Affiliations of authors: M. S. Sandhu (Department of Public Health and Primary Care, Institute of Public Health), D. B. Dunger (Department of Paediatrics, Addenbrooke's Hospital), University of Cambridge, Cambridge, U.K.; E. L. Giovannucci, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, and Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston.
Correspondence to: Manjinder S. Sandhu, M.Sc., Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, U.K. (e-mail: manj.sandhu{at}srl.cam.ac.uk).
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ABSTRACT |
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INTRODUCTION |
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In this review, we integrate and assess data from the scientific literature relating to insulin and its biologic interactions with IGF-I and insulin-like growth factor binding proteins (IGFBPs) in the context of colorectal carcinoma. To this end, we critically assess data from experimental, clinical, and observational studies that have investigated the physiologic and pathophysiologic role of IGF-I and its binding proteins and how they relate to insulin levels. A model for colorectal carcinogenesis based on these biologic interactions will also be described. We end by outlining possible therapeutic and preventive strategies and providing suggestions for future research.
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INSULIN AND COLORECTAL CANCER |
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Recent prospective observational studies (79) have shown that colorectal adenomas and cancer are positively, albeit moderately, associated with type 2 diabetes. Such associations are consistent with reports that hyperglycemia is associated with an increased risk of colorectal cancer (1012). These results, together with the marked and consistent similarities in the dietary and lifestyle risk factors for type 2 diabetes and colorectal cancer (4), have led to the suggestion that hyperinsulinemia might underlie the link between type 2 diabetes and colorectal cancer (4,7,8). Indeed, both cross-sectional and prospective population studies (1012) have found that colorectal cancer is more common in people with hyperinsulinemia and its metabolic correlates, including hypertriglyceridemia. Of the two prospective studies, one (11) found a statistically significant twofold higher risk of colorectal cancer among people in the highest quartile of serum insulin concentrations compared with those in the lowest after more than 6 years of follow-up. The other study (5) found a statistically significant, nearly threefold increased risk of colorectal cancer in individuals in the highest quintile of serum C-peptide (a marker of pancreatic insulin secretion) compared with individuals in the lowest quintile.
These epidemiologic observations are consistent with in vivo experimental studies (1316) that demonstrate growth-promoting effects of exogenous insulin, dietary-induced hyperinsulinemia, and hypertriglyceridemia on colon cancer and aberrant crypt foci, a putative precursor of colon cancer. In addition, insulin has been shown to increase the growth of colon epithelial and carcinoma cells in vitro (17,18).
Taken together, these results indicate that insulin may play an important role in colorectal carcinogenesis. It has been suggested that insulin may promote colorectal carcinogenesis directly by activating its own receptor, the receptors for IGF-I, or hybrid insulin/IGF-I receptors (4), all of which are expressed by colorectal epithelial and carcinoma cells (19). However, such direct action is unlikely because insulin has been found to be a relatively weak mitogen in vitro, acting as such only at very high concentrations (4,18). In addition, insulin has extremely low affinity for IGF-I receptors and competes poorly with IGF-I for binding to hybrid insulin/IGF-I receptors (20). An alternative model proposes that insulin acts indirectly to promote colorectal carcinogenesis. In this model, consumption of excess dietary energy results in the development of insulin resistance, which is characterized by increased circulating levels of insulin, triglycerides, and nonesterified fatty acids. These circulating factors may, in turn, initiate a general proliferative response from colonic epithelial cells and promote colorectal carcinogenesis (21).
A third model for the role of insulin in colorectal carcinogenesis is supported by recent experimental and observational studies that implicate IGF-I, a potent mediator of cell survival and growth, in the etiology of colorectal cancer (19,22,23). Specifically, elevated circulating levels of insulin may lead to increased IGF-I bioavailability as a result of insulin-mediated changes in IGFBP concentrations (5,24). Thus, chronic hyperinsulinemia may indirectly promote colorectal carcinogenesis by inducing pathophysiologic changes in concentrations of circulating IGF-I and IGFBPs (5).
