The Role of the IGF Axis in Hepatocarcinogenesis

J.-G. Scharf; T. Braulke

doi:10.1055/s-2004-814151

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2003; 35(11/12): 685-693
DOI: 10.1055/s-2004-814151

Review

The Role of the IGF Axis in Hepatocarcinogenesis

J.-G. Scharf ¹ , T. Braulke ²

¹Department of Medicine, Georg-August-Universität, Göttingen, Germany
²Department of Biochemistry, Children’s Hospital, Universitätsklinikum Eppendorf, Hamburg, Germany

Abstract

Primary hepatocellular carcinoma (HCC) is one of the most common forms of malignant cancer with the fourth highest mortality rate worldwide. Major risk factors for the development of HCC include chronic infections with the hepatitis B or C virus, alcohol consumption, exposure to dietary aflatoxin B1, hereditary liver disease or liver cirrhosis of any etiology. Recent studies have discovered changes in the insulin-like growth factor (IGF) axis that affect the molecular pathogenesis of HCC, including the autocrine production of IGFs, IGF binding proteins (IGFBPs), IGFBP proteases, and IGF receptor expression. Characteristic alterations detected in HCC and hepatoma cell lines comprise the overexpression of IGF-II and the IGF-I receptor emerging as critical events in malignant transformation and growth of tumors. Simultaneous reduction of IGFBP expression and the increase in proteolytic cleavage of IGFBPs result in an excess of bioactive IGFs. Finally, defective functions of the IGF-II/mannose 6-phosphate receptor involved in degradation of IGF II, the activation of the growth inhibitor TGF-β1, and the lysosomal targeting of cathepsin proteases capable to degrade extracellular matrix proteins may contribute to the development of HCC.

Key words

Insulin-like Growth Factors - IGF Binding Proteins - IGF-I Receptor - IGF-II/ Mannose 6-Phosphate Receptor - Hepatocarcinogenesis - Hepatocellular Carcinoma

