1. Fibroblast Growth Factors (FGFs) • www-cryst.bioc.cam.ac.uk/ structure_gallery.html

2. Definition • According to General Practice Notebook: • Fibroblast Growth Factor is a peptide with cellular communication abilities e.g. • Stimulation of fibroblast and endothelial cell division • Stimulation of angiogenesis

3. FGFs Function in the Cell • FGF is a ligand that binds to Fibroblast Growth Factor Receptors (FGFR), which in turn through tyrosine phosphorylation propagate signals through transduction pathway

4. Cell Lines • FGFs induce mitogenic, chemotactic, and angiogenic activity • What effects does FGF have in the Mouse?

5. Knock-Out Mice • Dr. Miller et al, decided to knock-out: • FGF-1 • FGF-2 • Double Knock-out of FGF-1 and FGF-2 • There results were:

6. Mouse Knock-outs had no major phenotypic variation from wild-type • Why these results?

7. There are 22 known FGFs • It is thought that the redundancy among the 22 Fibroblast Growth Factors compensate for the knock-out of FGF-1 and FGF-2

8. Angiogenesis is: • The formation of new capillary blood vessels from pre-existing ones • Requires migration, proliferation and differentiation of endothelial cells into blood vessels • Plays an important role in wound healing • Plays an important role in cancer as well

9. Angiogenic Factors: FGF and VEGF

10. Tumor Cells release angiogenic factors • Some scientist suggest that a tumor requires blood supply in order to grow beyond a few cubic millimeters • A tumor cell releases FGF and VEGF • As a result of receptor activation, endothelial cells will secrete proteases • The proteases digest basement membrane, which migrate and proliferate to form new blood vessels

11. FGF-3 (int-2) • Primarily expressed during development • First discovered in mouse mammary carcinogenesis • MMTV induces mammary tumors by acting as an insertional mutagen, and activating transcription of the nearby genes • FGF-3 (int) was found to be the site where the mouse mammary tumor virus (MMTV) usually integrates

12. Mouse Mammary Tumor Virus • Activates the promoter for FGF-3 • This “turns on” FGF-3 at improper times during development

13. MMTV and Human Breast Cancer • Detectable MMTV env gene-related antigenic reactivity has been found in tissue sections of human breast cancer • The human homologue of the int-2 locus has been found to be amplified and expressed in 15% of the breast cancers • There are still no clear proof that the human homologs to MMTV are related to human breast cancer

14. Breast Cancer • Dr. Granato et al., researched the effects of FGFs in breast cancer • They concluded that bFGF (basic fibroblast growth factor) serum level is associated with the presence of breast cancer • They proposed that bFGF as a noninvasive diagnostic tool for breast cancer

15. There are Elevated Levels of FGF in Breast Cancer Patients