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IGF-I PHYSIOLOGY |
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IGF-I stimulates growth and metabolism by binding to the IGF-I receptor, thereby activating a protein tyrosine phosphorylation signal transduction cascade that is similar to the one involved in insulin action (31). The liver is the major source of IGF-I (32), with both hepatic and peripheral production being mainly regulated by GH (20). Higher GH levels lead to increased concentrations of circulating IGF-I. Other hormonal, genetic, and nutritional factors may also be important determinants of intra- and inter-individual variability in IGF-I (20,3335).
Most circulating IGF-I is bound to the IGFBPs, especially IGFBP-3, which binds more than 90% of the circulating IGF-I in a 150-kd ternary complex consisting of IGF-I, IGFBP-3, and an 80-kd acid-labile subunit. In this form, IGFBP-3 sequesters IGF-I in the vascular system, increasing its half-life and providing an IGF-I reservoir. Other IGFBPs form binary complexes with IGF-I that may cross the capillary boundary, allowing selective transport of IGF-I to various tissues. IGFBPs generally inhibit IGF-I action by binding competitively to it and thereby reducing its bioavailability; however, in some cases, they appear to enhance IGF-I activity or to act independently of IGF-I (20,36). Cleavage of IGFBPs by their specific proteases also influences IGF-I bioavailability by reducing the amount of bioavailable IGFBPs. Overall IGF-I bioactivity in vivo, therefore, represents the combined effect of interactions involving endocrine, autocrine, and paracrine sources of IGF-I, IGFBPs, and IGFBP proteases.
The IGFBPs are produced by a variety of different tissues via complex regulatory processes. Similar to IGF-I, GH stimulates the production of hepatic IGFBP-3 and its acid-labile subunit, which is the major source of circulating IGFBP-3 and its acid-labile subunit (36). However, whereas insulin is the primary regulator of hepatic IGFBP-1 production, relatively little is known about the principal regulatory mechanisms that control expression of IGFBP-2, IGFBP-4, IGFBP-5, and IGFBP-6 (26,33,36).
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IGF-I AND COLORECTAL CANCER |
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Recently, accumulating evidence has suggested that GH and IGF-I may be important components of the pathophysiologic mechanisms that underlie the growth of neoplasms, including colorectal carcinoma (2730). For example, patients with acromegaly, who have elevated levels of circulating GH and IGF-I, may be at increased risk of developing colorectal adenoma and carcinoma (37,38), although reports are inconsistent and may be prone to bias. Moreover, colorectal mucosal cell proliferation rates in the sigmoid colon of acromegalics correlate with serum IGF-I concentrations and are substantially higher in acromegalics than in nonacromegalics (39). In addition, acromegalics with newly detected adenomas at follow-up colonoscopy have higher serum IGF-I concentrations than acromegalic patients without new adenomas (40).
Prospective Observational Studies
A number of prospective studies have also found that physiologic variations in GH and IGF-I are associated with changes in cancer incidence and mortality. For example, healthy men with high serum GH levels have a statistically significantly increased risk of mortality from cancer compared with healthy men with low serum GH levels (41). In addition, two recent prospective epidemiologic studies (22,23) have shown that higher plasma IGF-I and lower plasma IGFBP-3 concentrations are associated with an increased risk of colorectal adenoma and cancer among both men and women. However, the associations between IGF-I and IGFBP-3 and risk of colorectal cancer were statistically significant only after adjustment for each other (22,23). One of the studies (23) found a fourfold increased risk of colorectal cancer in men who were in both the highest tertile of IGF-I and lowest tertile of IGFBP-3 compared with that of men in the lowest tertiles of both IGF-I and IGFBP-3. Both studies noted that high levels of IGFBP-3, independently of IGF-I, were associated with a lower risk of colorectal adenoma and cancer.
