IGF, IGF Receptor and Overgrowth Syndromes

IGF, IGF Receptor and Overgrowth Syndromes Itay Bentov, MD, Haim Werner, PhD Department of Clinical Biochemistry, Sackler Faculty of Medicine, Tel Aviv University and Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Corresponding Author: Haim Werner, Ph.D., Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 ISRAEL, Phone: 972-3-6408542, Fax: 972-3-6406087, Email: [email protected]

Abstract

T

he insulin-like growth factors are a family of growth

factors, binding proteins and receptors that are involved in

normal growth as well as in a number of pathological states. Overgrowth syndromes are a group of disorders characterized by a phenotype of excessive somatic and visceral growth. In addition, patients suffering from overgrowth syndromes are predisposed to develop cancer. Several specific defects linked to the insulin-like growth factor system were elucidated for a group of these disorders, including Simpson-Golabi-Behmel syndrome, Bannayan-Ruvalcaba-Riley syndrome and Beckwith-Wiedemann syndrome. The aim of this review is to examine recent data linking the phenotype of overgrowth syndromes, visceral growth and increased risk of neoplasia, with the molecular machinery of the IGF system. Ref: Ped. Endocrinol. Rev. 2004;4:????? Key words: IGF-1, IGF-2, IGF-1 receptor, Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, BannayanRuvalcaba-Riley syndrome, Wilms' tumor, overgrowth.

Introduction Assisted reproduction technologies have gained worldwide acceptance in the last twenty-five years. The recent recognition that the incidence of the Beckwith-Wiedemann Syndrome (BWS) is significantly increased in babies conceived with the aid of in-vitro fertilization spurred a renewed interest in the molecular and pathological processes leading to the overgrowth syndromes (1-3). The Insulin-Like Growth Factor (IGF) family of ligands, receptors and binding proteins plays a

pivotal role in growth processes as well as in the development of neoplasia. In view of the fact that both unrestrained growth and augmented incidence of cancer are typical hallmarks of most overgrowth syndromes, significant efforts have been invested in recent years in examining the potential involvement of the IGF axis in the etiology of overgrowth. The aim of this review is to evaluate evidence linking the overgrowth phenotype with the molecular machinery of the IGF system.

The IGF System The IGFs are a family of mitogenic growth factors, binding proteins and receptors that are involved in normal growth and differentiation of most organs and are also implicated in a wide array of pathological states. The existence of the IGFs was postulated in the late 1950’s, following the seminal observation by Salmon and Daughaday that growth hormone stimulated the incorporation of sulfate into cartilage in an indirect fashion, which involved activation of a specific serum factor. The factor that was originally termed “sulfation factor” and then “somatomedin” is now accepted as insulin-like growth factor-1 (4).

Ligands The IGF system consists of two ligands, IGF-1 and IGF-2. At the cellular level IGF-1 is a progression factor that is required by the cell to traverse the cell cycle (5). Circulating IGF-1 levels are mostly dependent on liver production, which is tightly controlled by growth hormone. In addition to its classical endocrine role, many extrahepatic tissues produce IGF-1, which exhibits paracrine and autocrine modes of action in these tissues. In rodents, very low levels of IGF-1 and high IGF-2 levels are observed during the prenatal period, while

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postnatal stages are characterized by an increase in circulating IGF-1 and disappearance of IGF-2. These observations might have led to an erroneous generalized interpretation of the roles of IGF-2 and IGF-1 as fetal and pubertal growth factors, respectively. In humans, however, this expression pattern does not exist and both ligands are produced from the prenatal to the postnatal periods. In fact, in normal healthy adult subjects circulating IGF-2 levels are higher than IGF-1.