Full Text

References

1 Chen C J, Yu M W, Liaw Y F. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997; 12 S294-S308
2 Khandwala H M, McCutcheon I E, Flyvbjerg A, Friend K E. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev. 2000; 21 215-244
3 LeRoith D, Roberts C T, Jr. The insulin-like growth factor system and cancer. Cancer Lett. 2003; 195 127-137.
4 LeRoith D, Werner H, Beitner-Johnson D, Roberts C T, Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995; 2 143-163
5 Blakesley V A, Stannard B S, Kalebic T, Helman L J, LeRoith D. Role of the IGF-I receptor in mutagenesis and tumor promotion. J Endocrinol. 1997; 152 339-344
6 Baserga R. The IGF-I receptor in cancer research. Exp Cell Res. 1999; 253 1-6.
7 LeRoith D. Insulin-like growth factor I receptor signaling-overlapping or redundant pathways?. Endocrinology. 2000; 141 1287-1288
8 Braulke T. Type-2 IGF receptor: a multi-ligand binding protein. Horm Metab Res. 1999; 31 242-246
9 De Souza A T, Yamada T, Mills J J, Jirtle R L. Imprinted genes in liver carcinogenesis. FASEB J. 1997; 11 60-67
10 Jones J I, Clemmons D R. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995; 16 3-34
11 Bach L A, Rechler M M. Insulin-like growth factor binding proteins. Diabet Rev. 1995; 3 38-61
12 Clemmons D R. Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev. 1997; 8 45-62
13 Firth S M, Baxter R C. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002; 23 824-854
14 Shimasaki S, Ling N. Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6). Prog Growth Factor Res. 1991; 3 243-266
15 Maile L A, Holly J M. Insulin-like growth factor binding protein (IGFBP) proteolysis: occurrence, identification, role and regulation. Growth Horm IGF Res. 1999; 9 85-95
16 Hwa V, Oh Y, Rosenfeld R G. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 1999; 20 761-787
17 Monzavi R, Cohen P. IGFs and IGFBPs: role in health and disease. Best Pract Res Clin Endocrinol Metab. 2002; 16 433-447
18 Sjogren K, Liu J L, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Tornell J, Isaksson O G, Jansson J O, Ohlsson C. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci U S A. 1999; 96 7088-7092
19 Yakar S, Liu J L, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999; 96 7324-7329
20 Scott C D, Martin J L, Baxter R C. Production of insulin-like growth factor I and its binding protein by adult rat hepatocytes in primary culture. Endocrinology. 1985; 116 1094-1101
21 Kachra Z, Barash I, Yannopoulos C, Khan M N, Guyda H J, Posner B I. The differential regulation by glucagon and growth hormone of insulin-like growth factor (IGF)-I and IGF binding proteins in cultured rat hepatocytes. Endocrinology. 1991; 128 1723-1730
22 Scharf J G, Schmidt-Sandte W, Pahernik S A, Koebe H G, Hartmann H. Synthesis of insulin-like growth factor binding proteins and of the acid-labile subunit of the insulin-like growth factor ternary binding protein complex in primary cultures of human hepatocytes. J Hepatol. 1995; 23 424-430
23 Scharf J G, Knittel T, Dombrowski F, Muller L, Saile B, Braulke T, Hartmann H, Ramadori G. Characterization of the IGF axis components in isolated rat hepatic stellate cells. Hepatology. 1998; 27 1275-1284
24 Scharf J-G, Braulke T, Hartmann H, Ramadori G. Regulation of the components of the 150 kDa IGF binding protein complex in cocultures of rat hepatocytes and Kupffer cells by 3’,5’-cyclic adenosine monophosphate. J Cell Physiol. 2001; 186 425-436
25 Su T S, Liu W Y, Han S H, Jansen M, Yang-Fen T L, P’eng F K, Chou C K. Transcripts of the insulin-like growth factors I and II in human hepatoma. Cancer Res. 1989; 49 1773-1777
26 Stuver S O, Kuper H, Tzonou A, Lagiou P, Spanos E, Hsieh C C, Mantzoros C, Trichopoulos D. Insulin-like growth factor 1 in hepatocellular carcinoma and metastatic liver cancer in men. Int J Cancer. 2000; 87 118-121
