Clinical implications of insulin-like growth factors through the presence of their binding proteins and receptors expressed in gynecological cancers

Since insulin-like growth factors (IGFs) are known to play critical roles in the development of cancers, we examined the expression of the mRNA and protein of IGF-binding protein (IGFBP) and cognate receptors to assess their possible involvement in gynecological malignancy. The specimens were obtained from 46 endometrial, 32 cervical, and 20 ovarian cancers, and 28 normal endometrium. In endometrial cancers, IGFBP-1, -2, -3 and IGF-1 receptor (IGF-1R) mRNAs were detected in 8.7, 89.1, 95.6, and 91.3% of tumors, respectively, and the corresponding proteins in 54.3, 54.3, 95.6, and 91.3% of tumors, respectively. Clinical staging was significantly related to the expression of IGFBP-1 and -2 proteins. In ovarian cancers, their mRNAs were detected in 10.0, 90.0, 95.0, and 100.0%, and proteins in 15.9, 50.0, 90.0, and 80.0%. In cervical cancers, their mRNAs were detected in 6.3, 90.6, 96.8, and 87.5%, and proteins in 44.4, 18.8, 84.4, and 87.5%. IGF-1R was highly expressed in all specimens. The abnormally balanced co-expression of IGFBPs and high levels of IGF-R in gynecological cancers suggest that IGF signals might be involved in the growth of these tumors.

IGFBP, IGF-R; Endometrial cancer; Cervical cancer; Ovarian cancer; Clinical implication

[1] Clemmons D., Busby W., Arai T., Nam T., Clarke J., Jones J. et al.: "Role of insulin-like growth factor binding proteins in the control of IGF actions". Prog. Growth Factor. Res., 1995, 6, 357.

[2] Daughaday W., Rotwein P.: "Insulin-like growth factors I and II Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations". Endocr. Rev., 1989,10, 68.

[3] Rosenfeld R., Lamson G., Pham H., Oh Y., Conover C., DeLeon D. et al.: "lnsulinlike growth factor-binding proteins". Recent. Prag. Horm. Res., 1990, 46, 99.

[4] Jones J., Clemmons D.: "Insulin-like growth factors and their binding proteins: biological actions". Endocr. Rev., 1995, 16, 3.

[5] Rutanen E., Pekonen F., Nyman T., Wahlstrom T.: "Insulin-like growth factors and their binding proteins in benign and malignant uterine diseases". Growth Regul.,1993, 3, 74.

[6] Maccario M., Tassone F., Grottoli S., Rossetto R., Gauna C., Ghigo E.: "Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-1 axis to obesity". Ann. Endocrinol. (Paris), 2002, 63, 140.

[7] Wang Y., Sun Y.: "Insulin-like growth factor receptor-I as an anttcancer target: blocking transformation and inducing apoptosis" Curr. Cancer Drug. Targets, 2002, 2, 191.

[8] Katsaros D., Yu H., Levesqu eM., Danese S., Gent aF., Richiardi G. et al.: "IGFBP-3 in epithelial ovarian carcinoma and its associaton with clinico-pathological features and patient survival". Eur. J. Cancer, 2001, 37, 478.

[9] Bermont L., Fauconnet S., Lamielle F., Adessi G.: "Cell-associated insulin-like growth factor-binding proteins inhibit insulin-like growth factor-I-induced endometrial cancer cell proliferation" Cell. Mot. Biol., 2000, 46, 1173.

[10] Rutanen E., Nyman T., Lehtovirta P., Ammala M., Pekonen F "Suppressed expression of insulin-like growth factor binding protein-I mRNA in the endometrium: a molecular mechanism associating endometrial cancer with its risk factors". Int. J. Cancer 1994, 59, 307.

[11] Moschos SJ., Mantzoros C.S.: "The role of the IGF system in cancer: from basic to clinical studies and clinical applications" Oncology, 2002, 63, 317.

[12] Bermont L., Lamielle F., Fauconnet S., Esumi H., Weisz A., Adessi G.: "Regulation of vascular endothelial growth factor expression by insulin-like growth factor-I in endometrial adenocarcinoma cells". Int. J. Cancer, 2000, 85, 117.

[13] Furstenberger G., Senn H.: "Insulin-like growth factors and cancer". Lancet Oncol., 2002, 3, 298.

[14] Nagamani M., Stuart C., Dunhardt P., Doherty M.: "Specific binding sites for insulin and insulin-like growth factor I in human endometrial cancer". Am. J. Ohstet. Gynecol., 1991, 165, 1865.

[15] Ayabe T., Tsutsumi O., Sakai H., Yoshikawa H., Yano T., Kurimoto F. et al.: "Increased circulating levels of insulin-like growth factorI and decreased circulating levels of insulin-like growth factor binding protein-1 in postmenopausal women with endometrial cancer". Endocr. J., 1997, 44, 419.

[16] Park J., McCusker R., Vanderhoof J., Mohammadpour H., Harty R., MacDonald R.: "Secretion of insulin-like growth factor II (IGF-11) and IGF-binding protein-2 by intestinal epithelial (IEC-6) cells: implications for autocrine growth regulation". Endocrinology, 1992, 131, 1359.

