1Cell and Development Group, Department of Zoology, University of Oxford, Oxford; 2Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
Received 15 June 2001; revised 5 October 2001; accepted 23 October 2001.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: colorectal cancer, growth factors, insulin-like growth factor-I, insulin-like growth factor-II, insulin-like growth factor-I receptor, insulin-like growth factor-II receptor
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This review addresses the recent evidence in colorectal cancer in support of another growth factor pathway, the IGF system, that may also be a suitable target for the development of therapeutic molecules (see also [4, 5]). For the sake of brevity, we have concentrated on areas of interest that will have implications for colorectal cancer. The reader is directed to a recent review for a broader coverage of the IGF system and cancer [6].
![]() |
The insulin-like growth factor system |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
There are structural and protein sequence similarities between the IGF1 receptor and the insulin receptors, such that hybrids between the two often form in some cell types. Such similarities present a technical hurdle in the development of IGF1 receptor specific inhibitors, particularly of the tyrosine kinase domain. However, other potential interventions require further investigation, such as inhibitory antibodies, peptides and anti-sense RNA constructs [2325]. Finally, IGF-II binds a large receptor not directly involved in signal transduction, the IGF-II/M6P receptor (referred to as IGF2R) [26]. This receptor binds IGF-II with very high affinity (109 to 1010 M), and acts to internalise the ligand for degradation in the endosomal compartment of the cell [2628]. Thus, all cells have a mechanism for limiting the bioavailability of IGF-II at the cell surface. IGF2R also binds mannose 6-phosphate residues on proteins such as lysosomal hydrolases, latent TGFß1 and granzyme B [26, 29]. The binding to these various different of ligands is because this receptor transports these proteins during their production using glycosylated mannose 6-phosphate residues added post-translationally. The mannose 6-phosphate modification targets protein delivery from the Golgi to the endosomal compartment and the cell surface. In some instances the binding of these proteins has functional consequences in terms of cell signalling, e.g. activation of latent TGFß1 to active TGFß1 and transport of granzyme B from cytotoxic T-cells into target cells.
![]() |
Modification of the IGF system, growth and cancer |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The genetic evidence for the general growth effects of IGF-II have came from embryonic stem cell knock-out technology. The phenotype following disruption of the gene coding for IGF-II in mouse (Igf2) leads to symmetrical embryonic growth retardation [31, 32]. Two surprises followed the investigation of these animals. First, unlike the knock-outs of the other main members of the IGF system, these mice were viable and fertile. (The individual IGFBP knock-outs are also viable, but do not have gross growth defects, suggesting redundancy in their function). Secondly, the Igf2 knock-outs appeared to inherit the defect from their fathers only, an effect known as genomic imprinting. In this case this leads to silencing of gene expression from the allele of the gene inherited from mothers.
Imprinting is one important mechanism where the expression of the IGF-II gene can be limited. Relaxation of imprinting appears to occur frequently in cancers and if it occurs during development, can result in similar human and mouse embryonic overgrowth syndromes (confirming the normal function of IGF-II as an embryonic growth promoter). One important theory of imprinting relates to the competition between a transcriptional enhancer located downstream of Igf2 and a non-coding RNA gene called H19 (Figure 2). If a boundary in the chromatin domain occurs, as in the maternal allele, H19 is preferentially expressed relative to Igf2. Conversely, if the domain boundary is not set up during gametogenesis, then the enhancer stimulates Igf2 expression from the paternal allele. The boundary is controlled by methylation of CpG nucleotides within the DNA sequence upstream of H19. Methylation reduces the affinity of the DNA sequence to proteins that set up the boundary, e.g. a protein called CTCF [33]. Thus, defects in DNA methylation (epigenetic modification) can modify imprinting, and consequently the expression of critical growth control. Imprinting of IGF2 occurs in humans [34] and Beckwith Weidemann is the overgrowth syndrome associated with increased IGF2 expression [35].
|
The specific role for IGF-II in cancer progression was initially supported by experiments using T-antigen expression in the pancreas, a way of genetically inducing tumours by molecular mechanisms that include binding of p53 and Rb. Using in situ hybridisation, Christofori et al. found that expression of T antigen in Islet cells led to early pancreatic adenomas that also expressed IGF-II mRNA [39, 40]. This indicated that reactivation of embryonic expression patterns of this gene can occur during tumour growth. Smaller and fewer tumours arose when IGF-II was eliminated following crosses between these mice and mice with disruption of Igf2. These experiments also showed that the expression of Igf2 was often biallelic, due to relaxation of imprinting. Similar results have also been observed in mice with genetic susceptibility to tumours/adenoma arising in the liver and intestine [4143].