27 Mazziotti G, Sorvillo F, Morisco F, Carbone A, Rotondi M, Stornaiuolo G, Precone D F, Cioffi M, Gaeta G B, Caporaso N, Carella C. Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study. Cancer. 2002; 95 2539-2545
28 Nielsen F C, Christiansen J. Posttranscriptional regulation of insulin-like growth factor II mRNA. Scand J Clin Lab Invest Suppl. 1995; 220 37-46
29 Lamas E, Zindy F, Seurin D, Guguen-Guillouzo C, Brechot C. Expression of insulin-like growth factor II and receptors for insulin-like growth factor II, insulin-like growth factor I and insulin in isolated and cultured rat hepatocytes. Hepatology. 1991; 13 936-940
30 Zindy F, Lamas E, Schmidt S, Kirn A, Brechot C. Zindy F, Lamas E, Schmidt S, et al. Expression of insulin-like growth factor II (IGF-II) and IGF-II, IGF-I and insulin receptors mRNAs in isolated non-parenchymal rat liver cells. J Hepatol. 1992; 14 30-34
31 Norstedt G, Levinovitz A, Moller C, Eriksson L C, Andersson G. Expression of insulin-like growth factor-I (IGF-I) and IGF-II mRNA during hepatic development, proliferation and carcinogenesis in the rat. Carcinogenesis. 1988; 9 209-213
32 Yang D, Rogler C E. Analysis of insulin-like growth factor II (IGF-II) expression in neoplastic nodules and hepatocellular carcinomas of woodchucks utilizing in situ hybridization and immunocytochemistry. Carcinogenesis. 1991; 12 1893-1901
33 Schirmacher P, Held W A, Yang D, Chisari F V, Rustum Y, Rogler C E. Reactivation of insulin-like growth factor II during hepatocarcinogenesis in transgenic mice suggests a role in malignant growth. Cancer Res. 1992; 52 2549-2556
34 Yang D, Alt E, Rogler C E. Coordinate expression of N-myc 2 and insulin-like growth factor II in precancerous altered hepatic foci in woodchuck hepatits virus carriers. Cancer Res. 1993; 53 2020-2027
35 Christofiori G, Naik P, Hanahan D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature. 1994; 369 414-418
36 Casola S, Ungaro P, Pedone P V, Lazzaro D, Fattori E, Ciliberto G, Zarrilli R, Bruni C B, Riccio A. Loss of heterozygosity of imprinted genes in SV 40 t/T antigen-induced hepatocellular carcinomas. Oncogene. 1995; 11 711-721
37 Harris T M, Rogler L E, Rogler C E. Reactivation of the maternally imprinted IGF2 allele in TGFalpha induced hepatocellular carcinomas in mice. Oncogene. 1998; 16 203-209
38 Fan Z R, Yang D H, Cui J, Qin H R, Huang C C. Expression of insulin-like growth factor II and its receptor in hepatocellular carcinoma. World J Gastroenterol. 2001; 7 285-288
39 Cariani E, Lasserre C, Seurin D, Hamelin B, Kemeny F, Franco D, Czech M P, Ullrich A, Brechot C. Differential expression of insulin-like growth factor II mRNA in human primary liver cancers, benign liver tumors, and liver cirrhosis. Cancer Res. 1988; 48 6844-6849
40 Sohda T, Yun K, Iwata K, Soejima H, Okumura M. Increased expression of insulin-like growth factor 2 in hepatocellular carcinoma is primarily regulated at the transcriptional level. Lab Invest. 1996; 75 307-311
41 Wang Z, Ruan YB, Guan Y, Liu S H. Expression of IGF-II in early experimental hepatocellular carcinomas and its significance in early diagnosis. World J Gastroenterol. 2003; 9 267-270
42 Uchida K, Kondo M, Takeda S, Osada H, Takahashi T, Nakao A, Takahashi T. Altered transcriptional regulation of the insulin-like growth factor 2 gene in human hepatocellular carcinoma. Mol Carcinog. 1997; 18 193-198
43 Li X, Nong Z, Ekstrom C, Larsson E, Nordlinder H, Hofmann W J, Trautwein C, Odenthal M, Dienes H P, Ekstrom T J, Schirmacher P. Disrupted IGF2 promoter control by silencing of promoter P1 in human hepatocellular carcinoma. Cancer Res. 1997; 57 2048-2054
44 Aihara T, Noguchi S, Miyoshi Y, Nakano H, Sasaki Y, Nakamura Y, Monden M, Imaoka S. Allelic imbalance of insulin-like growth factor II gene expression in cancerous and precancerous lesions of the liver. Hepatology. 1998; 28 86-89
