending on cellular and environmental context, and also serve as transport proteins for IGFs throughout the body. Furthermore, in the intestine, IGFBPs are expressed in the lamina propria, implying a role in epithelial-mesenchymal interactions. An additional means of control is through compartmentalization of receptors in the GI epithelium. Similar to EGFR, IGFRs are primarily localized on the basolateral compartment of these cells, in vivo and in vitro.


The understanding of IGFs as significant regulators of cellular growth has in large part advanced through the use of in vivo models. In both IGFR-1 and IGF-1-deficient mice, animals are born significantly smaller than controls, grow poorly, and fail to thrive into adulthood. Secondary control of IGF signaling in the GI tract is highlighted by the finding that mice overexpressing IGF-1 exhibit normal GI epithelium and lamina propria, though smooth muscle throughout the body is hyperplastic and hypertrophic. On the other hand, rats receiving continuous administration of IGF-1 have significant growth of all GI organs and increased crypt and villus cell numbers. Mice heterozygous for IGF-1 have normal GI development, but fibrosis in the TNBS model of colitis was attenuated in this line. Oral delivery of porcine IGF-1-expressing Lactococcus lactis also attenuated DSS colitis in mice, suggesting potentially variable effects depending on localization of the ligand.


Evidence for proliferative and antiapoptotic effects of IGF-1 on the GI tract has been provided by studies in multiple experimental models. Oral feeding of IGF-1 to neonatal pigs increases small intestinal weight and small intestinal villus height. In mice that overexpress IGF-1 under control of the metallothionein-I promoter, small intestinal apoptosis was reduced both at baseline and in response to irradiation. Furthermore, these mice had greater small intestinal length and weight and increased villus height and crypt depth. Interestingly, endogenous growth hormone and IGF-1 gene expression were suppressed in these animals, suggesting the presence of a sensitive negative feedback loop. A wealth of other studies have been performed, reinforcing these findings (e.g., see Refs. ).


The role of IGF signaling has also been studied extensively in the context of disease. IGF-1 augments adaptive mucosal proliferation in rats that have undergone partial small intestinal resection and improves intestinal transplant outcomes in a rat model. The mucosal atrophy observed in the jejunum of parenterally fed rats is blunted by including IGF-1 in the formula, while IGF inhibitor attenuates intestinal adaptation following small bowel resection in zebrafish. Similarly, the small intestinal atrophy that occurs in chronic liver disease or sepsis is reduced by IGF-1. In cancer, a role for IGF was postulated due to observation that acromegaly, a disorder of dysregulated IGF and GH signaling, presented at elevated rates with colon cancer. Indeed, studies showed IGF-1, IGF-2, and IGF-1R to be increased in colorectal cancer. Findings suggest that they may be involved in the transformation of normal colon cells, and are implicated in chemotherapeutic drug resistance development. Serum levels of free IGF-1 are decreased while serum IGFBP3 is increased in type 1 diabetes, potentially contributing to intestinal inflammation and dysfunction in diabetic patients. In Crohn’s disease, IGF has also been implicated in the generation of fibrotic tissue, and reduced levels of IGF may contribute to growth failure observed with this disease. In line with this finding, some studies show decreased IGF-1 expression in IBD. These reports all provide evidence that proper IGF signaling is required for health, and dysregulation of this growth factor can contribute to disease.




3.5


Hepatocyte Growth Factor (HGF)


3.5.1


Introduction


Since its identification in the 1980s as factor driving hepatocyte proliferation/liver regeneration, HGF expression has been described throughout the body. It has many functional roles in human physiology, including significant roles in the development and repair of the fetal and adult digestive system. It signals with its cosignaling amplifier, HGF activator (HGFA), and through its receptor, the c-Met receptor tyrosine kinase, to elicit cell proliferation, motility, and differentiation ( Fig. 3.6 ). HGF signaling is also an important component of mucosal repair. Dysregulated HGF activity has been shown to be a feature of a number of diseases, including GI cancer.




