Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis

Oncogene volume 27, pages 2868–2876 (2008)Cite this article

Abstract

The insulin-like growth factor-1 (IGF-1) signaling axis is important for cell growth, differentiation and survival and increased serum IGF is a risk factor for prostate and other cancers. To study IGF-1 action on the prostate, we created transgenic (PB-Des) mice that specifically express human IGF-1des in prostate epithelial cells. This encodes a mature isoform of IGF-1 with decreased affinity for IGF binding proteins (IGFBP) due to a 3-amino acid deletion in the N terminus. Expression of IGF-1des was sufficient to cause hyperplastic lesions in all mice, however the well-differentiated lesions did not progress to adenocarcinoma within a year. Remarkably, crossing the PB-Des mice to an established model of prostate cancer delayed progression of organ-confined tumors and emergence of metastatic lesions in young mice. While dissemination of metastatic lesions was widespread in old bigenic mice we did not detect IGF-1des in poorly differentiated primary tumors or metastatic lesions. Expression of endogenous IGF-1 and levels of P-Akt and P-Erk were reduced independent of age. These data suggest that increased physiologic levels of IGF-1 facilitate the emergence of hyperplastic lesions while imposing a strong IGF-1-dependent differentiation block. Selection against IGF-1 action appears requisite for progression of localized disease and metastogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Ahlen J, Wejde J, Brosjo O, von Rosen A, Weng WH, Girnita L et al. (2005). Insulin-like growth factor type 1 receptor expression correlates to good prognosis in highly malignant soft tissue sarcoma. Clin Cancer Res 11: 206–216.

    CAS  PubMed  Google Scholar 

  • Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T et al. (2007). IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448: 1015–1021.

    Article  CAS  Google Scholar 

  • Burger PE, Xiong X, Coetzee S, Salm SN, Moscatelli D, Goto K et al. (2005). Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proc Natl Acad Sci USA 102: 7180–7185.

    Article  CAS  Google Scholar 

  • Byrne RL, Leung H, Neal DE . (1996). Peptide growth factors in the prostate as mediators of stromal epithelial interaction. Br J Urol 77: 627–633.

    Article  CAS  Google Scholar 

  • Carboni JM, Lee AV, Hadsell DL, Rowley BR, Lee FY, Bol DK et al. (2005). Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res 65: 3781–3787.

    Article  CAS  Google Scholar 

  • Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P et al. (1998). Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279: 563–566.

    Article  CAS  Google Scholar 

  • Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano JM, Pollak M et al. (2002). Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 94: 1099–1106.

    Article  CAS  Google Scholar 

  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ . (1979). Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18: 5294–5299.

    Article  CAS  Google Scholar 

  • Chott A, Sun Z, Morganstern D, Pan J, Li T, Susani M et al. (1999). Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor. Am J Pathol 155: 1271–1279.

    Article  CAS  Google Scholar 

  • Colao A, Marzullo P, Spiezia S, Ferone D, Giaccio A, Cerbone G et al. (1999). Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases: an ultrasonographic and endocrine study in acromegaly, GH deficiency, and healthy subjects. J Clin Endocrinol Metab 84: 1986–1991.

    Article  CAS  Google Scholar 

  • Cunha GR, Donjacour AA . (1989). Mesenchymal-epithelial interactions in the growth and development of the prostate. Cancer Treat Res 46: 159–175.

    Article  CAS  Google Scholar 

  • Damon SE, Plymate SR, Carroll JM, Sprenger CC, Dechsukhum C, Ware JL et al. (2001). Transcriptional regulation of insulin-like growth factor-I receptor gene expression in prostate cancer cells. Endocrinology 142: 21–27.

    Article  CAS  Google Scholar 

  • DiGiovanni J, Bol DK, Wilker E, Beltran L, Carbajal S, Moats S et al. (2000a). Constitutive expression of insulin-like growth factor-1 in epidermal basal cells of transgenic mice leads to spontaneous tumor promotion. Cancer Res 60: 1561–1570.

    CAS  PubMed  Google Scholar 

  • DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L et al. (2000b). Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci USA 97: 3455–3460.

    Article  CAS  Google Scholar 

  • Evangelou AI, Winter SF, Huss WJ, Bok RA, Greenberg NM . (2004). Steroid hormones, polypeptide growth factors, hormone refractory prostate cancer, and the neuroendocrine phenotype. J Cell Biochem 91: 671–683.