45 Takeda S, Kondo M, Kumada T, Koshikawa T, Ueda R, Nishio M, Osada H, Suzuki H, Nagatake M, Washimi O, Takagi K, Takahashi T, Nakao A, Takahashi T. Allelic-expression imbalance of the insulin-like growth factor 2 gene in hepatocellular carcinoma and underlying disease. Oncogene. 1996; 12 1589-1592
46 Lin S B, Hsieh S H, Hsu H L, Lai M Y, Kan L S, Au L C. Antisense oligodeoxynucleotides of IGF-II selectively inhibit growth of human hepatoma cells overproducing IGF-II. J Biochem. 1997; 122 717-722
47 d’Arville C N, Nouri-Aria K T, Johnson P, Williams R. Regulation of insulin-like growth factor II gene expression by hepatitis B virus in hepatocellular carcinoma. Hepatology. 1991; 13 310-315
48 Su Q, Liu Y F, Zhang J F, Zhang S X, Li D F, Yang J J. Expression of insulin-like growth factor II in hepatitis B, cirrhosis and hepatocellular carcinoma: its relationship with hepatitis B virus antigen expression. Hepatology. 1994; 20 788-799
49 Park B C, Huh M H, Seo J H. Differential expression of transforming growth factor alpha and insulin-like growth factor II in chronic active hepatitis B, cirrhosis and hepatocellular carcinoma. J Hepatol. 1995; 22 286-294
50 Nardone G, Romano M, Calabro A, Pedone P V, de Sio I, Persico M, Budillon G, Bruni C B, Riccio A, Zarrilli R. Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatology. 1996; 23 1304-1312
51 Tanaka S, Takenaka K, Matsumata T, Mori R, Sugimachi K. Hepatitis C virus replication is associated with expression of transforming growth factor-alpha and insulin-like growth factor-II in cirrhotic livers. Dig Dis Sci. 1996; 41 208-215
52 Sedlaczek N, Hasilik A, Neuhaus P, Schuppan D, Herbst H. Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis. Br J Cancer. 2003; 88 733-739
53 Lee S, Park U, Lee Y I. Hepatitis C virus core protein transactivates insulin-like growth factor II gene transcription through acting concurrently on Egr1 and Sp1 sites. Virology. 2001; 283 167-77
54 Lee Y I, Lee S, Lee Y, Bong Y S, Hyun S W, Yoo Y D, Kim S J, Kim Y W, Poo H R. The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor II promoter 4. Oncogene. 1998; 16 2367-2380
55 Kang-Park S, Lee J H, Shin J H, Lee Y I. Activation of the IGF-II gene by HBV-X protein requires PKC and p44/p42 map kinase signalings. Biochem Biophys Res Commun. 2001; 283 303-307
56 Kang-Park S, Lee Y I, Lee Y I. PTEN modulates insulin-like growth factor II (IGF-II)-mediated signaling; the protein phosphatase activity of PTEN downregulates IGF-II expression in hepatoma cells. FEBS Lett. 2003; 545 203-208
57 Steck P A, Pershouse M A, Jasser S A, Yung W K, Lin H, Ligon A H, Langford L A, Baumgard M L, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng D H, Tavtigian S V. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997; 15 356-362
58 Chen C J, Wang L Y, Lu S N, Wu M H, You S L, Zhang Y J, Wang L W, Santella R M. Elevated aflatoxin exposure and increased risk of hepatocellular carcinoma. Hepatology. 1996; 24 38-42
59 Lee Y I, Lee S, Das G C, Park U S, Park S M, Lee Y I. Activation of the insulin-like growth factor II transcription by aflatoxin B1induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. Oncogene. 2000; 19 3717-3726
60 Gonzalgo M L, Jones P A. Mutagenic and epigenetic effects of DNA methylation. Mutat Res. 1997; 386 107-118
61 Eriksson T, Frisk T, Gray S G, von Schweinitz D, Pietsch T, Larsson C, Sandstedt B, Ekstrom T J. Methylation changes in the human IGF2 P3 promoter parallel IGF2 expression in the primary tumor, established cell line, and xenograft of a human hepatoblastoma. Exp Cell Res. 2001; 270 88-95
62 Hu J F, Vu T H, Hoffman A R. Promoter-specific modulation of insulin-like growth factor II genomic imprinting by inhibitors of DNA methylation. J Biol Chem. 1996; 271 18 253-18 262
63 Yao X, Hu J F, Daniels M, Shiran H, Zhou X, Yan H, Lu H, Zeng Z, Wang Q, Li T, Hoffman A R. A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma. J Clin Invest. 2003; 111 265-273