Fig. 3.6


HGF signaling. HGF is predominantly sourced through mesenchymal tissue as a proprotein (proHGF). Mucosal injury stimulates release of thrombin and IL-1β that promote HGFA activity. HGFA converts pro-HGF to active HGF, which binds to the c-Met receptor, often in the context of amplifying coreceptors such as CD44, and promotes wound repair in GI epithelial cells and angiogenesis in vascular endothelial cells.


3.5.2


Hepatocyte Growth Factor (HGF)


In the GI tract, HGF is predominantly synthesized by mesenchymal tissue as a proprotein (proHGF). Plasma-derived HGF secreted from the liver is also a source of this ligand in the adult gut, and milk-derived HGF is a source for the fetal GI tract. The precise regulation and control of HGF signaling are maintained in large part through activity of its cosignaling regulator, HGFA, a serine protease that converts proHGF to active ligand. Like HGF, HGFA is produced and secreted from the liver; it is also expressed at high levels in the GI tract in epithelial compartments that also express the HGF receptor, c-Met. Additionally, c-Met is primarily expressed basolaterally, which would place it in close association with its mesenchymally sourced ligand. A further control on HGF signaling is the expression of HGFA inhibitors types 1 and 2 (HAI-1 and HAI-2) and the expression of c-Met coreceptors such as CD44. The pattern of HGFA and HAI expression represents a mechanism of tight regulation on the activity of a widely produced ligand. Upon binding HGF, c-Met induces its cellular effects through multiple pathways, including JAK-STAT, Ras-MAPK, PI3K, and NF-κB.


HGF expression is induced by EGF, whereas TGF-β downregulates it. Its receptor, c-Met, is regulated by various factors including HGF itself, EGF, IL-1, IL-6, TNF, and several steroid hormones. The result of HGF signaling is increased growth of intestinal epithelial cells and enhanced wound healing/mucosal repair. HGF is also required for proper organ development, as it supports the generation of the enteric nervous system and the liver.


HGF signaling is a classic example of epithelial-mesenchymal communication and paracrine signaling of a growth factor in the GI tract. In the developing gut, it is a potent stimulator of growth in epithelial subpopulations. Furthermore, subepithelial intestinal fibroblasts potently stimulate the proliferation of epithelial cells via HGF release. The expression of the HGF coreceptor CD44 facilitates cell proliferation by direct activation of MEK/Erk signaling. Notably, in the stomach, CD44 is also required for epithelial progenitor proliferation. During development, HGF and c-Met are expressed by 6 weeks throughout the GI tract, and HGF-null mice are embryonic lethal. Conversely, mice overexpressing HGF develop tumors and other developmental abnormalities. In mice that specifically overexpress HGF in the GI tract, ulcerative proctitis, rectal prolapse, and intestinal pseudo-obstruction are observed.


In response to tissue injury, HGF and c-Met expressions are dramatically induced, and HAI-1 and CD44 are elevated in the regenerating epithelium. Induction is also evident in intestinal inflammatory diseases, though this is likely a protective response to injury as administering exogenous ligand ameliorates animal IBD models. Splice variant-specific isoforms of CD44 likely mediate some of these responses including epithelial regeneration. In response to epithelial injury, inflammatory cytokines like IL-1β appear to promote the release of HGFA/HAI-1 complexes from the cell surface, suggesting that HAI-1 may function as a reservoir of active HGFA in regions of epithelial repair, thus providing efficient localization to sites of mucosal injury. Interestingly, this repair appears to be dependent upon TGFβ signaling and may be involved in regulating the tight junctions between epithelial cells by altering the stability of E-cadherin and decreasing protein expression of E- and P-cadherins.


HGF signaling has been implicated in tumorigenesis and a wide range of tumor functions including cell motility, proliferation, invasion, progression, and neovascularization. HGF and c-Met are highly overexpressed in esophageal, stomach, colon, and rectal tumors. Furthermore, in some instances, c-Met activation can also be coopted and activated through interaction with other molecules such as the bacterially derived product cagA. The coreceptor CD44 has also been implicated in the development of gastric cancer. As HGF/c-Met signaling is increased on a variety of cancers and directly implicated in regulating cellular proliferation, a dysregulated feature of tumor cells, HGF signaling represents a promising target of oncogenic therapy.