These observations suggest that the ratio of circulating IGF-I/IGFBP-3 may be a marker of circulating and tissue IGF-I bioavailability. As noted earlier, GH increases hepatic production of both IGF-I and IGFBP-3, which, at least in part, may account for the positive association between circulating levels of IGF-I and IGFBP-3. Studies of acromegalics and nonacromegalic control subjects (42,43) have also shown that the IGF-I/IGFBP-3 ratio increases with increasing serum GH concentrations, indicating that GH differentially stimulates IGF-I and IGFBP-3 secretion. Experimental data suggest that IGF-I itself may also regulate hepatic IGFBP-3 production (44).
However, a subsequent prospective study (5) found different results than the earlier studies: Women in the highest quintile of serum IGFBP-3 had a statistically significantly increased risk of colorectal cancer compared with women in the lowest quintile. Furthermore, this effect was not independent of serum IGF-I levels. In a more recent prospective study of Chinese men living in Shanghai (45), a secondary analysis of case patients diagnosed within 8 years of follow-up also found that IGFBP-3 was positively associated with risk of colorectal cancer. In this study, high serum levels of IGF-II, but not IGF-I, were associated with an increased risk of colorectal cancer. It is possible that the different findings may be the result of variations in the specificity of laboratory assay techniques for intact and proteolytically cleaved IGFBP-3 (46).
It is also possible that some physiologic mechanism underlies these divergent findings. The inconsistent results for the association of IGFBP-3 with colorectal cancer risk imply that there may be other important determinants of IGFBP-3 and IGF-I bioavailability and bioactivity, possibly including IGFBP-3-specific proteases and their regulators (36). Clinical studies have revealed that co-administration of IGF-I and IGFBP-3 does not inhibit the hypoglycemic action of IGF-I, and in vivo studies have shown that IGFBP-3 infusion or overexpression does not attenuate glucose tolerance (47,48). The dual role of the IGFBPs as both inhibitors and enhancers of IGF-I bioactivity may also explain the inconsistent associations between IGFBP-3 and risk of colorectal cancer (20,36). For example, differences in the relative affinity of IGF-I for its receptor and for IGFBPs have been proposed to contribute to IGFBP-3 enhancement of IGF-I function (36).
Experimental Studies
Additional evidence for the role of IGF-I and its binding proteins in colorectal carcinogenesis comes from in vitro models, which have shown that IGFs have potent antiapoptotic and mitogenic properties in both normal and neoplastic cells (2729). These data suggest that IGF-I may play a role in various stages of cancer progression. Colorectal epithelia and cancer cells express IGF-I receptors, which stimulate mitogenesis when activated by IGF-I in vitro (17,18,49,50). Moreover, IGF-I receptor mRNA expression is increased in human colorectal carcinoma cell lines (50,51); conversely, blockade of the IGF-I receptor inhibits survival and growth of human colorectal cancer cells (52,53). The phosphorylated tyrosine residues of an activated IGF-I receptor serve as docking sites for a variety of intracellular signaling molecules, including Shc, PI3 kinase, Grb2, Grb10, PLC1, IRS-1, and IRS-2 (54). Depending on the cell type, IGF-I receptor activation and recruitment of these downstream effectors induces proliferation, differentiation, or inhibition of apoptosis. These signaling pathways may also be differentially regulated by the relative availability of immediate intracellular receptor substrates (55,56).
The IGF-I signal transduction pathway involved in the regulation of apoptosis and mitogenicity is also partly mediated by activation of the Ras protein (20,57). Farnesylation of Ras, catalyzed by farnesyl transferase, is required for its functional and transforming capabilities. Insulin promotes Ras farnesylation and may therefore prime cellular responses to IGF-I (58). Mutant Ras proteins with increased activity are found in approximately half of all colonic tumors and may promote the growth of adenomas into carcinomas.
IGF-I can also induce the expression of vascular endothelial growth factor, thus promoting colorectal tumor progression by inducing the development of blood vessels (59). This growth-promoting role of IGF-I is in contrast to the IGF-I-independent growth inhibitory effect of IGFBP-3, which has been shown to enhance p53-dependent apoptosis and differentiation in colonic epithelial cells (60).