Receptors Both ligands activate a common receptor, the IGF-1 receptor (IGF1R), which signals mitogenic, antiapoptotic and transforming activities. The IGF1R is a cell-surface tyrosine kinase receptor coupled to several intracellular second messenger pathways, including the ras-raf-MAPK and PI3'K signaling cascades (6). IGF1R is vital for cell survival, as illustrated by the lethal phenotype of mice in which the IGF1R gene was disrupted by homologous recombination (7) (see below). During normal ontogenesis, the IGF1R is expressed at every developmental period, including the oocyte stage. Late embryonic and adult stages, in which the percentage of rapidly proliferating cells declines, are associated with an overall reduction in the levels of IGF1R mRNA. In the neoplastic process a "primitive" pattern of IGF1R expression is established again. Transformed cells display augmented numbers of IGF1R on their cell surface as well as increased levels of IGF1R mRNA. Examination of various tumors (including breast, ovarian, prostate, colon, hematopoietic, rhabdomyosarcoma and renal), show an abundant expression of IGF1R (8), suggesting that up regulation of the IGF1R gene constitutes a common paradigm in different types of cancer. Molecular cloning of the IGF-2 receptor revealed that a single cell-surface receptor is able to bind both Mannose 6-Phosphate (M6P)-containing moieties and IGF-2 molecules (9). The IGF-2/M6P receptor targets IGF-2 for lysosomal degradation (10) and thus reduces the bioavailability of circulating IGF-2. Diminished levels of IGF-2 lead to a depressed activation of the IGF1R. Accordingly, the IGF-2/M6P receptor has been postulated to function as a tumor suppressor. A mutated or deleted IGF-2/M6P receptor was described in several neoplasms (11). Interestingly, IGF-2 can also signal via a particular isoform of the insulin receptor which is generated by alternative splicing of the insulin receptor gene (12). Finally, IGF-2 and IGF-2/M6P receptor are epigenetically silenced in a reciprocal manner. Thus, in humans, IGF-2 is translated only from the paternal allele while the IGF-2/M6P receptor is translated only from the maternal allele (13).

IGF Binding Proteins - IGFBPs The IGF system also includes at least six high affinity IGF Binding Proteins (IGFBP1-6). In general, the IGFBPs inhibit IGFs' metabolic and proliferative actions, although some IGFBPs may

display IGF-potentiating effects as well. In the serum, the majority of circulating IGFs are found in a ternary complex with IGFBP3 and an acid-labile subunit. This complex modulates IGF action by protecting the growth factors from proteolysis and prolonging their half lives in the circulation (14). In addition, some IGFBPs exert their biological effects in an IGF-independent manner. IGFBP3 is recognized as an inhibitor of proliferation, driving the cell to apoptosis (15). An inverse relation between serum IGFBP3 levels and IGF action has been observed. Several potential mechanisms of action were postulated to explain IGFBP-3 inhibition of IGF action. These include sequestration of IGF-1 from the receptor (16) and binding competition with the receptor (17) as well as IGF-independent mechanisms of action (18). Recently, the IGFBP family has been extended to include three new IGFBP-related proteins (IGFBP-rPs). The IGFBP-rPs are cysteine rich proteins characterized by their similarity to the IGFBP’s. IGFBP-rPs share a conserved aminoterminal domain and affinity to both IGF-1 and insulin. IGFBP-rPs have been suggested to function as tumor suppressors on the basis of experiments showing a growth inhibitory role in a prostate cellular model (19).

IGF and Size The essential role played by the IGF system in growth and development was demonstrated by the severe growth deficits observed in mice in which various components of the IGF system were disrupted by homologous recombination. The quantitative effect of IGF-1 and IGF-2 on body size has gained substantial support from several models.

Figure 1: Overgrowth syndromes and the IGF axis. IGF-1 and IGF-2 activate the IGF1R, which signals via the PI3K and MAPK pathways. The PI3K is negatively regulated by PTEN, which is mutated in the Bannayan-Ruvalcaba-Riley syndrome. IGF-1 synthesis is controlled by growth hormone (GH). IGF-2 production depends on the imprinting status of the IGF-2 gene. In addition, circulating IGF-2 levels are controlled by IGF2R. Specific disruptions of the IGF axis in Beckwith-Wiedemann syndrome (BWS), Simpson-Golabi-Behmel syndrome (SGBS), Bannayan-Ruvalcaba-Riley syndrome (BRR), and acromegaly are highlighted (see text for details).