    Article  CAS  Google Scholar 

  • Forbes K, Gillette K, Kelley LA, Sehgal I . (2004). Increased levels of urokinase plasminogen activator receptor in prostate cancer cells derived from repeated metastasis. World J Urol 22: 67–71.

    Article  CAS  Google Scholar 

  • Foulstone E, Prince S, Zaccheo O, Burns JL, Harper J, Jacobs C et al. (2005). Insulin-like growth factor ligands, receptors, and binding proteins in cancer. J Pathol 205: 145–153.

    Article  CAS  Google Scholar 

  • Gingrich JR, Barrios RJ, Morton RA, Boyce BF, DeMayo FJ, Finegold MJ et al. (1996). Metastatic prostate cancer in a transgenic mouse. Cancer Res 56: 4096–4102.

    CAS  PubMed  Google Scholar 

  • Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO et al. (1995). Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92: 3439–3443.

    Article  CAS  Google Scholar 

  • Greenberg NM, DeMayo FJ, Sheppard PC, Barrios R, Lebovitz R, Finegold M et al. (1994). The rat probasin gene promoter directs hormonally and developmentally regulated expression of a heterologous gene specifically to the prostate in transgenic mice. Mol Endocrinol 8: 230–239.

    CAS  PubMed  Google Scholar 

  • Hadsell DL, Greenberg NM, Fligger JM, Baumrucker CR, Rosen JM . (1996). Targeted expression of des(1-3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression. Endocrinology 137: 321–330.

    Article  CAS  Google Scholar 

  • Hadsell DL, Murphy KL, Bonnette SG, Reece N, Laucirica R, Rosen JM . (2000). Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis. Oncogene 19: 889–898.

    Article  CAS  Google Scholar 

  • Hudson DL . (2004). Epithelial stem cells in human prostate growth and disease. Prostate Cancer Prostatic Dis 7: 188–194.

    Article  CAS  Google Scholar 

  • Huss WJ, Gray DR, Greenberg NM, Mohler JL, Smith GJ . (2005). Breast cancer resistance protein-mediated efflux of androgen in putative benign and malignant prostate stem cells. Cancer Res 65: 6640–6650.

    Article  CAS  Google Scholar 

  • Kaplan PJ, Mohan S, Cohen P, Foster BA, Greenberg NM . (1999). The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Cancer Res 59: 2203–2209.

    CAS  PubMed  Google Scholar 

  • Kaplan-Lefko PJ, Chen TM, Ittmann MM, Barrios RJ, Ayala GE, Huss WJ et al. (2003). Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 55: 219–237.

    Article  Google Scholar 

  • Kwabi-Addo B, Giri D, Schmidt K, Podsypanina K, Parsons R, Greenberg N et al. (2001). Haploinsufficiency of the PTEN tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci USA 98: 11563–11568.

    Article  CAS  Google Scholar 

  • Le Roith D . (2003). The insulin-like growth factor system. Exp Diabesity Res 4: 205–212.

    Article  Google Scholar 

  • Le Roith D, Roberts Jr CT . (2003). The insulin-like growth factor system and cancer. Cancer Lett 195: 127–137.

    Article  CAS  Google Scholar 

  • MacGrogan D, Bookstein R . (1997). Tumour suppressor genes in prostate cancer. Semin Cancer Biol 8: 11–19.

    Article  CAS  Google Scholar 

  • Majeed N, Blouin MJ, Kaplan-Lefko PJ, Barry-Shaw J, Greenberg NM, Gaudreau P et al. (2005). A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. Oncogene 24: 4736–4740.

    Article  CAS  Google Scholar 

  • Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JK et al. (2007). Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci USA 104: 5563–5568.

    Article  CAS  Google Scholar 

  • Nakamura M, Miyamoto S, Maeda H, Zhang SC, Sangai T, Ishii G et al. (2004). Low levels of insulin-like growth factor type 1 receptor expression at cancer cell membrane predict liver metastasis in Dukes' C human colorectal cancers. Clin Cancer Res 10: 8434–8441.

    Article  CAS  Google Scholar 

  • Oh Y, Muller HL, Lee DY, Fielder PJ, Rosenfeld RG . (1993). Characterization of the affinities of insulin-like growth factor (IGF)-binding proteins 1–4 for IGF-I, IGF-II, IGF-I/insulin hybrid, and IGF-I analogs. Endocrinology 132: 1337–1344.