Models of colorectal cancer
Relaxation of imprinting effects were seen in crosses between the Min mouse, a model for Familial adenomatous polyposis, and Igf2 knock-out mouse [43]. The Min mouse (ApcMin/+) has a single point mutation in the gene coding for APC, which is also commonly mutated in sporadic human colorectal cancer. This gene is regarded as one of the first to develop mutations and loss of heterozygosity in the development of colorectal cancer. As with the human syndrome, polyps in the mouse can develop into carcinomas. However, on the C57Bl6 genetic background, mice develop multiple intestinal adenoma by around 100 days of age and can become moribund due to anaemia and intestinal obstruction. This model is regarded as the closest mouse cancer susceptibility model to a human cancer. Using genetic crosses, increased IGF-II supply in the Min mouse results in increased growth of polyps and an increased progression from adenoma to carcinoma [43]. Furthermore, reduced IGF-II supply in Min crosses with Igf2 paternal allele knock-out mice resulted in reduced adenoma size and frequency. Importantly, Igf2 expression could be detected in adenoma that did form, suggesting that loss of imprinting occurs in these adenoma (LOI) [43]. The effects of IGF-II supply in other models of colorectal cancer, such as SMAD knockouts and defects in genes controlling mismatch repair is not known. In conclusion, evidence from murine models suggest that genetic manipulation of IGF supply (and the downstream signalling pathways) are a potent mechanism which can modify both normal and tumour tissue growth control. Recent evidence also suggests that the IGF system can modify colorectal tumour progression in a well defined mouse model of colorectal cancer, and which therefore provides a test bed for novel agents.
![]() |
IGF system and human colorectal cancer |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
IGF system and colorectal cancer predisposition
Two recent studies provide important new information with regard to the prospective correlation of IGF supply and tumour predisposition. The first concerns the systemic supply of IGF-I in humans. It is well known that an increase in colonic adenoma can occur in patients with acromegaly, with an increased supply of IGF-I [47]. Prospective case controlled studies in healthy adults have now observed an increased relative risk of developing colorectal cancer in patients with pre-morbid IGF-I levels in the highest quartile many years prior to diagnosis [48]. A total of 14 916 normal men were followed for 14 years in the Physicians Health Study reported in 1999. Blood was taken for IGF-I, IGF-II and IGFBP3 levels at study entry when men were well. Only 193 cases of colorectal cancer developed during follow-up, and these were compared with age matched controls (n = 318). After adjusting for smoking, age, alcohol consumption and body mass, men with high IGF-I levels had a relative risk of developing colorectal cancer of 2.51 (95% CI 1.15 to 5.46; P = 0.02). Interestingly, the effect was reciprocal to the level of IGFBP3, the main binding protein that controls circulating levels, which was associated with a decreased relative risk (0.28, 95% CI 0.12 to 0.66; P = 0.005). The increased relative risk associated with high IGF-I levels equates to the average increased relative risk of colorectal cancer with a positive family history defined by the Amsterdam criteria [49]. The current hypothesis is that high IGF-I levels predispose to colorectal cancer and may identify a subgroup of people at particularly high risk. This information reinforces the evidence suggesting that most forms of cancer are not accounted for by genetic predisposition alone [50]. The question remains whether screening will be more cost-effective in this patient group, or whether low toxicity therapeutic interventions can also minimise this relative risk. However, IGF-I levels also correlate with diet and physical activity, and so the relationship may still be indirect. Further studies are underway to address these issues, including examination of polymorphisms in IGFBP3 that might modify IGF-I levels. Although increased IGF-II levels are sometimes found in patients with pre-existing and often invasive adenomas, there does not appear to be a predictive influence of systemic IGF-II supply on the susceptibility of colorectal cancer [48, 51].