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Knock-Out Mice Experiments Crossing of heterozygous mice containing a disrupted IGF-1 allele (20) led to the production of three phenotypically distinct groups: wild-type homozygote mice (wt/wt), heterozygotes (wt/igf1-) and homozygotes for the disrupted allele (igf1-/igf1-). The body weight of heterozygote mice at the time of birth was about 10-20% less than wild-type animals, whereas igf1-/igf1- homozygotes weighed about 40% less than wild type. In addition, igf1-/igf1- homozygotes showed a very high perinatal mortality, delayed ossification, underdeveloped muscles and lungs and infertility. To evaluate the effect of IGF-2 on normal growth, IGF-2 gene-disrupted chimeras were crossed with normal littermates (21). When the paternal mice was a chimera, the heterozygote offspring were healthy "dwarves" that weighed about 60% of the normal littermates at birth. All other offspring (including the heterozygotes bred from the maternal chimeras) were normal (22). These observations highlight two important points: 1. The rodent IGF-2 gene is imprinted (silenced) in the maternal allele and, 2. IGF-1 is essential for correct embryonic development whereas IGF-2 action is less critical (23). Disruption of the IGF1R gene by homologous recombination resulted in small (more than 50% reduction in weight) animals that died in the immediate postnatal period from respiratory failure. These animals exhibited generalized developmental abnormalities, including hypoplasia, abnormal skin formation, delayed bone development and abnormal central nervous system morphology. A double mutant generated by knocking out the IGF-1 gene in addition to the IGF1R gene showed essentially the same phenotype as that of the IGF1R mutant (24). However a double IGF-2/IGF1R mutant revealed a profound growth impairment (birth weight about 30% of normal littermates) (25), suggesting that IGF-2 can signal via alternative signaling pathways. As mentioned above, an isoform of the insulin receptor was identified in fetal and cancer cells as a potential alternative pathway for IGF-2 signaling (26). Finally, in accordance with its role as a repressor of the IGF1R cascade, mice with a deletion of the IGF-2/M6P receptor gene are larger (135% body weight of controls), probably as a result of the elevated levels of circulating IGF-2.

Epidemiological Studies In addition to the phenotypes of IGF component-deleted animals, a number of epidemiological observations in certain human populations highlight the pivotal role of the IGF axis in normal growth. For example, circulating IGF-1 levels in African pygmies are markedly lower than in the general population (27). Moreover, an important contribution to our understanding of the role of IGF-1 in growth was derived from the observation that growth hormone and IGF-2 levels are normal in African pygmies, whereas IGF-1 levels in adolescent males and females

were significantly lower. As a result of this reduction, the growth spurt that usually accompanies adolescence is absent (28). Interestingly, screening of another short statured population, the Mountain Ok people of Papua New Guinea, revealed normal circulating IGF-1 levels (29). The importance of IGF-1 in normal growth is classically illustrated by the Laron Syndrome (LS). LS patients are characterized by defects in growth hormone receptor (30). Their resistance or insensitivity to growth hormone results in diminished IGF-1 production despite normal or even high growth hormone levels. LS patients’ height is four to ten standard deviations below median normal height. Acceleration of linear growth was demonstrated by continuous, long term treatment of affected patients with recombinant IGF-1 (31). Screening of IGF levels in non-human species with distinct phenotypic features revealed that in different breeds of dogs circulating IGF-1 levels are matched with breed size. As a general rule, smaller breeds have lower IGF-1 levels than larger breeds (32).

Overgrowth Syndromes Overgrowth Syndromes are a group of disorders associated with a phenotype of excessive somatic and visceral growth. Although widely recognized and extensively reviewed (33), several classifications were used to define and classify the overgrowth syndromes. A typical classification based on purely phenotypic features divides the overgrowth syndromes in generalized versus regional versus parameter-specific overgrowth. A more complex classification has also been suggested which groups overgrowth cases according to the following features (34): 1. Familial tall stature. 2. Pre- or postnatal onset overgrowth. 3. Intrinsic cellular hyperplasia versus humerally mediated hyperplasia. These classification schemes address the differences in growth pattern in a non-rigid, organizing manner rather than by a molecular causative parameter. The limiting step toward a causative classification is inadequate genetic information concerning these disorders. The molecular nature of several specific defects, however, was elucidated for a small subgroup of these disorders. These include mutation of the GPL3 gene in the Simpson-Golabi-Behmel syndrome (35), mutation of PTEN in the Bannayan-Ruvalcaba-Riley syndrome (36) and imprinting of genes in the 11p15.5 locus in the Beckwith-Wiedemann syndrome, the classical overgrowth syndrome (37). We will try to demonstrate that all of these defects may impinge upon the IGF system (Figure 1). [A putative molecular mechanism for Sotos syndrome, another overgrowth syndrome , was suggested to be caused by haploinsufficiency of the NSD1 gene (38). As the function of this gene is still unclear, Sotos syndrome will

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not be included in this discussion. Noteworthy, NSD1 has been suggested to be involved in development, as shown by the early fetal mortality in NSD1 knock-out mice(39)].