Circulating and Tissue IGF-I Levels
Although it is well documented that IGF-I can promote carcinogenesis at the cellular level, it is unclear whether circulating IGF-I can do so as well. Accumulating evidence indicates that this may be the case. For example, as already mentioned, investigations of acromegalics suggest that rates of colorectal mucosal cell proliferation are associated with circulating IGF-I levels (39). Similarly, reduction of serum IGF-I by dietary restriction in animal models slows tumor progression and increases apoptosis in tumor cellseffects that are both reversed by infusions of recombinant IGF-I (61,62). Likewise, infusions of recombinant GH and IGF-I have been found to promote tumor growth in vivo (63).
More recently, hepatic IGF-I gene deletion mice have been created that show a 75% reduction in circulating IGF-I levels (32,44). Orthotopic transplantation of adenocarcinoma cells into the cecum of control and transgenic mice has shown that the incidence of tumor growth and hepatic metastasis was statistically significantly higher in control animals (64). Moreover, in both control and transgenic mice, treatment with recombinant human IGF-I led to statistically significantly increased rates of tumor development and metastatis to the liver. Although transgenic mice have dramatically reduced circulating IGF-I levels, they also exhibit compensatory GH hypersecretion (44), which suggests that the decreased rates of tumor development and metastases seen in these animals may be directly attributable to the lower circulating IGF-I levels.
Investigators have also noted that absence of the wild-type allele of a microsatellite polymorphism in the promoter region of the IGF-I gene is associated with low circulating IGF-I concentrations and an increased risk of type 2 diabetes and myocardial infarction (65). This IGF-I genetic polymorphism may represent the effects of long-term exposure to IGF-I at both the tissue and circulatory levels. Similarly, a recently identified single nucleotide (T to A) polymorphism in the human growth hormone gene, GH1, has been associated with a reduced risk of colorectal cancer (66). Specifically, this study found that A/A individuals had a statistically significantly reduced risk of colorectal cancer and relatively lower circulating concentrations of IGF-I and the IGF-I/IGFBP-3 ratio than T/T individuals. The study also showed a similar association for colorectal adenomas.
The above gene association study (66) was conducted in an ethnically diverse population consisting of Japanese, Native Hawaiians, and Caucasians. However, the association between the GH1 genetic polymorphism and risk of colorectal cancer was not evident in the Japanese study subjects, even though the GH1 polymorphism was related to circulating IGF-I concentrations in this ethnic group. This finding is consistent with an earlier prospective study of Chinese men (45), which found no association between circulating IGF-I concentrations and risk of colorectal cancer. Thus, environmental and lifestyle differences, as well as other unidentified genetic factors, may explain differences in risk among ethnic groups seen in prospective observational studies assessing the association between circulating IGF-I concentrations and subsequent risk of colorectal cancer.
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BIOLOGIC INTERACTIONS AMONG INSULIN, IGF-I, AND IGFBPS |
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The processes that link nutrition and growth are thought to involve complex interactions among insulin, GH, IGF-I, and IGFBPs (Fig. 1). Short-term changes in nutritional status do not substantially alter serum concentrations of IGF-I and IGFBP-3; however, during prolonged fasting and severe nutrient restriction, circulating levels of IGF-I and, to a lesser extent, IGFBP-3 decrease, whereas circulating levels of IGFBP-1 and IGFBP-2 increase (24,33,67). The opposite is observed during refeeding (67,68).
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Rapid changes in serum IGFBP-1 concentrations are regulated primarily by changes in insulin levels, and several studies (69,71,72) have shown that insulin inhibits the synthesis of IGFBP-1 in the liver. Low-insulin states, including long- and short-term fasting or poorly controlled type 1 diabetes, are characterized by elevated serum IGFBP-1 levels (67,69,73,74). Conversely, individuals with chronic hyperinsulinemia or whose serum insulin concentration is temporarily raised, such as during the postprandial period, during insulin infusions in healthy control individuals, and among people with obesity, insulinomas, or congenital hyperinsulinism with hypoglycemia, all show statistically significantly lower serum IGFBP-1 levels than control subjects (68,71,75,76).
