Download PDF
Exp Clin Endocrinol Diabetes 2010; 118(2): 113-120
DOI: 10.1055/s-0029-1202832
Article

© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Platelet-derived Growth Factor (PDGF) and PDGF Receptor Expression and Function in Folliculostellate Pituitary Cells

M. Kowarik 1 , C. Onofri 1 , T. Colaco 1 , G. K. Stalla 1 , U. Renner 1
  • 1Max-Planck-Institute of Psychiatry, Neuroendocrinology Group, Munich, Germany
Further Information

Publication History

received 08.07.2008 first decision 24.10.2008

accepted 03.02.2009

Publication Date:
16 April 2009 (online)

Also available at
    Permissions and Reprints

Abstract

Homo- and heterodimers of platelet-derived growth factor-A (PDGF-A) and PDGF-B chains are involved through PDGF α- and β-receptors in the growth regulation of multiple normal and tumoural cell types as well as in tumour neovascularization. Since little information is available on the impact of PDGF/PDGF receptors in normal and adenomatous pituitary, we studied the expression and action of this growth factor system in a variety of pituitary tumour cell lines and in rat anterior pituitary cell cultures. By RT-PCR, mRNA expression of PDGF-A and -B chains and of both receptors was found in rat pituitary and mouse folliculostellate TtT/GF pituitary tumour cells. Rat somatotroph MtT-S and mouse corticotroph AtT20 tumor cells expressed only a part of the PDGF/PDGF receptor components whereas mouse gonadotroph αT3-1 and rat lactosomatotroph GH3 pituitary tumour cells contained neither PDGF nor PDGF receptors. To further characterize the role of PDGF in TtT/GF cells, the effect of PDGF-AB and -BB on growth and vascular endothelial growth factor-A (VEGF-A) release was studied. Proliferation of TtT/GF cells was weakly but significantly stimulated by PDGF. Both in rat pituitary cell cultures and in TtT/GF cells, PDGF-AB and -BB strongly enhanced VEGF-A secretion. The PI3 kinase inhibitor LY 294002 blocked the increase in VEGF-A. Western immunoblotting confirmed the participation of key components of the PI3 kinase/Akt signal pathway (PDK1, Akt-Ser476) in PDGF-stimulated VEGF production. Thus the PDGF/PDGF receptor system is expressed in folliculostellate cells and is involved in VEGF regulation. Its role in endocrine pituitary tumour cell lines and pituitary adenomas need to be clarified in future studies.

Key words

Platelet-derived growth factor - PDGF receptors - folliculostellate cells - vascular endothelial growth factor - PI3 kinase/Akt pathway