The second observation relates to the local supply of IGF-II in the normal colon and in colon tumours [5255]. It appears that some individuals express both alleles of IGF2 (~12%) [52]. The inference is that these individuals may be producing twice as much IGF-II peptide and increased supply at the level of the IGF1 receptor. These patients also have bialleic expression in their colon tumours. However, in cases of micro-satellite instability (MSI), assessed by the NCI panel of markers, almost all appeared bialleic expressers of IGF2 [52, 54, 56]. The catch is that these patients appeared not to have inherited mutations of MSM2, MLH1 or PMS2, but have a methylator phenotype whose origin is entirely epigenetic. The latter group of MSI positive, but mutation negative, tumours accounts for 15% of colorectal cancers with MSI and is associated with methylation of the MLH1 promoter. Methylation also occurs in the IGF2/H19 imprinting domain, which modifies binding of the chromatin boundary protein CTCF. Methylation of this region on the maternal allele results in biallelic expression of IGF2 and explains this novel observation in micro-satellite unstable tumours [54]. Further prospective studies are needed to determine whether local biallelic expression of IGF2 in normal mucosa is a predisposing factor to the development of colorectal cancer.
![]() |
Future directions |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Finally, in patients with cancer, an IGF system inhibitor may modify the growth of established tumours. It is not known what will be the best overall strategy, e.g. gene therapy, anti-sense therapy, small kinase inhibitor molecules, therapeutic receptors, therapeutic antibodies, etc. In particular, these approaches may either alter chemotherapy resistance if used in combination or may act via an unpredictable mechanisms. For example, experiments first reported in glioblastoma, and more recently in murine colon cancer cells, suggest that cell death induced by blocking IGF-I signalling resulted in systemic anti-tumour immune responses [58, 59]. Importantly, the effect occurred following use of anti-sense agents and prevented tumour growth following re-challenge. A recent clinical study has been reported using this antisense approach in malignant astrocytoma derived cells transfected with anti-sense constructs to the IGFI receptor and then encapsulated in diffusion chambers and placed in the abdominal wall [60]. It is thought that the apoptotic material generated may be antigenic and deliver an immune response to the primary tumour. However, the induction of class I restricted CTLs, the underlying basis for this immune type of effect, still remains unclear [61]. Overall, this type of experiment highlights the sometimes unpredictable interactions between different cell types and signalling systems within tumours.
Further high quality experimental studies and prospective trials will be required to understand fully the biology and pathology of the IGF system in colorectal cancer. In time, we hope this will ultimately accelerate the development of tailored therapeutic strategies in this common cancer.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2.
Geng L, Donnelly E, McMahon G et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 2001; 61: 24132419.
3.
Shin DM, Donato NJ, Perez-Soler R et al. Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 2001; 7: 12041213.
4.
Baserga R, Helman L, Roberts CT Jr, LeRoith D. Insulin-like growth factors and cancer. Ann Intern Med 1995; 122: 5459.
5. Singh P, Rubin N. Insulin like growth factors and binding proteins in colon cancer. Gastroenterology 1993; 105: 12181237.[ISI][Medline]
6.
Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000; 92: 14721489.
7. Nielsen FC. The molecular and cellular biology of insulin-like growth factor II. Prog Growth Factor Res 1992; 4: 257290.[Medline]
8. Baker J, Liu JP, Robertson EJ et al. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993; 75: 7382.[ISI][Medline]
9.
Burns JL, Hassan AB. Cell survival and proliferation are modified by insulin-like growth factor 2 between days 9 to 10 of mouse gestation. Development 2001; 128: 38193830.
10.
Martin DC, Fowlkes JL, Babic B, Khokha R. Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-7. J Cell Biol 1999; 146: 881892.
11. Michell NP, Langman MJ, Eggo MC. Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers. Br J Cancer 1997; 76: 6066.[ISI][Medline]
12.
Esposito DL, Blakesley VA, Koval AP et al. Tyrosine residues in the C-terminal domain of the insulin-like growth factor-I receptor mediate mitogenic and tumorigenic signals. Endocrinology 1997; 138: 29792988.
13.
Frasca F, Pandini G, Scalia P et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999; 19: 32783288.
14.
Luo RZ, Beniac DR, Fernandes A et al. Quaternary structure of the insulininsulin receptor complex. Science 1999; 285: 10771080.
15. Datta SR, Dudek H, Tao X et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91: 231241.[ISI][Medline]
16.
Playford MP, Bicknell D, Bodmer WF, Macaulay VM. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proc Natl Acad Sci USA 2000; 97: 1210312108.