64 Kim K W, Bae S K, Lee O H, Bae M H, Lee M J, Park B C. Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res. 1998; 58 348-351
65 Song B C, Chung Y H, Kim J A, Lee H C, Yoon H K, Sung K B, Yang S H, Yoo K, Lee Y S, Suh D J. Association between insulin-like growth factor-2 and metastases after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma: a prospective study. Cancer. 2001; 91 2386-2393
66 Zhang J Y, Chan E K, Peng X X, Tan E M. A novel cytoplasmic protein with RNA-binding motifs is an autoantigen in human hepatocellular carcinoma. J Exp Med. 1999; 189 1101-1110
67 Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen A H, Wewer U M, Nielsen F C. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol. 1999; 19 1262-1270
68 Lu M, Nakamura R M, Dent E D, Zhang J Y, Nielsen F C, Christiansen J, Chan E K, Tan E M. Aberrant expression of fetal RNA-binding protein p62 in liver cancer and liver cirrhosis. Am J Pathol. 2001; 159 945-953
69 Villafuerte B C, Goldstein S, Murphy L J, Phillips L S. Nutrition and somatomedin. XXV. Regulation of insulin-like growth factor binding protein-1 in primary cultures of normal rat hepatocytes. Diabetes. 1991; 40 837-841
70 Böni-Schnetzler M, Schmid C, Mary J L, Zimmerli B, Meier P J, Zapf J, Schwander J, Froesch E R. Insulin regulates the expression of the insulin-like growth factor binding protein 2 mRNA in rat hepatocytes. Mol Endocrinol. 1990; 4 1320-1326
71 Menuelle P, Binoux M, Plas C. Regulation by insulin-like growth factor (IGF) binding proteins of IGF-II-stimulated glycogenesis in cultured fetal rat hepatocytes. Endocrinology. 1995; 136 5305-5310
72 Chin E, Zhou J, Dai J, Baxter R C, Bondy C A. Cellular localization and regulation of gene expression for components of the insulin-like growth factor ternary binding protein complex. Endocrinology. 1994; 134 2498-2504
73 Villafuerte B C, Koop B L, Pao C I, Gu L, Birdsong G G, Phillips L S. Coculture of primary rat hepatocytes and nonparenchymal cells permits expression of insulin-like growth factor binding protein-3 in vitro. Endocrinology. 1994; 134 2044-2050
74 Villafuerte B C, Koop B L, Pao C I, Phillips L S. Glucocorticoid regulation of insulin-like growth factor-binding protein-3. Endocrinology. 1995; 136 1928-1933
75 Scharf J-G, Ramadori G, Braulke T, Ramadori G. Cellular localization and hormonal regulation of biosynthesis of insulin-like growth factor binding proteins and of the acid-labile subunit within rat liver. Prog Growth Factor Res. 1995; 6 175-180
76 Scharf J-G, Ramadori R, Braulke T, Ramadori G. Synthesis of insulinlike growth factor binding proteins and of the acid-labile subunit in primary cultures of rat hepatocytes, of Kupffer cells, and in cocultures: regulation by insulin, insulinlike growth factor, and growth hormone. Hepatology. 1996; 23 818-827
77 Zimmermann E M, Li L, Hoyt E C, Pucilowska J B, Lichtman S, Lund P K. Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver. Am J Physiol. 2000; 278 447-457
78 Novosyadlyy R, Tron K, Dudas J, Ramadori G, Scharf J G. Expression and regulation of the insulin-like growth factor axis components in rat liver myofibroblasts. J Cell Physiol. in press;
79 Gong Y, Cui L, Minuk G Y. The expression of insulin-like growth factor binding proteins in human hepatocellular carcinoma. Mol Cell Biochem. 2000; 207 101-104
80 Hanafusa T, Yumoto Y, Nouso K, Nakatsukasa H, Onishi T, Fujikawa T, Taniyama M, Nakamura S, Uemura M, Takuma Y, Yumoto E, Higashi T, Tsuji T. Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma. Cancer Lett. 2002; 176 149-158
81 Huynh H, Chow P K, Ooi L L, Soo K C. A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. Cell Growth Differ. 2002; 13 115-122