Beckwith-Wiedemann Syndrome The most extensively studied overgrowth syndrome is Beckwith-Wiedemann syndrome. BWS is an overgrowth malformation syndrome that occurs with an incidence of 1/13,700 live births. It is manifested at birth by macroglossia, hepatosplenomegaly, nephromegaly and abdominal wall defects. Laboratory investigation often reveals hypoglycemia, secondary to pancreatic beta cell hyperplasia. Children suffering from BWS are predisposed to childhood neoplasm. The risk of developing a neoplasm in the early years of life in BWS patients is estimated to be about 7.5-12.5% (compared to 1:10000 in the general population). The most common neoplasias associated with BWS are Wilms' tumor, hepatoblastoma and neuroblastoma (40). BWS is often considered to be a prototype for the study of aberrant genomic imprinting diseases. Genomic imprinting refers to the process of differential parent specific expression of particular genes, resulting in exclusive expression from either the maternal or the paternal allele (41). Only a small number of genes in the human genome are known to be imprinted. Interestingly, several of these genes (IGF-2, H19, p57kip2, KVLQT1) are located in the small arm of chromosome 11. Overexpression of the IGF-2 gene is most likely one of the leading causes of BWS. As mentioned above, the IGF-2 gene is an imprinted one (i.e., it is only expressed from the paternal allele). Overexpression of IGF-2 in BWS may be caused by a number of genetic events, including gene duplication, loss of heterozygosity and loss of imprinting of the IGF-2 gene. Biallelic expression was observed in about half of sporadic BWS cases (42). The transcription of the IGF-2 gene is under the control of four promoters (P1-P4). P1 is not normally imprinted while the other three promoters undergo silencing by DNA methylation (43). Imprinting alterations in all four IGF-2 gene promoters were reported in hepatocellular carcinoma (44) and Wilms tumor (45). Closely linked to the IGF-2 gene is the H19 gene that encodes a nontranslated mRNA, which is nevertheless biologically active as a tumor suppressor (46). The maternally expressed H19 and the paternally expressed IGF-2 genes are coordinately regulated. A targeted deletion of the H19 gene in mice results in biallelic IGF-2 expression (47). Loss of imprinting of IGF-2 is associated with an 80-fold down regulation of H19 expression, which was shown to be related to alterations in DNA methylation of the H19 promoter (48). Recently, synthetic zinc-finger transcription factors were shown to both positively and negatively regulate the expression of the IGF-2 and H19 genes (49). The ability to override epigenetically controlled states is an encouraging prospect in the treatment of both overgrowth syndromes and malignancy. Two other maternally expressed genes, p57kip2 (a member of the

cyclin-dependant kinase inhibitor family) (50) and KVLQT1 (part of a potassium channel) (51), are compactly located in the proximity of the IGF-2 and H19 loci, in the short arm of chromosome 11. Imprinting abnormalities in the p57kip2 and KVLQT1 genes were described in a minority of BWS patients. The significance of these imprinting defects in BWS etiology remains to be established. Finally, a number of recent reports showed that the incidence of BWS was increased in babies conceived with the help of assisted reproduction technologies. The results of these studies may suggest that manipulations that are inherent to the fertilization technologies and that occur at critical periods for the establishment and maintenance of specific epigenetic modifications, could lead to severe pathological defects (52).