3.6


Fibroblast Growth Factors


3.6.1


Introduction


FGF family is another growth factor family known to play an important role in the development, homeostasis, and injury/repair of the GI tract. It represents a family of 22 structurally similar peptides, divided into three groups based on their mode of action: canonical FGFs, intracellular FGFs, and endocrine or hormone-like FGFs. Each FGF ligand binds to one or more of the four described FGF receptors with tyrosine kinase activity: FGFR1, FGFR2, FGFR3, and FGFR4. Two splice variants (IIIb and IIIc forms) of FGFR1, FGFR2, and FGFR3 determine the specificity of their ligands. FGFR4, on the other hand, has no known splice variants.


3.6.2


Endocrine FGFs


Endocrine FGFs consist of 3 FGFs: FGF21, FGF23, and FGF15/19 (FGF15 is the mouse ortholog of human FGF19). Endocrine FGFs have very low affinity for FGFRs. Thus, the dimerization of FGFRs to klotho receptors (α and β) is necessary for the stabilization of ligand binding. FGF15 is the main endocrine FGF produced by the enterocytes, and is released in response to bile acid absorption in the ileum. Signaling of FGF15 to FGFR4 and β-klotho controls bile acid secretion and absorption; mice lacking FGF15, FGFR4, or β-klotho manifest increased synthesis of bile acids. On the other hand, FGF21 signaling is mainly active during the neonatal period, as FGF21 is present in breast milk and signals to abundant β-klotho in the lumen of the intestine. This interaction results in the secretion of digestive enzymes and intestinal hormones allowing for better lactose digestion and absorption. Lastly, FGF23, which mainly binds to FGFR1 and the coreceptor α-klotho, regulates phosphate absorption in the intestine through an unknown mechanism. Thus, endocrine FGF signaling in the intestine is necessary to maintain adequate digestive, absorptive, and endocrine functions ( Fig. 3.7 ).




Fig. 3.7


FGF signaling. FGFs are sourced from various epithelial and subepithelial cell types in the GI tract. FGFR1-4 are all expressed in GI tissue. Released FGFs bind dimerized FGFR and induce (1) PI3K signaling, (2) MAPK signaling, and (3) phospholipase C (PLC)-mediated calcium release, to regulate cell proliferation, differentiation, migration, and survival.


3.6.3


Canonical FGFs


Canonical FGFs are the most extensively studied FGFs in the intestine. Several are present in the mouse intestine including FGF1, FGF2, FGF7, FGF9, and FGF10, whereas FGF3, FGF20, and FGF22 are absent. All four FGFRs are present in the intestine. FGFR1 and FGFR2 are expressed throughout the mucosa, while FGFR3 expression is confined to the lower half of the crypts, and FGFR4 is only expressed in the epithelium of the embryonic gut.


FGF1, also known as acidic FGF, is present in intestinal enterochromaffin cells and the myenteric plexus of the enteric nervous system in the colon. FGF1 administered in vivo prior to radiation injury increases crypt number, epithelial cell proliferation in the intestine, and crypt survival. In contrast, treatment with FGF1 after radiation injury did not have any rescue effect on the intestine. However, FGF1 displays a protective and antiapoptotic effect in response to dexamethasone-induced apoptosis in mouse intestine. A mutant form of FGF1, lacking its mitogenic activity, enhanced this antiapoptotic and protective effect, through maintaining ERK1/2 activation. FGF1 binds to all FGFRs, and could mediate its activity in the intestine through any of these receptors. However, given the special localization of FGFR3 isoform IIIb, predominantly present in the crypts of the small intestine and the colon, it is likely that FGF1 also plays an important role in the regulation of intestinal crypt and the fate determination of epithelial stem cells. Further studies are needed to investigate these possibilities. Similar to FGF1, FGF2 (also known as basic fibroblast growth factor) promotes intestinal growth and intestinal epithelial cell proliferation and differentiation. It is present in the mesenchyme of the intestine, but can also be secreted by regulatory T cells; it binds to FGFR1. FGF1 and FGF2 promote intestinal epithelial restitution by regulating TGF-β signaling. Furthermore, FGF2 is commonly used for the maintenance of stem cell pluripotency in vitro. Following radiation injury, FGF2 enhances the survival of intestinal stem cells in the crypt. Deletion of Fgf2 in mice protects the intestinal barrier from DSS-induced damage and cell death. FGF1 and FGF2 are both protective against ischemia reperfusion injury in rats via the regulation of P53 and ERK/P38 MAPK respectively. They also reduce intestinal inflammation in colitis as well as in ischemia/reperfusion injuries.