82 Gray S G, Eriksson T, Ekstrom C, Holm S, von Schweinitz D, Kogner P, Sandstedt B, Pietsch T, Ekstrom T J. Altered expression of members of the IGF-axis in hepatoblastomas. Br J Cancer. 2000; 82 1561-1567
83 Scharf J G, Schmidt-Sandte W, Pahernik S A, Ramadori G, Braulke T, Hartmann H. Characterization of the insulin-like growth factor axis in a human hepatoma cell line (PLC). Carcinogenesis. 1998; 19 2121-2128
84 Kalme T, Loukovaara M, Koistinen H, Koistinen R, Seppala M, Leinonen P. Factors regulating insulin-like growth factor binding protein-3 secretion from human hepatoma (HepG2) cells. J Steroid Biochem Mol Biol. 2001; 78 131-135
85 Kim D G, Lee D Y, Cho B H, You K R, Kim M Y, Ahn D S. Down-regulation of insulin-like growth factor binding proteins and growth modulation in hepatoma cells by retinoic acid. Hepatology. 1999; 29 1091-1098
86 Baxter R C. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab. 2000; 278 E967-E976
87 Mohan S, Baylink D J. IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol. 2002; 175 19-31
88 Komatsu S, Okazaki Y, Tateno M, Kawai J, Konno H, Kusakabe M, Yoshiki A, Muramatsu M, Held W A, Hayashizaki Y. Methylation and downregulated expression of mac25/insulin-like growth factor binding protein-7 is associated with liver tumorigenesis in SV40T/t antigen transgenic mice, screened by restriction landmark genomic scanning for methylation (RLGS-M). Biochem Biophys Res Commun. 2000; 267 109-117
89 von Horn H, Hwa V, Rosenfeld R G, Hall K, Teh B T, Tally M, Ekstrom T J, Gray S G. Altered expression of low affinity insulin-like growth factor binding protein related proteins in hepatoblastoma. Int J Mol Med. 2002; 9 645-649
90 Zwad O, Kubler B, Roth W, Scharf J G, Saftig P, Peters C, Braulke T. Decreased intracellular degradation of insulin-like growth factor binding protein-3 in cathepsin L-deficient fibroblasts. FEBS Lett. 2002; 510 211-215
91 Brouillet J P, Hanslick B, Maudelonde T, Pivat M T, Grenier J, Blanc F, Rochefort H. Increased plasma cathepsin D concentration in hepatic carcinoma and cirrhosis but not in breast cancer. Clin Biochem. 1991; 24 491-496
92 Tumminello F M, Leto G, Pizzolanti G, Candiloro V, Crescimanno M, Crosta L, Flandina C, Montalto G, Soresi M, Carroccio A, Bascone F, Ruggeri I, Ippolito S, Gebbia N. Cathepsin D, B and L circulating levels as prognostic markers of malignant progression. Anticancer Res. 1996; 16 2315-2319
93 Martin D C, Fowlkes J L, Babic B, Khokha R. Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1. J Cell Biol. 1999; 146 881-892
94 Sakai K, Clemmons D R. Glucosamine induces resistance to insulin-like growth factor I (IGF-I) and insulin in Hep G2 cell cultures: biological significance of IGF-I/insulin hybrid receptors. Endocrinology. 2003; 144 2388-2395
95 Sakai K, Lowman H B, Clemmons D R. Increases in free, unbound insulin-like growth factor I enhance insulin responsiveness in human hepatoma G2 cells in culture. J Biol Chem. 2002; 277 13 620-13 627
96 McElduff A, Poronnik P, Baxter R C, Williams P. A comparison of the insulin and insulin-like growth factor I receptors from rat brain and liver. Endocrinology. 1988; 122 1933-1939
97 Caro J F, Poulos J, Ittoop O, Pories W J, Flickinger E G, Sinha M K. Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal liver. J Clin Invest. 1988; 81 976-981
98 Hartmann H, Schmitz F, Christ B, Jungermann K, Creutzfeldt W. Metabolic actions of insulin-like growth factor-I in cultured hepatocytes from adult rats. Hepatology. 1990; 12 1139-1143
99 Scharf J-G, Ramadori G, Hartmann H. Contribution of Kupffer cells to the biosynthesis of insulin-like growth factor system in rat liver. In: Wisse E, Knook DL, Balabaud C (eds) Cells of the Hepatic Sinusoid. Leiden; The Kupffer Cell Foundation 1997: 363-365
100 Brenzel A, Gressner A M. Characterization of insulin-like growth factor (IGF)-I binding sites during in vitro transformation of rat hepatic stellate cells to myofibroblasts. Eur J Clin Chem Clin Biochem. 1996; 34 401-409