Simpson-Golabi-Behmel Syndrome The first description of this syndrome by Simpson in 1975 reported two maternally related cousins with macrocephaly and a “coarse” face. Ten years later Behmel and, independently, Golabi described two families in which affected males had the same features and early infant death. In addition, X-linked inheritance was suggested. Several years later, in a description of another family showing similar features, the term Simpson-Golabi-Behmel syndrome (SGBS) was coined (53) SGBS, sometimes mistakenly diagnosed as BWS, shares many similarities with BWS. This similarity is manifested not only by the somatic and visceral gigantism (especially enlargement of the liver, kidneys and spleen) but also by an increased risk of developing malignancies. Unlike the various malignancies that have been described in association with BWS, only cases of Wilms' tumor, usually diagnosed before two years of age, have been reported in SGBS. Similar to BWS, the molecular pathology of SGBS seems to involve disruption of IGF-2 action (54). SGBS is an X-linked recessive trait with mild expression in heterozygous females. Deletions in an extracellular proteoglycan designated Glypican 3 (GPC3) have been implicated in SGBS (55). The GPC3 gene contains eight exons and it encodes a heparan sulphate proteoglycan which can function on the cell surface as a receptor (56). Noteworthy is the fact that GPC3 interacts with IGF-2 (57). Dysfunction of GPC3 may lead to release of IGF-2 from GPC3 control, hence enhancing IGF-2 action.

Bannayan-Ruvalcaba-Riley Syndrome/Cowden Syndrome Bannayan-Ruvalcaba-Riley syndrome is an autosomal dominant condition that presents as a triad of macrocephaly, a speckled penis and subcutaneous and visceral lipomata and hemangiomata (58). The term Bannayan-Ruvalcaba-Riley syndrome has replaced three distinct syndromes: Riley-Smith, Bannayan-Zonana and Ruvalcaba-Myhre-Smith (59). Cowden syndrome is an autosomal dominant condition characterized by

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multiple hamartomas and by an increased risk of breast, thyroid and endometrial malignancies (60). A germline mutation in the PTEN (Phosphatase and tensin homologue deleted on chromosome Ten) gene was demonstrated in 80% of the patients suffering from Cowden syndrome (61) and 60% of the Bannayan-Ruvalcaba-Riley Syndrome patients (62). A recent report showed that the majority of the “non germline mutation” cases displayed PTEN promoter mutations and deletions, leading to aberrant PTEN protein production (63). This has led to the suggestion that Bannayan-Ruvalcaba-Riley syndrome and Cowden syndrome are in fact a single entity (64). PTEN is a tumor suppressor gene that was found to be frequently (second only to p53) altered in neoplasia (65). In breast cancer, decreased PTEN expression was associated with invasiveness and poor prognosis (66). PTEN regulates Akt (a cell survival kinase) phosphorylation in a negative fashion and thereby antagonizes the PI3K/Akt pathway, a major signaling pathway of the IGF system. It has been postulated that loss of PTEN action augments IGF action and creates a tumorigenic environment. New insight into an intrinsic negative feedback mechanism of the IGF system was recently suggested by the finding that IGF-2 induces PTEN expression (67). Combined, these results imply that IGF-2 may exert both mitogenic activities (with important consequences in mammary carcinogenesis) and inhibitory types of action (that may lead to a hypomorphic effect during mammary gland development).

Acromegaly Although not considered a "classical" overgrowth syndrome, acromegaly shares many of the properties discussed above (i.e., increased size, elevated risk of neoplasia and a strong connection to the IGF system). Acromegaly is a disorder that results from an excessive secretion of growth hormone from the pituitary gland, leading to elevated circulating IGF-1 levels. Acromegaly is characterized by bone overgrowth presenting as acral enlargement and visceromegaly. Studies linking acromegaly with an elevated risk of colon polyps and cancer led to the establishment of guidelines for routine colonoscopic screening of acromegalic patients (68). Of importance, the risk of colonic neoplasia is substantially higher in acromegalic patients with the highest serum levels of IGF-1 as compared to those with lower levels (69).

Gene Dosage of the IGF1R The important role of the IGF1R in normal and pathological human growth has been directly demonstrated by the phenotypes of patients with chromosomal abnormalities that disrupt the IGF1R locus. The IGF1R gene is located on the long arm of chromosome 15 (15q26). Ring chromosome is a rare chromosomal abnormality resulting from the breakage and reunion of both chromosome arms. The phenotype of a ring