FGF4 is required in early development for hindgut specification. It acts in synergy with Wnt3a to induce the differentiation of pluripotent stem cells to ultimately give rise to the epithelial and mesenchymal intestinal cell types except for the enteric nervous system. Following radiation injury, it acts like FGF1 and FGF2, by promoting crypt cell survival and preventing apoptosis.


Administration of exogenous FGF7 (also known as keratinocyte growth factor, KGF) increases villus height, crypt depth, cell proliferation, and goblet cell differentiation in adult rat intestine. This increase in goblet cell differentiation is due to the regulation of intestinal trefoil factor/TFF3 by the goblet cell specific transcription factor GCSI-binding protein. In a disease context, FGF7 is secreted by fibroblasts or intraepithelial lymphocytes and acts on the epithelium by binding to FGFR1. Several studies have shown protective effects for FGF7 in colitis. In rat and mouse models of experimental colitis, administration of FGF7 prior to (but not after) the induction of colitis resulted in decreased ulcerations and cell death in the intestine. Moereover, FGF7 null mice present more severe damage in response to DSS as compared to wild-type animals. FGF7 also plays an important role in other intestinal diseases including short bowel syndrome and ischemia/reperfusion. Expression of both FGF7 and its receptor FGFR1 is significantly increased following massive short bowel resection in mice. FGF7 administration to rats that underwent small bowel resection results in increased crypt depth, villus height, and goblet cell differentiation. FGF7 also reduces cell death and dysregulation of tight junctions in ischemia reperfusion injury by upregulating IL-7, which in turn controls intraepithelial lymphocytes. This effect of FGF7 on IL-7 upregulation is abrogated by blocking FGFR2, thus suggesting that FGF7 signals via FGFR2 to induce upregulation of IL-7. In addition, FGF7 enhances epithelial healing in colonic anastomoses, where it increases cell proliferation and reduces inflammation. A truncated form of recombinant FGF7, called Palifermin or Kepivance, is currently clinically in use for the treatment of oral mucositis. However, despite the proven protective role of FGF7 in animal models of colitis, the administration of a growth factor with mitogen activity to treat patients with IBD is still under debate, as the risk of developing cancer raises questions regarding the long-term benefit of the drug.


FGF10 is another member of the family that appears to be important in intestinal development and disease. During development, lack of FGF10 results in duodenal, cecal, and colonic atresia, as well as anorectal malformations. This ligand is mostly present in the duodenum, cecum, and colon in mice. We recently demonstrated that it is present in the human ileum, and that overexpression of FGF10 in adult mice results in increased villus height, crypt depth, crypt cell proliferation, and goblet cell differentiation, and decreased Paneth cell numbers in the small intestine. Furthermore, in an in vitro model of mouse intestinal enteroids, exogenous FGF10 treatment resulted in the decrease of several stem cell markers (Lgr5, Lrig1, Hopx, Ascl2, and Sox9) and an increase in the intermediate secretory progenitor cells coexpressing Mmp7 and Muc2. Thus, FGF10 signaling plays an important role in intestinal development, lineage specification, and homeostasis. Additionally, FGF10 is a key growth factor in several intestinal diseases, such as IBD and short bowel syndrome. FGF10 expression is induced in the intestinal crypts following acute small bowel resection in mice, suggesting a role in the adaptation/repair process. It reduces disease severity, cell death, weight loss, and inflammatory cytokine secretion (IL-6, TNF, and IL-8) in mouse and rat models of DSS-induced colitis and indomethacin-induced ulceration. However, it should be noted that repifermin, a truncated form of FGF10, has been tested on 88 patients with active ulcerative colitis in a randomized clinical trial, and did not prove efficacious at reducing disease. Thus, further study is required to understand the role of this ligand in preventing or treating colitis and define the similarities and differences in this pathway in mice versus humans.