References

  • 1 Abramsson A, Lindblom P, Betsholtz C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors.  J Clin Invest. 2003;  112 1142-1151
    PubMedSearch in Google Scholar
  • 2 Alexander JM, Biller BM, Bikkal H. et al . Clinically nonfunctioning pituitary tumors are monoclonal in origin.  J Clin Invest. 1990;  86 336-340
    PubMedSearch in Google Scholar
  • 3 Asa SL, Ezzat S. The pathogenesis of pituitary tumours.  Nat Rev Cancer. 2002;  2 836-849
    PubMedSearch in Google Scholar
  • 4 Betsholtz C. Insight into the physiological functions of PDGF through genetic studies in mice.  Cytokine Growth Factor Rev. 2004;  15 215-228
    CrossrefPubMedSearch in Google Scholar
  • 5 Board R, Jayson GC. Platelet-derived growth factor receptor (PDGFR): A target for anticancer therapeutics.  Drug Resist Updat. 2005;  8 75-83
    CrossrefPubMedSearch in Google Scholar
  • 6 Brader S, Eccles SA. Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis.  Tumori. 2004;  90 2-8
    PubMedSearch in Google Scholar
  • 7 Carvalho I, Milanezi F, Martins A. et al . Overexpression of platelet-derived growth factor receptor a in breast cancer is associated with tumour progression.  Breast Cancer Res. 2005;  7 R788-R795
    CrossrefPubMedSearch in Google Scholar
  • 8 Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer.  Trends Mol Med. 2007;  13 433-442
    CrossrefPubMedSearch in Google Scholar
  • 9 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanat-phenol-chloroform extraction.  Anal Biochem. 1987;  162 156-159
    PubMedSearch in Google Scholar
  • 10 Distler JH, Hirth A, Kurowska-Stolarska M. et al . Angiogenic and angiostatic factors in the molecular control of angiogenesis.  Q J Nucl Med. 2003;  47 149-161
    PubMedSearch in Google Scholar
  • 11 Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents.  Nat Rev Drug Discov. 2006;  5 671-688
    CrossrefPubMedSearch in Google Scholar
  • 12 Farnoud MR, Kujas M, Derome P. et al . Interactions between normal and tumoral tissues at the boundary of human anterior pituitary adenomas.  Virchows Arch. 1994;  424 75-82
    PubMedSearch in Google Scholar
  • 13 Fauquier T, Lacampagne A, Travo P. et al . Hidden face of the anterior pituitary.  Trends Endocrinol Metab. 2002;  13 304-309
    PubMedSearch in Google Scholar
  • 14 Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.  Biochem Biophys Res Commun. 1989;  161 851-858
    CrossrefPubMedSearch in Google Scholar
  • 15 Frederiksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms.  Cytokine Growth Factor Rev. 2004;  15 197-204
    CrossrefPubMedSearch in Google Scholar
  • 16 Guo P, Hu B, Gu W. et al . Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment.  Am J Pathol. 2003;  162 1083-1093
    PubMedSearch in Google Scholar
  • 17 Heinrich MC, Corless CL, Duensing A. et al . PDGFRA activating mutations in gastrointestinal stromal tumors.  Science. 2003;  299 708-710
    CrossrefPubMedSearch in Google Scholar
  • 18 Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor.  Physiol Rev. 1999;  79 1283-1316
    PubMedSearch in Google Scholar
  • 19 Höpfner M, Schuppan D, Scherübl H. Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer.  World J Gastroenterol. 2008;  14 1-14
    CrossrefPubMedSearch in Google Scholar
  • 20 Homsi J, Daud AI. Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors.  Cancer Control. 2007;  14 285-294
    PubMedSearch in Google Scholar
  • 21 Inoue K, Couch EF, Takano K. et al . The structure and function of folliculo-stellate cells in the anterior pituitary gland.  Arch Histol Cytol. 1999;  62 205-218
    PubMedSearch in Google Scholar
  • 22 Inoue K, Hattori M, Sakai T. et al . Establishment of a series of pituitary clonal cell lines differing in morphology, hormone secretion, and response to estrogen.  Endocrinology. 1990;  126 2313-2320
    PubMedSearch in Google Scholar
  • 23 Lederle W, Stark H-J, Skobe M. et al . Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells.  Am J Pathol. 2006;  169 1767-1783
    CrossrefPubMedSearch in Google Scholar
  • 24 Leon SP, Carroll RS, Dashner K. et al . Messenger ribonucleic acid expression of platelet-derived growth factor subunits and receptors in pituitary adenomas.  J Clin Endocrinol Metab. 1994;  79 51-55
    CrossrefPubMedSearch in Google Scholar
  • 25 Lohrer P, Gloddek J, Hopfner U. et al . Vascular endothelial growth factor production and regulation in rodent and human pituitary tumor cells in vitro.  Neuroendocrinology. 2001;  74 95-105
    CrossrefPubMedSearch in Google Scholar