chromosome depends upon the genetic sequences deleted or duplicated. Patients suffering from ring chromosome 15 were evaluated in order to establish a potential correlation between growth retardation and the presence or absence of the IGF1R gene. Hemizygotes for the IGF1R locus showed severe growth failure, while a patient with a ring chromosome possessing two copies of the gene had borderline stature (70). Increased size and overgrowth were reported in two independent families with a balanced translocation involving 15q26.1 ∂ qter. Affected members exhibited three copies of the IGF1R gene, macrosomia at birth and macrocephaly (71). The dosage effect of IGF1R copy number was functionally assessed in studies of cellular proliferation. Results obtained showed that skin fibroblasts from a patient with a single copy of the IGF1R gene (due to a deletion on 15q26.2, presenting with growth retardation) showed slower cellular growth than controls. On the other hand, a patient with three IGF1R copies (due to a partial duplication of the long arm of chromosome 15, presenting with height and weight above the 97th percentile) showed accelerated cellular growth (72). An elegant example of the dosage effect of IGF1R came from a single family where the father had a balanced chromosomal translocation t(13;15)(q34;q26.1). One of the offspring, suffering from trisomy 15q26.1 and thus three copies of the IGF1R gene, exhibited postnatal overgrowth. A fetus with only one copy showed severe intrauterine growth retardation. Interestingly, another girl in the family with the same trisomy did not show accelerated growth, probably due to the fact that she suffered from cardiac abnormalities (endocardial cushion defect) that tend to cause growth failure (73). Chromosomal abnormalities, however, may include loss or gain of additional genes located in close proximity to the IGF1R locus. The recent report of two distinct IGF1R mutations provides convincing evidence that defects in the IGF1R lead to intrauterine and postnatal growth retardation. Specifically, two groups of children were examined. The first group consisted of 42 patients with unexplained intrauterine growth retardation and subsequent short stature and the second group included 50 children with short stature who had high circulating IGF-1 levels (74) . In the first cohort a girl was identified who was a compound heterozygote for point mutation in exon 2 of the IGF1R gene that altered the amino acid sequence to Arg108Gln in one allele and Lys115Asn in the other. Fibroblasts cultured from the patient had decreased IGF1R binding and phosphorylation. In the second cohort a boy was identified with a nonsense mutation, Arg59STOP, which reduced IGF1R number. Noteworthy is that although both cases showed prenatal and postnatal growth retardation, they were phenotypically different. Finally, homozygous partial deletion of the IGF-1 gene has been reported in a 15-year-old boy with severe prenatal and postnatal growth deficiency, sensorineural deafness and mental retardation (75).

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IGF and Malignancy A high cellular turnover in epithelial tissue is generally accepted as a contributing factor to the propagation of a neoplastic process. The proliferative effect of IGF-1 led to several observational studies that were intended to elucidate the possible connection between circulating IGF-1 levels and an increased risk of neoplasia. Initially, small retrospective studies failed to show a link between IGF-1 and breast (76) or prostate (77) cancer. Recent large epidemiological studies have suggested that high circulating IGF-1 concentrations are associated with an increased risk for breast, prostate, lung and colorectal cancer. Specifically, in a prospective nested control study (the Nurse's Health Study) the Relative Risk (RR) of breast cancer in premenopausal women was 4.6 in the upper tertile of IGF-1 values, in comparison to women in the lower tertile (78). The RR increased to 7.3 when the concentrations of IGFBP3 were included in the analysis. Likewise, the RR of prostate cancer in men (evaluated in the Physician's Health Study) in the upper quartile of IGF-1 values was 2.4 (4.3 when normalized for IGFBP3) (79). Noteworthy is that IGF-1 levels were measured an average of seven years before the diagnosis of prostate cancer. Recently a meta-analysis of fourteen studies confirmed the association between IGF-1 levels and prostate cancer (80). In addition to hormone-dependant prostate and breast carcinomas, the importance of IGF-1 as a risk factor was evaluated in various non hormone-dependant types of cancers. Analysis of colon cancer risk in the Nurse's Health Study (81) and the Physician's Health Study (82) showed an increased cancer risk in individuals with the highest IGF-1 values (although a lower RR was observed). Several mechanisms have been suggested to explain the possible role of the IGF system in the initiation and/or progression of neoplasia (83). Although IGF-1 was shown to increase chromosomal fragility under experimental conditions (84), it is usually considered to be nongenotoxic. The proliferative actions of IGF-1, however, have been well characterized. A biologically based, computerized description of carcinogenesis suggested that an increase in cell proliferation could account for the carcinogenicity of nongenotoxic compounds (85). Once a malignant transformation has occurred, cell survival in transformed cells depends on IGF-1 action (86). The disruption of internal checks and control mechanisms associated with the neoplastic phenotype is further emphasized by the finding that IGF-1 action can override the cellular signals of apoptosis (87). An encouraging observation for a possible role of the IGF system not only in screening for cancer but as an interventional target, is that blockade of the IGF-1 receptor by αIR3, a monoclonal antibody directed against the human IGF1R, inhibited proliferation of several carcinoma cell lines including colon, breast and others (88). Furthermore when nude mice

