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.
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