17. Rubin R, Baserga R. Insulin-like grwoth factor-1 receptor. Its role in cell proliferation, apoptosis and tumorigenicity. Lab Invest 1995; 73: 311331.[ISI][Medline]
18. Biddle C, Li CH, Schofield PN et al. Insulin-like growth factors and the multiplication of Tera-2, a human teratoma-derived cell line. J Cell Sci 1988; 90: 475484.[Abstract]
19. Harrington EA, Bennett MR, Fanidi A, Evan GI. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 1994; 13: 32863295.[Abstract]
20. Lamm GM, Christofori G. Impairment of survival factor function potentiates chemotherapy-induced apoptosis in tumor cells. Cancer Res 1998; 58: 801807.[Abstract]
21. Perer ES, Madan AK, Shurin A et al. Insulin-like growth factor I receptor antagonism augments response to chemoradiation therapy in colon cancer cells. J Surg Res 2000; 94: 15.[ISI][Medline]
22. Macaulay VM, Salisbury AJ, Bohula EA et al. Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase. Oncogene 2001; 20: 40294040.[ISI][Medline]
23. Kalebic T, Tsokos M, Helman LJ. In vivo treatment with antibody against IGF-I receptor suppresses growth of human rhabdomyosarcoma and down-regulates p34cdc2. Cancer Res 1994; 54: 55315534.[Abstract]
24. Pietrzkowski Z, Wernicke D, Porcu P et al. Inhibition of cellular proliferation by peptide analogues of insulin-like growth factor 1. Cancer Res 1992; 52: 64476451.[Abstract]
25. Resnicoff M, Sell C, Rubini M et al. Rat glioblastoma cells expressing an antisense RNA to the insulin-like growth factor-1 (IGF-1) receptor are nontumorigenic and induce regression of wild-type tumors. Cancer Res 1994; 54: 22182222.[Abstract]
26. Kornfeld S. Structure and function of the mannose 6-phosphate/ insulin-like growth factor II receptors. Annu Rev Biochem 1992; 61: 307330.[ISI][Medline]
27.
Linnell J, Groeger G, Hassan AB. Real time kinetics of insulin- like growth factor II (IGF-II) interaction with the IGF-II/mannose 6-phosphate receptor: the effects of domain 13 and pH. J Biol Chem 2001; 276: 2398623991.
28. Souza RF, Wang S, Thakar M et al. Expression of the wild-type insulin-like grwoth factor II receptor gene suppresses growth and causes death in colorectal carcinoma cells. Oncogene 1999; 18: 40634068.[ISI][Medline]
29. Motyka B, Korbutt G, Pinkoski MJ et al. Mannose 6-phosphate/ insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 2000; 103: 491500.[ISI][Medline]
30.
Toretsky JA, Helman LJ. Involvement of IGF-II in human cancer. J Endocrinol 1996; 149: 367372.
31. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 1990; 345: 7880.[ISI][Medline]
32. DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 1991; 64: 849859.[ISI][Medline]
33.
Burns JL, Jackson DA, Hassan AB. A view through the clouds of imprinting. FASEB J 2001; 15: 16941703.
34. Giannoukakis N, Deal C, Paquette J et al. Parental genomic imprinting of the human IGF2 gene. Nature Genet 1993; 4: 98101.[ISI][Medline]
35. Ward A. Beck-Wiedemann syndrome and Wilms tumour. Mol Hum Reprod 1997; 3: 157168.[Abstract]
36.
Ward A, Bates P, Fisher R et al. Disproportionate growth in mice with Igf-2 transgenes. Proc Natl Acad Sci USA 1994; 91: 1036510369.
37. Bates P, Fisher R, Ward A et al. Mammary cancer in transgenic mice expressing insulin-like growth factor II (IGF-II). Br J Cancer 1995; 72: 11891193.[ISI][Medline]
38.
Rogler CE, Yang D, Rossetti L et al. Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice. J Biol Chem 1994; 269: 1377913784.
39. Christofori G, Naik P, Hanahan D. Deregulation of both imprinted and expressed alleles of the insulin-like growth factor 2 gene during beta-cell tumorigenesis. Nature Genet 1995; 10: 196201.[ISI][Medline]
40. Christofori G, Naik P, Hanahan D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 1994; 369: 414418.[ISI][Medline]
41. Haddad R, Held WA. Genomic imprinting and Igf2 influence liver tumorigenesis and loss of heterozygosity in SV40 T antigen transgenic mice. Cancer Res 1997; 57: 46154623.[Abstract]
42. Harris TM, Rogler LE, Rogler CE. Reactivation of the maternally imprinted IGF2 allele in TGFalpha induced hepatocellular carcinomas in mice. Oncogene 1998; 16: 203209.[ISI][Medline]
43.
Hassan AB, Howell JA. Insulin-like growth factor II supply modifies growth of intestinal adenoma in Apc(Min/+) mice. Cancer Res 2000; 60: 10701076.
44.
