Liver-derived IGF 1 enhances the a ndrogenic response in prostate

Both IGF1 and androgens are major enhancers of prostate growth and are implicated in the development of prostate hyperplasia and cancer. The aim of the present study was to investigate whether liver-derived endocrine IGF1 modulates the androgenic response in prostate. Mice with adult, liverspecific inactivation of IGF1 (LI-IGF1 mice) displayed an w80% reduction in serumIGF1 levels associatedwith decreased prostate weight compared with control mice (anterior prostate lobeK19%, P!0.05; dorsolateral prostate (DLP) lobeK35%, P!0.01; ventral prostate (VP) lobeK47%,P!0.01).Reduced androgen receptor (Ar) mRNA and protein levels were observed in the VP lobe (K34% andK30% respectively, both P!0.05 versus control mice). Analysis of prostate morphology showed reductions in both the glandular and fibromuscular Journal of Endocrinology (2008) 199, 489–497 0022–0795/08/0199–489 q 2008 Society for Endocrinology Printed in Great compartments of the VP and DLP lobes that were proportional to the reductions in the weights of these lobes. Immunohistochemistry revealed reduced intracellular AR immunoreactivity in the VP and DLP lobes. The non-aromatizable androgen dihydrotestosterone increased VP weight to a lesser extent in orchidectomized (ORX) LI-IGF1 mice than in ORX controls (K40%, P!0.05 versus control mice). In conclusion, deficiency of liver-derived IGF1 reduces both the glandular and fibromuscular compartments of the prostate, decreases AR expression in prostate, and reduces the stimulatory effect of androgens onVPweight. These findings may explain, at least in part, the well-known clinical association between serum IGF1 levels and conditions with abnormal prostate growth. Journal of Endocrinology (2008) 199, 489–497

[1]  P. Cohen,et al.  Targeted deletion of hepatic Igf1 in TRAMP mice leads to dramatic alterations in the circulating insulin-like growth factor axis but does not reduce tumor progression. , 2008, Cancer research.

[2]  P. Cohen,et al.  Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis , 2007, Oncogene.

[3]  D. Leroith,et al.  The role of the IGF system in cancer growth and metastasis: overview and recent insights. , 2007, Endocrine reviews.

[4]  Fu-Ping Zhang,et al.  Estrogen-induced upregulation of AR expression and enhancement of AR nuclear translocation in mouse fallopian tubes in vivo. , 2007, American journal of physiology. Endocrinology and metabolism.

[5]  D. Yee,et al.  Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice. , 2007, Endocrinology.

[6]  B. Lokeshwar,et al.  Insulin-like growth factors and their binding proteins in prostate cancer: cause or consequence? , 2006, Urologic oncology.

[7]  Changlian Zhu,et al.  Nuclear progesterone receptor A and B isoforms in mouse fallopian tube and uterus: implications for expression, regulation, and cellular function. , 2006, American journal of physiology. Endocrinology and metabolism.

[8]  J. Lam,et al.  Secondary hormonal therapy for advanced prostate cancer. , 2006, The Journal of urology.

[9]  M. Pollak,et al.  A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model , 2005, Oncogene.

[10]  C. Roberts,et al.  Androgens Upregulate the Insulin-like Growth Factor-I Receptor in Prostate Cancer Cells , 2005 .

[11]  B. Leyland-Jones,et al.  Deregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions. , 2003, Endocrine-related cancer.

[12]  C. Ormandy,et al.  Prostate hyperplasia in a transgenic mouse with prostate-specific expression of prolactin. , 2003, Endocrinology.

[13]  A. Colao,et al.  Effect of growth hormone (GH) and/or testosterone replacement on the prostate in GH-deficient adult patients. , 2003, The Journal of clinical endocrinology and metabolism.

[14]  K. Sjögren,et al.  Effects of Liver‐Derived Insulin‐Like Growth Factor I on Bone Metabolism in Mice , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[15]  S. Boonen,et al.  Evidence From the Aged Orchidectomized Male Rat Model That 17β‐Estradiol Is a More Effective Bone‐Sparing and Anabolic Agent Than 5α‐Dihydrotestosterone , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[16]  G. Bergström,et al.  Liver-derived insulin-like growth factor-I is involved in the regulation of blood pressure in mice. , 2002, Endocrinology.

[17]  C. Ling,et al.  Progressive prostate hyperplasia in adult prolactin transgenic mice is not dependent on elevated serum androgen levels , 2002, The Prostate.

[18]  C. Ohlsson,et al.  Liver-Derived IGF-I Regulates GH Secretion at the Pituitary Level in Mice. , 2001, Endocrinology.

[19]  G. Pacini,et al.  Liver-derived IGF-I is of importance for normal carbohydrate and lipid metabolism. , 2001, Diabetes.

[20]  M. Pollak,et al.  Insulin-like growth factors and prostate cancer. , 2001, Epidemiologic reviews.

[21]  D. Leroith,et al.  Normal growth and development in the absence of hepatic insulin-like growth factor I. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  K. Sjögren,et al.  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. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  B. Foster,et al.  The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. , 1999, Cancer research.

[24]  J. Kopchick,et al.  Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development. , 1999, Endocrinology.

[25]  D. Leroith,et al.  Insulin-like growth factor-I affects perinatal lethality and postnatal development in a gene dosage-dependent manner: manipulation using the Cre/loxP system in transgenic mice. , 1998, Molecular endocrinology.

[26]  R. McNally,et al.  Mortality and Cancer Incidence in Acromegaly: A Retrospective Cohort Study , 1998 .

[27]  M. Stampfer,et al.  Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. , 1998, Science.

[28]  C. Mantzoros,et al.  Insulin-like growth factor 1 and prostate cancer risk: a population-based, case-control study. , 1998, Journal of the National Cancer Institute.

[29]  P. Marzullo,et al.  Prostatic hyperplasia: an unknown feature of acromegaly. , 1998, The Journal of clinical endocrinology and metabolism.

[30]  S. Orme,et al.  Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. , 1998, The Journal of clinical endocrinology and metabolism.

[31]  C. Mantzoros,et al.  Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. , 1997, British Journal of Cancer.

[32]  M Aguet,et al.  Inducible gene targeting in mice , 1995, Science.

[33]  H. Klocker,et al.  Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor and epidermal growth factor. , 1995, European urology.

[34]  D. Peehl,et al.  Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. , 1994, The Journal of endocrinology.

[35]  D. Peehl,et al.  The IGF axis in the prostate. , 1994, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[36]  M. Papa,et al.  Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. , 1993, The Journal of clinical endocrinology and metabolism.

[37]  L. Giudice,et al.  Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. , 1992, The Journal of clinical endocrinology and metabolism.

[38]  S. Mohan,et al.  An inhibitory insulin-like growth factor binding protein (In-IGFBP) from human prostatic cell conditioned medium reveals N-terminal sequence identity with bone derived In-IGFBP. , 1990, The Journal of clinical endocrinology and metabolism.