FGF9 is expressed in the mesenchyme and epithelium of the developing cecum and intestine, and is important for cecal formation and intestinal elongation during development. Global or mesenchymal specific deletion of FGF9 results in a severely hypoplastic cecum and shortening of the small intestine starting embryonic day E14.5. Lack of FGF9 results in decreased mesenchymal cell proliferation and premature differentiation of intestinal fibroblasts into myofibroblasts. Simultaneous deletion of mesenchymal FGFR1 and FGFR2 in mice results in similar intestinal phenotype obtained with FGF9 deletion. FGF9 binds to FGFR1, FGFR2, and FGFR3. FGF18 also binds to FGFR3. FGFR3 null mice have only half the number of stem cells and decreased Paneth cell number and increased crypt depth compared to wild-type mice. In contrast, the administration of FGF18 to adult mice results in decreased crypt cell proliferation. Increased levels of FGF9 and FGF18 are found in a mouse model of doxorubicin- induced damage, along with an expansion of Paneth cells, suggesting a role for these growth factors in Paneth cell differentiation. In vitro expression of FGFR3IIIb decreases in Caco-2 cells as they become more differentiated, but increases in response to an inflammatory stimulus such as IL-2 treatment. The exact role of FGFR3 and its ligands FGF9 and FGF18 in intestinal diseases is still poorly understood. Further studies are needed to elucidate the role and mechanisms through which these two growth factors act on intestinal stem cells and Paneth cell differentiation.


3.6.4


FGFs in GI Cancers


Like many other mitogenic factors, FGF ligands and their receptors are prominent players in carcinogenesis. Importantly, FGFs are targets of canonical Wnt signaling, a central pathway in cancer development and progression. The involvement of FGFs/FGFRs in different cancers has been reviewed in detail by Tanner and Grose in 2016. The FGF7/FGFR2 signaling axis is increased in diffuse gastric cancers. Furthermore, cancer-associated fibroblasts in the colon are known to secrete higher levels of FGF1 and FGF3 than normal fibroblasts. Conversely, neutralizing FGF1 and FGF3 or inhibiting their receptor FGFR4 reduces cancer cell proliferation and neovascularization in the colon, through the regulation of MMP7 and Erk. FGF20 is upregulated in human colon cancers, while it is nearly undetectable in normal colon tissues. Finally, FGF18 induces growth and survival of tumor cells in colorectal cancer and its expression is increased in those cancers.




3.7


Other Growth Factors in the Gastrointestinal Tract


Several other classes of growth factors have been identified over the past few decades that have mitogenic roles in the development and adult function of the GI tract, which we will touch on only briefly as they are discussed in depth in other chapters or in comprehensive reviews. These include trefoil family factors (TFF), the Wingless (Wnt) family, and Hedgehog (Hh) family proteins. These families each have distinct roles in regulating the physiology of the GI tract from embryonic to adult stags.


TFFs are expressed throughout the GI tract with regional specificity for individual molecules in the adult. These peptides—small, stable proteins produced by mucin-secreting epithelial cells —are critical for maintaining epithelial integrity and are involved in mucosal defense, tissue restitution, development, and inflammatory processes. They are secreted into the mucus barrier, where they maintain their structural and biological activities. Three distinct trefoil peptides have been identified in mammals: TFF1 (originally designated pS2), TFF2 (or spasmolytic polypeptide), and TFF3 (or intestinal trefoil factor). TFF1 and TFF2 expression is spatially restricted to gastric tissue with limited expression in the intestine (Brunner’s glands of the duodenum), whereas TFF3 is most highly expressed in intestinal tissue. Regulated expression of these proteins is known to be controlled by various factors. For instance, TFF1 is responsive to insulin, IGF-1, FGF, and retinoic acid, TFF2 is silenced in response to Helicobacter pylori infection in the stomach, and TFF3 responds to neuropeptides, acetylcholine, hypoxia, and short-chain fatty acids. Notably, TFF3 levels appear to be linked to expression of Muc2, an important glycoprotein critical to limiting inflammation in the intestinal mucosa, through sharing a goblet cell response element for transcriptional control. It has been hypothesized that one aspect of TFF function is through cross-linking with mucin glycoproteins to reinforce the mucus barrier. Through this mechanism and the ability to regulate packaging and secretion of mucin glycoproteins, it is evident TFFs play a key role in establishing and maintaining the mucosal epithelial surface, with coordinated biological activities aimed at promoting GI homeostasis. A number of recent and thorough reviews are available on the roles and functions of trefoil factors.