were implanted with colon cancer cells, expression of a dominant-negative truncated IGF1R resulted in reduced tumor progression (89). The search for anticancer treatments prompted the study of the intracellular signaling cascades that regulate IGF system expression as possible therapeutic targets. For example, tumor suppressor p53 is a transcription factor that protects mammalian cells against cancer. Accordingly, mutations in p53 are a common finding in many human cancers. Consistent with its role as a tumor suppressor, wild-type p53 was shown to inhibit, while mutated p53 up-regulated, IGF1R expression (90). Understanding the relationships between the IGF system and other cell survival regulators, like Mdm-2, PTEN and NF-kB, as well as the interactions with cellular migration effectors, like E-cadherin and β-catenin, is the goal of extensive investigation (91).

IGF and Wilms' Tumor The association of Beckwith-Wiedemann and SimpsonGolabi-Behmel syndromes with Wilms' tumor is well established and warrants a careful investigation into the pathological process leading to the sometimes fatal neoplastic process in early childhood. In 1899, Max Wilms described seven children suffering from nephroblastoma. Important contributions by other pathologists led to the definition of this form of childhood cancer as nephroblastoma or Wilms' tumor (92). Wilms' tumor accounts for almost all of the renal neoplasms in infancy. In children under the age of fifteen years it occurs with an annual frequency of 7.8 per million, affecting both sexes equally. Wilms' tumor often accompanies congenital anomalies as genitourinary malformations, hemihypertrophy (that is sometimes only noted during the growth spurt of puberty) and aniridia. Wilms' tumor commonly presents as a large, often asymptomatic, abdominal mass, typically diagnosed at the age of three years. Treatment options include surgical removal followed by radiotherapy and chemotherapy. Prognosis is better with small, early-diagnosed tumors but is mainly dependant on the histological findings and clinical staging (93). WT1 is a cell-type specific zinc-finger transcription factor whose deletion or mutation has been implicated in the etiology of Wilms' tumor (94). Consistent with the putative tumor suppressor role of WT1, it was shown that WT1 inhibits the expression of the IGF1R gene via a mechanism that involves binding of its zinc-finger domain to multiple cis-elements in the IGF1R promoter (95,96). Suppression of IGF1R promoter activity by WT1 constitutes a potential mechanism by which terminally-differentiated cells remain at a postmitotic stage. Loss-of-function mutation of WT1 can de-repress the IGF1R promoter, resulting in increased production of cell-surface receptors and augmented mitogenic activation by locally produced and/or circulating IGFs. Similarly, IGF-2 is

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overexpressed in Wilms' tumor and may support cancer progression. Like with the IGF1R gene, WT1 binds multiple sites in the IGF-2 promoter and functions as a repressor of IGF-2 transcription. Mutation of WT1 may lead to relaxation of IGF-2 gene repression, with a resulting increase in IGF-2 levels (97). A feedback mechanism was suggested by the finding that WT1 expression was shown to be down-regulated following activation of the IGF1R by IGF-1. Using specific inhibitors it has been demonstrated that IGF-1 action is mediated through the mitogenic ras-raf-MAPK pathway (98).

Conclusions The IGF system has a crucial role in normal development. Alterations in the IGF signaling axis are associated with a number of pathological states. In this review, we have presented evidence that suggests that the etiology of several overgrowth syndromes is closely linked to the IGF system. A better knowledge and understanding of the complex machinery of the IGF system will undoubtedly improve our ability to develop treatment modalities for those conditions in which the IGF system is involved.

Acknowledgments Work in the laboratory of H.W. is supported in part by a grant from the Israel Cancer Association.

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