1. FGFR3 and Bladder Cancer Amy Fair March 29, 2005 Biol 169

2. Overview  Family of receptor tyrosine kinases.  FGF’s enhance proliferation of both epithelial and mesenchymal cells both epithelial and mesenchymal cells  Also regulate cell migration & differentiation,  Mutations can lead to constitutive activation of the receptor in the absence of a ligand.

4. Ligand-Receptor Interactions  Each FGFR recognizes a subset of FGF ligands.  Receptors have 2-3 extracellular immunoglobulin-like domains, a transmembrane domain and a split tyrosine kinase domain.

6. Specificity  The receptors are tissue specific with epithelial receptors and mesenchymal receptors.  This specificity is then further refined by the herapan sulfate interactions.  Allows for local signaling of proliferation, migration, and differentiation.

7. Pathways  Studies involving bone diseases have shown that FGFR’s are involved in the IHH/PTHrR/BMP signaling pathway.  These studies have shown that FGFR3 has a direct proliferating activity in a pathway involving; IHH, PTC, SMO, BMP’s, PTHrP, and PPR.

9. Involvement in Mouse Development  Analysis of mouse bone development of both gain-of- function and loss-of-function showed that this receptor ultimately limits chondrocyte proliferation.  Mice with an activating mutation in FGFR3 had decreased expression of Ihh, Ptc, and Bmp4 and resulted in dwarfism.  Mice lacking FGFR3 showed up regulation of Ihh, Ptc, and Bmp4 and overgrowth of long bones.  FGFR3 is a NEGATIVE regulator of bone growth.

11. Dwarfism  Achondroplasia.  Frequency of one in 10,000– 100,000 births.  In 99% of cases- caused by a mutation of amino-acid 380 in FGF-receptor-3.  The mutation is dominant.  Almost all cases are due to new, independently occurring mutations.  The defect in FGF signaling causes dwarfism by interfering with the growth of cartilage in developing long bones.

12. What does this mean?  This shows that the direct function of FGFR3 is in regulating chondrocyte proliferation and that it acts by regulating Hedgehog and BMP signaling.

13. What about Bladder Cancer?  Bladder cancer accounts for about 90% of urinary tract cancer cases.  Bladder cancer originates in the bladder lining, these cells can expand and deflate (transitional epithelial cells), smooth muscle, and a fibrous layer.  Tumors are categorized as low-stage (superficial) or high-stage (muscle invasive).

15. Symptoms and Diagnosis  Symptoms include blood in the urine, frequent urination, and pain upon urinating.  Urological and imaging test are required to diagnose bladder cancer.  The urine test checks for elevated levels of protein in the urine.  If detected, cytoscopy and biopsy are performed.

16. Incidence  Incidence of bladder cancer increases with age.  People over the age of 70 develop the disease 2 to 3 times more often than those aged 55– 69 and 15 to 20 times more often than those aged 30–54.  2 to 3 times more common in men than women.

17. FGFR3 and Bladder Cancer  FGFR3 appears to be the most frequently mutated oncogene in bladder and cervical cancer.  Studies have shown that it is mutated in 30% of cases.

18. Future of Bladder Cancer  Not much is known about FGFR3’s complete role in bladder and cervical tissues.  Studies have shown that FGFR3 seems to mediate opposite signals, acting as a negative regulator of bone growth and an oncogene of several tumor types.  More work will be required to find FGFR3’s complete role in cancer but we now know it is an important target.

19. Refrences  Bladder Cancer. The Urology Channel Online. http://www.urologychannel.com/bladdercancer/index.shtml http://www.urologychannel.com/bladdercancer/index.shtml  Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Jerome Bourdin, Xavier Sastre-Garau, Dominique Chopin, Jean Paul Thiery& Francois Radvanyi. Correspondence; Nature America, Inc., 1999; http://genetics.nature.com http://genetics.nature.com  FGF Signaling pathways in endochondral and intramembranous bone development and human genetic disease. David M. Ornitz and Pierre J. Marie; Genes and Development; 16:1446-1465. 2002; Cold Spring Harbor Press Laboratory Press. www.genesdev.com. www.genesdev.com  FGFsignaling in Skeletal Development. Michael Naski and David M. Ornitz. Frontiers in Bioscience3, d781-794. August 1, 1998.