Levels of IGFBP-2, unlike IGFBP-1, do not respond directly to acute changes in insulin or nutritional status (33). However, circulating levels of IGFBP-2 are elevated with prolonged fasting (77), and the elevation is more pronounced during protein restriction than during caloric restriction (67). Individuals with low insulin levels (e.g., patients suffering from malnutrition, anorexia nervosa, or untreated type 1 diabetes) also have elevated levels of IGFBP-2 (7880). Moreover, in previously untreated type 1 diabetics treated with insulin, IGFBP-2 levels return to normal (80). These conditions of high IGFBP-2 concentrations are in contrast to the low levels of IGFBP-2 found in the chronically obese, which may be the result of obesity-related chronic hyperinsulinemia or its correlates, including changes in circulating lipid concentrations (36,81). Therefore, long-term changes in circulating insulin concentrations may also result in substantial changes in circulating levels of IGFBP-2.
Collectively, these data indicate that insulin and its metabolic correlates may regulate levels of both IGFBP-1 and IGFBP-2 and, as a result, levels of bioavailable IGF-I. Both in vitro and in vivo studies (36,71) have shown that IGFBP-1 inhibits IGF-I-stimulated growth and differentiation and counteracts the potent insulin-like hypoglycemic activity of IGF-I (82,83). These observations imply that insulin-mediated changes in IGFBP-1 concentrations determine the amount of putatively free bioactive IGF-1 in circulation, a conclusion that is supported by the consistently observed inverse association between IGFBP-1 and free or readily dissociable IGF-I (24,33,71,72). A randomized trial (83) investigating the effects of continuous subcutaneous administration of IGF-I in humans found a further twofold increase in free IGF-I with a concomitant decrease in serum IGFBP-1 during a hyperinsulinemic clamp, in which insulin is infused at a constant rate to achieve physiologic suprabasal levels. This finding is compatible with the finding that obesity-related hyperinsulinemia is associated with statistically significantly higher levels of free IGF-I and lower levels of IGFBP-1 and IGFBP-2 than those found in nonobese adults and children (81,84).
The insulin-mediated increase in bioavailable IGF-I may also explain the paradoxical situation in which individuals with obesity or type 1 diabetes, despite having normal concentrations of total IGF-I, are characterized by hyposomatropinemia and hypersomatropinemia, respectively (85). In obese individuals, elevated free IGF-I may, as a result of hyperinsulinemia-induced IGFBP-1 suppression, increase IGF-I feedback to the pituitary gland to inhibit GH production. Consistent with this hypothesis is the finding that recovery of GH production following withdrawal of exogenous IGF-I administration is associated with changes in free rather than total IGF-I (86). Because IGF-I levels are normal in obese individuals, the low GH concentration indicates that insulin may increase GH-stimulated hepatic IGF-I synthesis via increases in hepatic GH receptor sensitivity or expression, as noted earlier (67,81,85). The increase in GH receptor levels is thought to be mirrored by plasma GH binding protein (GHBP) concentrations, which are elevated in obese individuals (85).
In addition, because GH differentially stimulates IGF-I and IGFBP-3 production, with a greater increase in IGF-I production, insulin may also indirectly increase total IGF-I levels (67,73,81,83,85). Studies of patients with type 1 diabetes have shown that insulin levels are positively correlated with serum IGF-I concentrations and that insulin withdrawal in such patients is associated with a substantial decrease in total IGF-I that can be reversed following insulin infusion (73,83,87). These insulin-associated increases in serum total IGF-I occur despite relatively small or no changes in serum IGFBP-3 and GH (71). Thus, insulin may also indirectly increase the circulating IGF-I/IGFBP-3 ratio (83). However, the relative magnitude of the two opposing effects of insulin on circulating IGF-I concentrationsi.e., increasing hepatic GH sensitivity via receptor upregulation (which increases IGF-I levels) and increasing IGF-I negative feedback on GH production via suppression of specific IGFBPs and increased IGF-I bioavailability (which decreases IGF-I levels)is likely be the main determinant of circulating IGF-I.