101 Svegliati-Baroni G, Ridolfi F, di Sario A, Casini A, Marucci L, Gaggiotti G, Orlandoni P, Macarri G, Perego L, Benedetti A, Folli F. Insulin and insulin-like growth factor-1 stimulate proliferation and type 1 collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology. 1999; 29 1743-1751
102 Skrtic S, Wallenius K, Gressner A M, Jansson J O. Insulin-like growth factor signaling pathways in rat hepatic stellate cells: importance for deoxyribonucleic acid synthesis and hepatocyte growth factor production. Endocrinology. 1999; 140 5729-5735
103 Tsai T F, Yauk Y K, Chou C K, Ting L P, Chang C, Hu C P, Han S H, Su T S. Evidence of autocrine regulation in human hepatoma cell lines. Biochem Biophys Res Commun. 1988; 153 39-45
104 Verspohl E J, Maddux B A, Goldfine I D. Insulin and insulin-like growth factor I regulate the same biological functions in HEP-G2 cells via their own specific receptors. J Clin Endocrinol Metab. 1988; 67 169-174
105 Duclos M J, Chevalier B, Upton Z, Simon J. Insulin-like growth factor-I effect on chicken hepatoma cells (LMH) is inhibited by endogenous IGF-binding proteins. Growth Horm IGF Res. 1998; 8 97-103
106 Zahradka P, Werner J, Yau L. Expression and regulation of the insulin-like growth factor-1 receptor by growing and quiescent H4IIE hepatoma. Biochim Biophys Acta. 1998; 1375 131-139
107 Kim S O, Park J G, Lee Y I. Increased expression of the insulin-like growth factor I (IGF-I) receptor gene in hepatocellular carcinoma cell lines: implications of IGF-I receptor gene activation by hepatitis B virus X gene product. Cancer Res. 1996; 56 3831-3836
108 Lee Y I, Han Y J, Lee S Y, Lee Y I, Park S K, Park Y J, Moon H B, Shin J H, Lee J H. Activation of insulin-like growth factor II signaling by mutant type p53: physiological implications for potentiation of IGF-II signaling by p53 mutant 249. Mol Cell Endocrinol. 2003; 203 51-63
109 Schmitz F, Bresciani R, Hartmann H, Braulke T. Effect of insulin-like growth factor II on uptake of arylsulfatase A by cultured rat hepatocytes and Kupffer cells. J Hepatol. 1995; 22 356-363
110 De Souza A T, Hankins G R, Washington M K, Fine R L, Orton T C, Jirtle R L. Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene. 1995; 10 1725-1729
111 Piao Z, Choi Y, Park C, Lee W J, Park J H, Kim H. Deletion of the M6P/IGF2r gene in primary hepatocellular carcinoma. Cancer Lett. 1997; 120 39-43
112 Byrd J C, Devi G R, De Souza A T, Jirtle R L, MacDonald R G. Disruption of ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor by cancer-associated missense mutations. J Biol Chem. 1999; 274 24 408-24 416
113 Devi G R, De Souza A T, Byrd J C, Jirtle R L, MacDonald R G. Altered ligand binding by insulin-like growth factor II/mannose 6-phosphate receptors bearing missense mutations in human cancers. Cancer Res. 1999; 59 4314-4319
114 Reiss M. Transforming growth factor-beta and cancer: a love-hate relationship?. Oncol Res. 1997; 9 447-457
115 Jirtle R L, Hankins G R, Reisenbichler H, Boyer I J. Regulation of mannose 6-phosphate/insulin-like growth factor-II receptors and transforming growth factor beta during liver tumor promotion with phenobarbital. Carcinogenesis. 1994; 15 1473-1478
116 Sue S R, Chari R S, Kong F M, Mills J J, Fine R L, Jirtle R L, Meyers W C. Transforming growth factor-beta receptors and mannose 6-phosphate/insulin-like growth factor-II receptor expression in human hepatocellular carcinoma. Ann Surg. 1995; 222 171-178
117 De Souza A T, Hankins G R, Washington M K, Orton T C, Jirtle R L. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet. 1995; 11 447-449
118 Oka Y, Waterland R A, Killian J K, Nolan C M, Jang H S, Tohara K, Sakaguchi S, Yao T, Iwashita A, Yata Y, Takahara T, Sato S, Suzuki K, Masuda T, Jirtle R L. M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. Hepatology. 2002; 35 1153-1163