[17] Barreca A., DeLuca M., Del Monte P., Bondanza S., Damonte G., Cariola G. et al.: "ln vitro paracrine regulation of human keratinocyte growth by fibroblast-derived insulin-like growth factors". J. Cell. Physiol., 1992, 151, 262.

[18] Richards J., Russell D., Ochsner S., Hsieh M., Doyle K., Falender A. et al.: "Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization". Recent Prog. Harm Res., 2002, 57, 195.

[19] Gambineri A., Pelusi C., Vicennati V., Pagotto U., Pasquali R "Obesity and the polycystic ovary syndrome". Int. J. Obes. Relat. Metab. Disord., 2002, 26, 883.

[20] Burns K., Matzuk M.: "Genetic models for the study of gonadotropin actions". Endocrinology, 2002, 143, 2823.

[21] Druckmann R., Rohr U.: "IGF-1 in gynaecology and obstetncs update 2002". Maturitas, 2002, 41 (suppl. 1), S65.

[221 Wood J.,S trauss Jr.: "Multiple signal transduction pathways regulate ovarian steroidogenesis". Rev. Endocr. Metah. Disord., 2002, 3, 33.

[23] Jesionowska H., R. H., H.J. G., Bi P.: "Determination of insulin and insulin-like growth factors in the ovarian circulation". Fertil. Steril., 1990, 53, 88.

[24] Hofmann J., Wegmann B., Hackenberg R., Kunzmann R., Schulz K., Havemann K.: "Production of insulin-like growth factor binding proteins by human ovarian carcinoma cells". J. Cancer Res. Clin. Oncol., 1994, 120, 137.

[25] Krywicki R., Figueroa J., Jackson J., Kozelsky T., Shimasaki S., Von Hoff D. et al.: "Regulation of insulin-like growth factor binding proteins in ovarian cancer cells by oestrogen". Eur. J. Cancer, 1993, 29A, 2015.

[26] Schedlich L., Graham L.: "Role of insulin-like growth factor binding protein-3 in breast cancer cell growth". Mic rose. Res Tech., 2002, 59, 12.

[27] Schernhammer E.: "In-utero exposures and breast cancer risk: joint effect of estrogens and insulin-like growth factor ?" Cancer Causes Control., 2002, 13, 505.

[28J Hembree J., Agarwal C., Eckert R.: "Epidermal growth factor suppresses insulin-like growth factor binding protein 3 levels in human papillomavirus type 16-immortalized cervical epithelial cells and thereby potentiates the effects of insulin-like growth factor 1". Cancer Res., 1994, 54, 3160.

[29] Laemmli W.: "Cleavage of structural proteins during the assembly of the head of bacteriophage lambda". Nature, 1970, 227, 680

[30] Lowry O.H., Rosenbrough N., Farr A.L., Randall R.J.: "Protein measurement with the Folin phenol reagent". J. Biol. Chem., 1951, 193, 265.

[31] Chomczynski P., Sacchi N.: "Single-step method of RNA isolation by acid guanidium thiocyanate-chloroform extraction". Anal Biochem., 1987, 162, 156.

[32] Buyalos R., Pekonen F., Halme J., Judd H., Rutanen E.: "The relationship between circulating androgens, obesity, and hyperinsulinemia on serum insulin-like growth factor binding protein-1 in the polycystic ovarian syndrome". Am. J. Obstet. Gynecol., 1995, 172, 932.

[33] Toneguzzo F., Glynn S., Levi E., Mjolseness S., Hayday A.: "Use of a chemically modified T 7 DNA polymerase for manual and automated sequencing of supercoiled DNA". Biotechniques, 1988, 6, 460.

[34] Lala P., Lee B., Xu G., Chakraborty C.: "Human placental trophoblast as an in vitro model for tumor progression". Can. J Physiol. Pharmacol., 2002, 80, 142.

[35] Chakraborty C., Gleeson L., McKinnon T., Lala P.: "Regulation of human trophoblast migration and invasiveness". Can. J. Physiol Pharmacol., 2002, 80, 116.

[36] Giudie L.: "Insulin-like growth factors and ovarian follicular development". Endocr. Rev., 1992, 13, 641.

[37] Yee D., Morales F., Hamilton T., VonHoff D.: "Expression of insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer". Cancer Res., 1991, 51, 5107.

[38] Kanety H., Kattan M., Goldberg I., Kopolovic J., Ravia J., Menczer J. et al.: "Increased insulin-like growth factor binding protein-2 (IGFBP-2) gene expression and protein production lead to high IGFBP-2 content in malignant ovarian cyst fluid". Br. J Cancer, 1996, 73, 1069.

[39] Karasik A., Menczer J., Pariente C., Kanety H.: "Insulin-like growth factor-I (IGF-I) and IGF-binding protein-2 are increased in cyst fluids of epithelial ovarian cancer". J. Clin. Endocrinol. Metab., 1994, 78, 271.

[40] Bast R.C. Jr., Xu F.J., Yu Y.H., Barnhill S., Zhang Z., Mills G.B "CA 125: the past and the future". Int. J. Biol. Markers, 1998, 13, 179.