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FGFR3 and Bladder Cancer. Amy Fair March 29, 2005 Biol 169. Overview. Family of receptor tyrosine kinases. FGF’s enhance proliferation of both epithelial and mesenchymal cells Also regulate cell migration & differentiation,

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Fgfr3 and bladder cancer

FGFR3 and Bladder Cancer

Amy Fair

March 29, 2005

Biol 169


Overview
Overview

  • Family of receptor tyrosine kinases.

  • FGF’s enhance proliferation of

    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.


Ligand receptor interactions
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.


Specificity
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.


Pathways
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.


Involvement in mouse development
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.


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.

Dwarfism


What does this mean
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.


What about bladder cancer
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).


Symptoms and diagnosis
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.


Incidence
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.


Fgfr3 and bladder cancer1
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.


Future of bladder cancer
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.


Refrences
Refrences

  • Bladder Cancer. The Urology Channel Online. 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

  • 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.

  • FGFsignaling in Skeletal Development. Michael Naski and David M. Ornitz. Frontiers in Bioscience3, d781-794. August 1, 1998.


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