  • 26 Maher EA, Furnari FB, Bachoo RM. et al . Malignant glioma: genetics and biology of a grave matter.  Genes Dev. 2001;  15 1311-1333
    CrossrefPubMedSearch in Google Scholar
  • 27 Onofri C, Theodoropoulou M, Losa M. et al . Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours.  J Endocrinol. 2006;  191 249-261
    CrossrefPubMedSearch in Google Scholar
  • 28 Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma.  Cytokine Growth Factor Rev. 2004;  15 275-286
    CrossrefPubMedSearch in Google Scholar
  • 29 Ray D, Melmed S. Pituitary cytokine and growth factor expression and action.  Endocr Rev. 1997;  18 206-228
    CrossrefPubMedSearch in Google Scholar
  • 30 Renner U, Lohrer P, Schaaf L. et al . Transforming growth factor-beta stimulates vascular endothelial growth factor production by folliculostellate pituitary cells.  Endocrinology. 2002;  143 3759-3765
    CrossrefPubMedSearch in Google Scholar
  • 31 Renner U, Newton CJ, Pagotto U. et al . Involvement of interleukin-1 and interleukin-1 receptor antagonist in rat pituitary cell growth regulation.  Endocrinology. 1995;  136 3186-3193
    CrossrefPubMedSearch in Google Scholar
  • 32 Renner U, Paez-Pereda M, Arzt E. et al . Growth factors and cytokines: function and molecular regulation in pituitary adenomas.  Front Horm Res. 2004;  32 96-109
    PubMedSearch in Google Scholar
  • 33 Sasahara M, Sato H, Iihara K. et al . Expression of platelet-derived growth factor B-chain in the mature rat brain and pituitary gland.  Brain Res Mol Brain Res. 1995;  32 63-74
    CrossrefPubMedSearch in Google Scholar
  • 34 Seeliger H, Guba M, Kleespies A. et al . Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis.  Cancer Metastasis Rev. 2007;  26 611-621
    CrossrefPubMedSearch in Google Scholar
  • 35 Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth.  Nature. 2006;  441 424-430
    CrossrefPubMedSearch in Google Scholar
  • 36 Simon MP, Pedeutour F, Sirvent N. et al . Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.  Nat Genet. 1997;  15 95-98
    PubMedSearch in Google Scholar
  • 37 Smits A, Funa K, Vassbotn FS. et al . Expression of platelet-derived growth factor and its receptors in proliferative disorders of fibroblastic origin.  Am J Pathol. 1992;  140 639-648
    PubMedSearch in Google Scholar
  • 38 Steer EJ, Cross NC. Myeloproliferative disorders with translocations of chromosome 5q31-35: role of the platelet-derived growth factor receptor Beta.  Acta Haematol. 2002;  107 113-122
    PubMedSearch in Google Scholar
  • 39 Sullivan NJ, Tashjian Jr AH. Platelet-derived growth factor selectively decreases prolactin production in pituitary cells in culture.  Endocrinology. 1983;  113 639-645
    CrossrefPubMedSearch in Google Scholar
  • 40 Tallquist M, Kazlauskas A. PDGF signaling in cells and mice.  Cytokine Growth Factor Rev. 2004;  15 205-213
    CrossrefPubMedSearch in Google Scholar
  • 41 Tammela T, Enholm B, Alitalo K. et al . The biology of vascular endothelial growth factors.  Cardiovasc Res. 2005;  65 550-563
    CrossrefPubMedSearch in Google Scholar
  • 42 Taniguchi Y, Morita I, Kubota T. et al . Human uterine myometrial smooth muscle cell proliferation and vascular endothelial growth-factor production in response tp platelet-derived growth factor.  J Endocrinol. 2001;  169 79-86
    CrossrefPubMedSearch in Google Scholar
  • 43 Theodoropoulou M, Zhang J, Laupheimer S. et al . Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression.  Cancer Res. 2006;  66 1576-1582
    CrossrefPubMedSearch in Google Scholar
  • 44 Ueta Y, Levy A, Chowdrey HS. et al . S-100 antigen-positive folliculostellate cells are not the source of IL-6 gene expression in human pituitary adenomas.  J Neuroendocrinol. 1995;  7 467-474
    PubMedSearch in Google Scholar
  • 45 Vlotides G, Cruz-Soto M, Rubinek T. et al . Mechanism for growth factor-induced pituitary tumor transforming gene-1 expression in pituitary folliculostellate TtT/GF cells.  Mol Endocrinol. 2006;  20 3321-3335
    CrossrefPubMedSearch in Google Scholar
  • 46 Yeh HJ, Silos-Santiago I, Wang YX. et al . Developmental expression of the platelet-derived growth factor alpha-receptor gene in mammalian central nervous system.  Proc Natl Acad Sci USA. 1993;  90 1952-1956
    CrossrefPubMedSearch in Google Scholar

Correspondence

U. RennerPhD 

Max-Planck-Institute of Psychiatry

Neuroendocrinology Group

Kraepelinstr. 10

D-80804 Munich

Germany

Phone: +49/89/306 22 349

Fax: +49/89/306 22 605

Email: renner@mpipsykl.mpg.de