Collectively, these studies suggest that hyperinsulinemia-induced changes in the levels of IGF-I and IGFBPs may increase IGF-I bioavailability (Fig. 1). Specifically, chronically elevated fasting and postprandial insulin levels may lead to a decrease in circulating IGFBP-1 and IGFBP-2 levels and to a possible increase in the circulating IGF-I/IGFBP-3 ratio.
Role in Colorectal Cancer
The long-term increase in IGF-I bioavailability may, over time, increase the risk of colorectal cancer. Indeed, Kaaks et al. (5), in a prospective observational study, showed that increased serum IGFBP-1 and IGFBP-2 are inversely associated with colorectal cancer risk and that serum C-peptide and IGF-I are positively associated with colorectal cancer risk. This finding, along with data relating to the biologic interactions among insulin, IGF-I, and IGFBPs, provides a potential mechanism through which previously identified environmental factors, such as diet and associated lifestyle factors, including high saturated fat and meat consumption, low physical activity, and obesity, may operate to increase the risk of this cancer (2,4,10).
Colorectal carcinogenesis is a multifactorial and multistep process that involves an accumulation of genetic mutations (88). These mutations occur spontaneously throughout life; the rate at which they occur may be increased by both exogenous mutagens and genetic predisposition. IGF-I is a potent antiapoptotic factor for many cell types (89), and the hyperinsulinemia-induced increase in IGF-I bioactivity may promote the survival of transformed and abnormal cells that would normally undergo apoptosis. For example, data from an observational study (90) have shown that high levels of circulating IGF-I and enhanced genetic instability (increased mutagen sensitivity) are independently associated with an increased risk of lung cancer. The study also demonstrated an interaction between elevated IGF-I levels and the mutagen-sensitivity phenotype, suggesting that there may be a synergistic effect between these two factors and risk of lung cancer. The finding that orthotopically transplanted adenocarcinoma tissue shows decreased tumor growth and development in the hepatic IGF-I gene deletion mouse model of reduced circulating IGF-I concentrations (64) also supports this mechanism.
Thus, long-term exposure to increased IGF-I, with its mitogenic and antiapoptotic effects, may promote cancer development and progression at various stages of the carcinogenic process (91). In this scenario, short-term changes in IGF-I bioavailability are unlikely to play an important role in carcinogenesis, because the probability of transformed cells developing into cancer cells may be much lower with short, transient changes in IGF-I bioavailability than with more sustained changes. In addition, so far as we are aware, because no experimental studies have directly assessed this hypothesis, it is unclear as to whether IGF-I is also involved in de novo carcinogenesis.
Indirect Epidemiologic Data
The direct epidemiologic evidence for the role of insulin, IGF-I, and IGFBPs in colorectal carcinogenesis is also consistent with more inferential data. Possible anthropometric markers of hyperinsulinemia, such as waist circumference, waist-to-hip ratio, and body mass index, have been positively associated with risk of colorectal cancer (2,5,11). Height is also positively related to risk of colorectal cancer (2) and may, to some extent, reflect adolescent IGF-I levels, which correlate modestly with height (92,93). High levels of physical activity have been consistently associated with a decreased risk of colorectal cancer (94). This relationship might be due to the association of physical activityespecially in individuals with lower body masswith lower fasting and postprandial serum insulin concentrations (95).
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LIMITATIONS OF THE MODEL |
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Recent studies (73,96) also suggest that inter-individual variability in concentrations of IGF-I and its binding proteins may be partly the result of genetic differences. At least two studies (65,66) have shown that polymorphic variations in the GH or IGF-I gene are associated with both serum IGF-I concentrations and chronic disease risk, including risk of colorectal cancer and adenoma. A study of twins (35) also indicates that variability in circulating IGF-I levels may have a heritable component; hence, it is possible that genetic factors and epigenetic processes that determine circulating concentrations of IGF-I and IGFBPs may interact to influence colorectal cancer risk. Thus, individuals with genetically determined elevated circulating IGF-I concentrations, who also have increased IGF-I bioavailability as a result of increased serum insulin concentrations, may have an elevated risk of colorectal cancer compared with individuals with relatively low insulin and IGF-I levels.