119 Wada I, Kanada H, Nomura K, Kato Y, Machinami R, Kitagawa T. Failure to detect genetic alteration of the mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene in hepatocellular carcinomas in Japan. Hepatology. 1999; 29 1718-1721
120 Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I, Kawata S, Matsuzawa Y. Lack of frameshift mutations at coding mononucleotide repeats in hepatocellular carcinoma in Japanese patients. Cancer. 2000; 88 1025-1029
121 Enomoto A, Esumi M, Yamashita K, Takagi K, Takano S, Iwai S. Abnormal nucleotide repeat sequence in the TGF-betaRII gene in hepatocellular carcinoma and in uninvolved liver tissue. J Pathol. 2001; 195 349-354
122 Buendia M A. Genetics of hepatocellular carcinoma. Semin Cancer Biol. 2000; 10 185-200
123 Bobek G, Scott C D, Baxter R C. Secretion of soluble insulin-like growth factor-II/mannose 6-phosphate receptor by rat tissues in culture. Endocrinology. 1991; 128 2204-2206
124 Causin C, Waheed A, Braulke T, Junghans U, Maly P, Humbel R E, von Figura K. Mannose 6-phosphate/insulin-like growth factor II-binding proteins in human serum and urine. Their relation to the mannose 6-phosphate/insulin-like growth factor II receptor. Biochem J. 1988; 252 795-799
125 MacDonald R G, Tepper M A, Clairmont K B, Perregaux S B, Czech M P. Serum form of the rat insulin-like growth factor II/mannose 6-phosphate receptor is truncated in the carboxyl-terminal domain. J Biol Chem. 1989; 264 3256-3261
126 Bobek G, Scott C D, Baxter R C. Radioimmunoassay of soluble insulin-like growth factor-II/mannose 6-phosphate receptor: developmental regulation of receptor release by rat tissues in culture. Endocrinology. 1992; 130 387-3394
127 Li M, Distler J J, Jourdian G W. Isolation and characterization of mannose 6-phosphate/insulin-like growth factor II receptor from bovine serum. Glycobiology. 1991; 1 511-517
128 Valenzano K J, Heath-Monnig E, Tollefsen S E, Lake M, Lobel P. Biophysical and biological properties of naturally occurring high molecular weight insulin-like growth factor II variants. J Biol Chem. 1997; 272 4804-4813
129 Scott C D, Ballesteros M, Madrid J, Baxter R C. Soluble insulin-like growth factor-II/mannose 6-P receptor inhibits deoxyribonucleic acid synthesis in cultured rat hepatocytes. Endocrinology. 1996; 137 873-878
130 Bannasch P. Pathogenesis of hepatocellular carcinoma: sequential cellular, molecular, and metabolic changes. Prog Liver Dis. 1996; 14 161-197
131 Dombrowski F, Bannasch P, Pfeifer U. Hepatocellular neoplasms induced by low-number pancreatic islet transplants in streptozotocin diabetic rats. Am J Pathol. 1997; 150 1071-1087
132 Dombrowski F, Lehringer-Polzin M, Pfeifer U. Hyperproliferative liver acini after intraportal islet transplantation in streptozotocin-induced diabetic rats. Lab Invest. 1994; 71 688-699
133 Dombrowski F, Filsinger E, Bannasch P, Pfeifer U. Altered liver acini induced in diabetic rats by portal vein islet isografts resemble preneoplastic hepatic foci in their enzymic pattern. Am J Pathol. 1996; 148 1249-1256
134 Scharf J-G, Ramadori G, Dombrowski F. Analysis of the IGF axis in preneoplastic foci and hepatocellular neoplasms developing after low-number pancreatic islet transplantation into the livers of streptozotocin diabetic rats. Lab Invest. 2000; 80 1399-1411
135 Rogler C E, Rogler L E, Yang D, Breiteneder-Geleef S, Gong S, Wang H. Contributions of hepadnavirus research to our understanding of hepatocarcinogenesis. In: Jirtle RL (ed) Liver regeneration and carcinogenesis: Molecular and cellular mechanisms. San Diego; Academic Press 1995: 113-140

PD Dr. med. J.-G. Scharf, M. D.

Zentrum Innere Medizin, Abteilung Gastroenterologie und Endokrinologie

Robert-Koch-Str. 40 · 37075 Göttingen · Germany

Phone: +49(551)398589

Fax: +49(551)392026

Email: jscharf@med.uni-goettingen.de