The diverse family of secreted Wnt ligands has significant impact on embryonic development of the GI tract. Recent studies have also implicated them in GI tissue renewal and maintenance. In particular, Wnt signaling is believed to be a principal force regulating GI regional specification. Wnts signal through the Frizzled family of cell surface receptors and LRP receptors that implement β-catenin and Ca 2 + signaling outcomes. A preponderance of ligands and receptors reflects the diversity of signaling outcomes observed within this family. The importance of Wnt signaling in maintaining the GI tract has been highlighted in the past several years by lineage tracing experiments in mice, and by the development of the GI organoid culture system. These 3D epithelial cultures rely on recombinant Wnt ligand for the establishment and expansion of epithelial cultures generated from either isolated stem cells or isolated crypts. Interestingly, removal of Wnt signaling promotes epithelial differentiation, indicating Wnt and β-catenin promotion are important signals in the self-renewal of the GI stem cell niche. A detailed description of Wnt signaling in the GI tract is provided in Chapter 9 .


Hedgehog (Hh) ligands and their receptors each play roles in not only the development of the GI tract but also in the maintenance of adult GI mucosa. Humans express three Hh proteins: Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh). Shh and Ihh are necessary for appropriate regional development of the gut. These ligands signal via the Glioma family of oncogenic transcription factors (Gli1-3). In the adult, Shh is predominantly involved in maintenance of the gastric epithelium and differentiation, whereas Ihh is involved in the homeostasis of the intestinal tract. Hh ligands are also secreted into circulation. Shh in particular is expressed in and secreted primarily from gastric parietal cells. This ligand is a biologically active signaling molecule with long- and short-range action. In the pancreas, members of the Hh pathway are overexpressed in cancer, and elevated Hh correlates with progression to metastasis. Furthermore, Hh signaling is elevated in liver responses to disease suggesting dysregulation of this pathway is a feature or outcome of liver injury. These findings show a significant role for Hh in homeostasis and disease. The role of Hh signaling in the GI tract is described in detail in Chapter 10 .




3.8


Conclusion


The discovery and study of growth factors over the past seven decades has revealed a complex interplay of regulatory mechanisms that exquisitely control location, timing, and strength of mitogenic signaling in the body. Defining these mechanisms has been foundational for understanding how the GI tract develops, functions, defends, repairs, and maintains itself. Furthermore, the study of growth factors has revealed the many pathways and redundancies that exist for maintenance and function of GI tissues.


Understanding the basic physiological processes by which growth factors operate and signal has been instrumental to identifying specific roles in health and disease, sometimes decades after the initial findings were made. These findings have led to advanced research and clinical applications (e.g., receptor tyrosine kinase inhibitors, metalloproteinase inhibitors, TGF-β inhibitors). Therapeutics that elicit growth factor signaling, or antagonists to these pathways, is being realized in the clinic today. Use of growth factors or additional avenues of targeting growth factor activity will likely be therapeutically useful in the near future in GI diseases such as inflammatory bowel disease, necrotizing enterocolitis, and GI cancers. Furthermore, as our tools progress for understanding the development and regeneration of GI tissues, our understanding of the impact that growth factors have in these areas will continue to expand and be refined, enabling precise control of the beneficial aspects of growth factor signaling while restraining the deleterious effects.


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Apr 21, 2019 | Posted by in ABDOMINAL MEDICINE | Comments Off on Growth Factors in the Intestinal Tract

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