The underlying goal of this project is to determine the mechanisms by which polypeptide growth factors control the proliferation of normal human cells and how these growth factors may be involved in the development of a malignant tumor. One growth factor that may be involved in this process is a polypeptide growth factor known as heparin-binding growth factor, type-2, or basic fibroblast growth factor (HBGF-2/bFGF). This growth factor can control the rate of proliferation of normal human cells in vitro under highly defined conditions. These cells include cells of stromal (fibroblastic) and epithelial origin. HBGF-2/bFGF may contribute to the development of a solid tumor mass by stimulating the proliferation of the tumor cells themselves (vis paracrine, autocrine or intracrine mechanisms), and/or by stimulating the proliferation and invasion of stromal elements including fibroblasts and endothelial cells.
The specific aims of this project will help elucidate possible roles of this growth factor in the proliferation of normal cells and examine the production of the growth factor by human cells of normal and neoplastic origin grown in vitro. A mouse cell line that is missing the receptor for the growth factor will be isolated. This cell line will be of value in future structure-function studies on the molecular mechanisms by which the ligand-receptor interaction can stimulate the proliferation of mammalian cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cellular Biology and Physiology Subcommittee 1 (CBY)
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Oregon Health and Science University
Schools of Medicine
United States
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Cook, P W; Ashton, N M; Karkaria, C E et al. (1995) Differential effects of a heparin antagonist (hexadimethrine) or chlorate on amphiregulin, basic fibroblast growth factor, and heparin-binding EGF-like growth factor activity. J Cell Physiol 163:418-29
Pittelkow, M R; Cook, P W; Shipley, G D et al. (1993) Autonomous growth of human keratinocytes requires epidermal growth factor receptor occupancy. Cell Growth Differ 4:513-21
Li, S; Plowman, G D; Buckley, S D et al. (1992) Heparin inhibition of autonomous growth implicates amphiregulin as an autocrine growth factor for normal human mammary epithelial cells. J Cell Physiol 153:103-11
Cook, P W; Pittelkow, M R; Keeble, W W et al. (1992) Amphiregulin messenger RNA is elevated in psoriatic epidermis and gastrointestinal carcinomas. Cancer Res 52:3224-7
Cook, P W; Mattox, P A; Keeble, W W et al. (1992) Inhibition of autonomous human keratinocyte proliferation and amphiregulin mitogenic activity by sulfated polysaccharides. In Vitro Cell Dev Biol 28A:218-22
Eckenstein, F P; Shipley, G D; Nishi, R (1991) Acidic and basic fibroblast growth factors in the nervous system: distribution and differential alteration of levels after injury of central versus peripheral nerve. J Neurosci 11:412-9
Cook, P W; Mattox, P A; Keeble, W W et al. (1991) A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin. Mol Cell Biol 11:2547-57
Root, L L; Shipley, G D (1991) Human dermal fibroblasts express multiple bFGF and aFGF proteins. In Vitro Cell Dev Biol 27A:815-22
Cook, P W; Pittelkow, M R; Shipley, G D (1991) Growth factor-independent proliferation of normal human neonatal keratinocytes: production of autocrine- and paracrine-acting mitogenic factors. J Cell Physiol 146:277-89
Li, S; Shipley, G D (1991) Expression of multiple species of basic fibroblast growth factor mRNA and protein in normal and tumor-derived mammary epithelial cells in culture. Cell Growth Differ 2:195-202

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