Zhang L, Zhou W, Velculescu VE et al. Gene expression profiles in normal and cancer cells. Science 1997; 276: 12681272.
45.
Notterman DA, Alon U, Sierk AJ, Levine AJ. Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res 2001; 61: 31243130.
46. Di Popolo A, Memoli A, Apicella A et al. IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PEG2 systhesis in Caco-2 human colon carcinoma cells. Oncogene 2000; 19: 55175524.[ISI][Medline]
47.
Jenkins PJ, Frajese V, Jones AM et al. Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly. J Clin Endocrinol Metab 2000; 85: 32183221.
48.
Ma J, Pollak MN, Giovannucci E et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999; 91: 620625.
49.
Dunlop M, Campbell H. Screening for people with a family history of colorectal cancer. BMJ 1997; 314: 17791780.
50.
Lichtenstein P, Holm NV, Verkasalo PK et al. Environmental and heritable factors in the causation of canceranalyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 7885.
51. Renehan AG, Painter JE, Atkin WS et al. High-risk colorectal adenomas and serum insulin-like growth factors. Br J Surg 2001; 88: 107113.[ISI][Medline]
52. Cui H, Horon IL, Ohlsson R et al. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nature Med 1998; 4: 12761280.[ISI][Medline]
53. Kinouchi Y, Hiwatashi N, Higashioka S et al. Relaxation of imprinting of the insulin-like growth factor II gene in colorectal cancer. Cancer Lett 1996; 107: 105108.[ISI][Medline]
54.
Nakagawa H, Chadwick RB, Peltomäki P et al. Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci USA 2001; 98: 591596.
55. Nishihara S, Hayashida T, Mitsuya K et al. Multipoint imprinting analysis in sporadic colorectal cancers with and without microsatellite instability. Int J Oncol 2000; 17: 317322.[ISI][Medline]
56. Boland CR, Thibodeau SN, Hamilton SR et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58: 52485257.[Abstract]
57. Zi X, Zhang J, Agarwal R, Pollak M. Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res 2000; 15: 56175620.
58. Liu Y, Wang H, Zhao J et al. Enhancement of immunogenicity of tumor cells by cotransfection with genes encoding antisense insulin-like growth factor-1 and B7.1 molecules. Cancer Gene Ther 2000; 7: 456465.[ISI][Medline]
59. Trojan J, Johnson TR, Rudin SD et al. Treatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA. Science 1993; 259: 9497.[ISI][Medline]
60.
Andrews DW, Resnicoff M, Flanders AE et al. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol 2001; 19: 21892200.
61. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998; 392: 8689.[ISI][Medline]
62. Winkler R, Delacroix L, Bensbaho K et al. IGF-II in primary human colorectal tumours: peptide level, activated promoters, parental imprinting and gene rearrangement. Horm Metab Res 1999; 31: 148154.[ISI][Medline]
63. Kawamoto K, Onodera H, Kondo S et al. Expression of insulin-like growth factor-2 can predict the prognosis of human colorectal cancer patients: correlation with tumor progression, proliferative activity and survival. Oncology 1998; 55: 242248.[ISI][Medline]
64.
Freier S, Weiss O, Eran M et al. Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon. Gut 1999; 44: 704708.
65. Guo YS, Narayan S, Yallampalli C, Singh P. Characterization of insulin-like growth factor I receptors in human colon cancer. Gastroenterology 1992; 102: 11011108.[ISI][Medline]
66. Tricoli JV, Rall LB, Karakousis CP et al. Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res 1986; 46: 61696173.[Abstract]
67. Lambert S, Vivario J, Boniver J, Gol-Winkler R. Abnormal expression and structural modification of the insulin-like growth-factor-II gene in human colorectal tumors. Int J Cancer 1990; 46: 405410.[ISI][Medline]
68. Zarrilli R, Pignata S, Romano M et al. Expression of insulin-like growth factor (IGF)-II and IGF-I receptor during proliferation and differentiation of CaCo-2 human colon carcinoma cells. Cell Growth Differer 1994; 5: 10851091.
69. Souza RF, Appel R, Yin J et al. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nature Genet 1996; 14: 255257.[ISI][Medline]
70. Hakam A, Yeatman TJ, Lu L et al. Expresion of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol 1999; 30: 11281133.[ISI][Medline]
71. Kawamoto K, Onodera H, Kan S et al. Possible paracrine mechanism of insulin-like growth factor 2 in the development of liver metastases from colorectal carcinoma. Cancer 1999; 85: 1825.[ISI][Medline]