    Article  CAS  Google Scholar 

  • Platz EA, Pollak MN, Leitzmann MF, Stampfer MJ, Willett WC, Giovannucci E . (2005). Plasma insulin-like growth factor-1 and binding protein-3 and subsequent risk of prostate cancer in the PSA era. Cancer Causes Control 16: 255–262.

    Article  Google Scholar 

  • Plymate SR, Tennant MK, Culp SH, Woodke L, Marcelli M, Colman I et al. (2004). Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors. Prostate 61: 276–290.

    Article  CAS  Google Scholar 

  • Pollak MN, Schernhammer ES, Hankinson SE . (2004). Insulin-like growth factors and neoplasia. Nat Rev Cancer 4: 505–518.

    Article  CAS  Google Scholar 

  • Reiss K, Wang JY, Romano G, Furnari FB, Cavenee WK, Morrione A et al. (2000). IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation. Oncogene 19: 2687–2694.

    Article  CAS  Google Scholar 

  • Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M . (2004). Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363: 1346–1353.

    Article  CAS  Google Scholar 

  • Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D . (2000). Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer 89: 506–513.

    Article  CAS  Google Scholar 

  • Shaneyfelt T, Husein R, Bubley G, Mantzoros CS . (2000). Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol 18: 847–853.

    Article  CAS  Google Scholar 

  • Shappell SB, Thomas GV, Roberts RL, Herbert R, Ittmann MM, Rubin MA et al. (2004). Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res 64: 2270–2305.

    Article  CAS  Google Scholar 

  • Wennbo H, Gebre-Medhin M, Gritli-Linde A, Ohlsson C, Isaksson OG, Tornell J . (1997a). Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest 100: 2744–2751.

    Article  CAS  Google Scholar 

  • Wennbo H, Kindblom J, Isaksson OG, Tornell J . (1997b). Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland. Endocrinology 138: 4410–4415.

    Article  CAS  Google Scholar 

  • Wu X, Jin C, Wang F, Yu C, McKeehan WL . (2003). Stromal cell heterogeneity in fibroblast growth factor-mediated stromal-epithelial cell cross-talk in premalignant prostate tumors. Cancer Res 63: 4936–4944.

    CAS  PubMed  Google Scholar 

  • Xin L, Lawson DA, Witte ON . (2005). The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci USA 102: 6942–6947.

    Article  CAS  Google Scholar 

  • Yakar S, Pennisi P, Wu Y, Zhao H, LeRoith D . (2005). Clinical relevance of systemic and local IGF-I. Endocr Dev 9: 11–16.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Tsuey-Ming Chen for help with immunoblotting, Diane Gentry and Caroline Castile for animal care and histology support and Jeffrey M Rosen and Stephen Plymate for their many helpful insights and constructive commentaries. This work was supported by grants from the National Cancer Institute CA82807 and CA84296 (to NMG), CA74589 (to PJK-L), and The Prostate Cancer Foundation (to PJK-L and NMG).

Author information

Author notes

  1. P J Kaplan-Lefko

    Present address: 9Current address: AMGEN, Thousand Oaks CA, 91320,

  2. B W Sutherland

    Present address: 10Current address: Biomedical Research Centre, UBC, Vancouver BC, Canada,

  3. A I Evangelou

    Present address: 11Current address: University of Toronto, Toronto, Ontario, Canada,

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    P J Kaplan-Lefko, A I Evangelou, D L Hadsell, F DeMayo & N M Greenberg

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    B W Sutherland, A I Evangelou & N M Greenberg

  3. Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA

    D L Hadsell

  4. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    D L Hadsell

  5. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    R J Barrios

  6. Pharmacology and Therapeutics Department, Roswell Park Cancer Institute, Buffalo, NY, USA

    B A Foster

  7. Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

    N M Greenberg

  8. Department of Pharmacology, University of Washington, Seattle, WA, USA

    N M Greenberg

Authors
  1. P J Kaplan-Lefko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B W Sutherland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A I Evangelou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D L Hadsell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R J Barrios
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B A Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F DeMayo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N M Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N M Greenberg.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaplan-Lefko, P., Sutherland, B., Evangelou, A. et al. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene 27, 2868–2876 (2008). https://doi.org/10.1038/sj.onc.1210943

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210943

Keywords

This article is cited by

Search

Advanced search

Quick links