Abstract

A common feature of advanced prostate cancer is metastasis to vertebral bone. Once metastasis to bone is evident, disease progresses rapidly and is almost uniformly fatal. Dissemination of malignant cells frequently occurs prior to diagnosis, and up to 25% of patients have bone metastases at the time of presentation. The mechanisms of tumor cell arrest in bone, proliferation at bony sites, and bone tissue destruction in prostate cancer ar poorly understood. In the proposed experiments, the principal investigator wil use a novel and highly sensitive bioassay, along with other methods, to determine to role of FGF-2 (basic fibroblast growth factor), and possibly othe bone-derived factors, in regulated cleavage-secretion from prostate carcinoma cells of the epidermal growth factor receptor (EGF-R) ligands, heparin-binding EGF-like growth factor (HB-EGF) amphiregulin and transforming growth factor-alpha (TGFalpha). Dr. Freeman presents preliminary data that FGF-2 activation of the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK-MAPK) pathway mediates cleavage-secretion of HB-EGF from prostatic tumor cells.
The specific aims are:
Specific Aim 1 : Determine if FGF-2 increases HB-EGF synthesis and secretion in human prostate adenocarcinoma cells by an extracellular signal-regulated kinase-(ERK-MAPK-) dependent mechanism. Specifi Aim 2: Determine if FGF-2 isolated from extracellular bone matrix mediates cleavage-secretion of HB-EFG by an ERK-MAPK-dependent mechanism. Determine if FGF-2 is the only heparin-binding factor in bone matrix capable of regulating cleavage-secretion of HB-EGF. Determine if osteoblasts secrete an activity capable of mediating secretion of HB-EGF.
Specific Aim 3 : Determine if cleavage-secretion of the EGF-R ligands, TGFalpha and amphiregulin, is regulated by FGF-2, factors derived from extracellular bone matrix, and osteoblast secretions in a similar fashion to cleavage-secretion of HB-EGF.
Specific Aim 4 : Determine the effect of endogenous proHB-EGF, proamphiregulin and proTGFalpha synthesis by Pca cells on metastasis to bone. These studies will expand our understanding of the pathways regulating activation of the EGF-R in prostate adenocarcinoma cells generally, and specifically within the bone microenvironment.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077386-02
Application #
2896414
Study Section
Special Emphasis Panel (ZRG2-CPA (02))
Program Officer
Mohla, Suresh
Project Start
1998-06-05
Project End
2003-03-31
Budget Start
1999-06-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Kim, Jayoung; Adam, Rosalyn M; Solomon, Keith R et al. (2004) Involvement of cholesterol-rich lipid rafts in interleukin-6-induced neuroendocrine differentiation of LNCaP prostate cancer cells. Endocrinology 145:613-9
Lin, Jianqing; Freeman, Michael R (2003) Transactivation of ErbB1 and ErbB2 receptors by angiotensin II in normal human prostate stromal cells. Prostate 54:1-7
Kim, Jayoung; Freeman, Michael R (2003) JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells. Breast Cancer Res Treat 79:321-8
Zhuang, Liyan; Lin, Jianqing; Lu, Michael L et al. (2002) Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res 62:2227-31
Zhuang, Liyan; Peng, Ji-Bin; Tou, Liqiang et al. (2002) Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest 82:1755-64
Kim, Jayoung; Adam, Rosalyn M; Freeman, Michael R (2002) Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation. Cancer Res 62:1549-54
Duque, J L; Adam, R M; Mullen, J S et al. (2001) Heparin-binding epidermal growth factor-like growth factor is an autocrine mediator of human prostate stromal cell growth in vitro. J Urol 165:284-8
Lin, J; Hutchinson, L; Gaston, S M et al. (2001) BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation. J Biol Chem 276:30127-32
Adam, R M; Orsola, A; Freeman, M R (2001) A novel method for implantation of LNCaP prostate tumor cells under the renal capsule. In Vitro Cell Dev Biol Anim 37:360-2
Peng, J B; Zhuang, L; Berger, U V et al. (2001) CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun 282:729-34

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