Alternatively, because tumors may themselves be a source of IGF-I, the reported associations among IGF-I, IGFBPs, and risk of colorectal cancer could be the result of undiagnosed cancer. The four prospective studies (5,22,23,45) that assessed the relationship between IGF-I levels and risk of colorectal cancer had between 6 and 14 years of follow-up, whereas the latency period between initiation and progression to symptomatic colorectal cancer may be more than 10 years. Indeed, one study (45) found an increased risk for IGF-II and IGFBP-3 only for cases diagnosed within 8 years of baseline assessment of serum IGF concentrations.
However, another study (23) found that the association between IGF-I and colorectal cancer was stronger for participants with longer follow-up, suggesting that the association was not due to undiagnosed cancer (because with such an association, an attenuation of the effect would be expected with longer follow-up). Furthermore, the positive association between the incidence of colorectal adenomas and circulating IGF-I levels also suggests that the association is unlikely to be due to undiagnosed carcinoma (22). More persuasive evidence comes from genetic association studies. As already noted, polymorphic variation in the growth hormone gene, GH1, was associated with both circulating IGF-I concentrations and risk of colorectal cancer, suggesting that lifetime exposure may be an important determinant of risk (66).
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PREVENTIVE AND THERAPEUTIC STRATEGIES |
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From a therapeutic viewpoint, one study (98) has shown that octreotide, a somatostatin analogue, reduces circulating IGF-I levels and tumor cell proliferation in patients with newly diagnosed colon cancer. However, controlled trials of this drug in patients with advanced colon cancer have yielded inconsistent results, with one study (99) finding longer median survival times and increased disease stability and another study (100) finding no benefit. A more targeted approach to modulating IGF-I bioactivity, i.e., using more specific antagonists, may be more effective.
However, any approach that reduces IGF-I bioavailability has the possibility of substantial adverse side effects, primarily because IGF-I is an important component of other physiologic systems. Indeed, it has been suggested that IGF-I may be an important therapeutic agent for conditions such as type 1 and possibly type 2 diabetes, osteoporosis, protein metabolism in critically ill patients, disease-induced catabolic states, and age-associated tissue degeneration (101105). Recently, a microsatellite polymorphism in the promotor region of the IGF-I gene that confers low serum IGF-I levels was found to be associated with an increased risk of type 2 diabetes and myocardial infarction (65). Therefore, attempts to influence IGF-I bioavailability in the context of colorectal cancer prevention will need to be considered in light of the possible effects on other chronic diseases (106).
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SUGGESTIONS FOR FUTURE RESEARCH |
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Further characterization of polymorphisms in genes for IGF-I, the IGF-I receptor, IGFBPs, and their regulatory proteins, particularly those that are predicted to change protein structure, may provide more precise assessments of local IGF-I tissue production, bioactivity, and the effects of long-term exposure.
The existence of variants of genes encoding insulin and its receptor, and of intracellular signaling proteins that transduce signals from both IGF-I and insulin receptors (5457,107,108), may also help explain the intracellular processes underlying cellular growth and proliferation, as will a better understanding of interactions of IGF-I receptor signaling pathways with other intracellular signaling mechanisms in carcinogenesis (109).
As noted earlier, transgenic mice have been created that show a 75% reduction in circulating IGF-I levels (32,64). Variants of this transgenic model, with more subtle changes in IGF-I levels, may be particularly useful in assessing the role of circulating IGF-I levels that are within the normal physiologic range in the development of colorectal cancer. Transgenic animals that overexpress IGF-I and IGFBPs could also be used in this context (110,111).
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CONCLUSION |
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NOTES |
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Manuscript received July 5, 2001; revised May 1, 2002; accepted May 10, 2002.
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