FGFR3 and Bladder FGFR3 and Bladder CancerCancer

Amy FairAmy Fair

March 29, 2005March 29, 2005

Biol 169Biol 169

OverviewOverview Family of receptor tyrosine kinases.Family of receptor tyrosine kinases.

FGF’s enhance proliferation of FGF’s enhance proliferation of both epithelial and mesenchymal cellsboth epithelial and mesenchymal cells

Also regulate cell migration & differentiation, Also regulate cell migration & differentiation,

Mutations can lead to constitutive activation Mutations can lead to constitutive activation of the receptor in the absence of a ligand.of the receptor in the absence of a ligand.

Ligand-Receptor Ligand-Receptor InteractionsInteractions

Each FGFR recognizes a subset of Each FGFR recognizes a subset of FGF ligands.FGF ligands.

Receptors have 2-3 extracellular Receptors have 2-3 extracellular immunoglobulin-like domains , a immunoglobulin-like domains , a transmembrane domain and a split transmembrane domain and a split tyrosine kinase domain.tyrosine kinase domain.

SpecificitySpecificity

The receptors are tissue specific with The receptors are tissue specific with epithelial receptors and mesenchymal epithelial receptors and mesenchymal receptors.receptors.

This specificity is then further refined by This specificity is then further refined by the herapan sulfate interactions. the herapan sulfate interactions.

Allows for local signaling of proliferation, Allows for local signaling of proliferation, migration, and differentiation.migration, and differentiation.

PathwaysPathways

Studies involving bone diseases have Studies involving bone diseases have shown that FGFR’s are involved in shown that FGFR’s are involved in the IHH/PTHrR/BMP signaling the IHH/PTHrR/BMP signaling pathway. pathway.

These studies have shown that These studies have shown that FGFR3 has a direct proliferating FGFR3 has a direct proliferating activity in a pathway involving; IHH, activity in a pathway involving; IHH, PTC, SMO, BMP’s, PTHrP, and PPR. PTC, SMO, BMP’s, PTHrP, and PPR.

Involvement in Mouse Involvement in Mouse DevelopmentDevelopment

Analysis of mouse bone development of both gain-Analysis of mouse bone development of both gain-of-function and loss-of-function showed that this of-function and loss-of-function showed that this receptor ultimately limits chondrocyte proliferation.receptor ultimately limits chondrocyte proliferation.

Mice with an activating mutation in FGFR3 had Mice with an activating mutation in FGFR3 had decreased expression of Ihh, Ptc, and Bmp4 and decreased expression of Ihh, Ptc, and Bmp4 and resulted in dwarfism.resulted in dwarfism.

Mice lacking FGFR3 showed up regulation of Ihh, Mice lacking FGFR3 showed up regulation of Ihh, Ptc, and Bmp4 and overgrowth of long bones.Ptc, and Bmp4 and overgrowth of long bones.

FGFR3 is a NEGATIVE regulator of bone growth.FGFR3 is a NEGATIVE regulator of bone growth.

DwarfismDwarfism Achondroplasia. Achondroplasia. Frequency of one in Frequency of one in

10,000–100,000 births.10,000–100,000 births. In 99% of cases- caused by In 99% of cases- caused by

a mutation of amino-acid a mutation of amino-acid 380 in FGF-receptor-3.380 in FGF-receptor-3.

The mutation is dominant.The mutation is dominant. Almost all cases are due to Almost all cases are due to

new, independently new, independently occurring mutations.occurring mutations.

The defect in FGF signaling The defect in FGF signaling causes dwarfism by causes dwarfism by interfering with the growth interfering with the growth of cartilage in developing of cartilage in developing long bones.long bones.

What does this mean?What does this mean?

This shows that the direct function of This shows that the direct function of FGFR3 is in regulating chondrocyte FGFR3 is in regulating chondrocyte proliferation and that it acts by proliferation and that it acts by regulating Hedgehog and BMP regulating Hedgehog and BMP signaling.signaling.

What about Bladder What about Bladder Cancer?Cancer?

Bladder cancer accounts for about 90% of Bladder cancer accounts for about 90% of urinary tract cancer cases.urinary tract cancer cases.

Bladder cancer originates in the bladder Bladder cancer originates in the bladder lining, these cells can expand and deflate lining, these cells can expand and deflate (transitional epithelial cells), smooth (transitional epithelial cells), smooth muscle, and a fibrous layer. muscle, and a fibrous layer.

Tumors are categorized as low-stage Tumors are categorized as low-stage (superficial) or high-stage (muscle (superficial) or high-stage (muscle invasive). invasive).

Symptoms and DiagnosisSymptoms and Diagnosis Symptoms include blood in the urine, Symptoms include blood in the urine,

frequent urination, and pain upon urinating. frequent urination, and pain upon urinating.

Urological and imaging test are required to Urological and imaging test are required to diagnose bladder cancer.diagnose bladder cancer.

The urine test checks for elevated levels of The urine test checks for elevated levels of protein in the urine.protein in the urine.

If detected, cytoscopy and biopsy are If detected, cytoscopy and biopsy are performed.performed.

IncidenceIncidence

Incidence of bladder cancer increases with Incidence of bladder cancer increases with age. age.

People over the age of 70 develop the People over the age of 70 develop the disease 2 to 3 times more often than those disease 2 to 3 times more often than those aged 55–69 and 15 to 20 times more often aged 55–69 and 15 to 20 times more often than those aged 30–54. than those aged 30–54.

2 to 3 times more common in men than 2 to 3 times more common in men than women.women.

FGFR3 and Bladder CancerFGFR3 and Bladder Cancer

FGFR3 appears to be the most FGFR3 appears to be the most frequently mutated oncogene in frequently mutated oncogene in bladder and cervical cancer. bladder and cervical cancer.

Studies have shown that it is Studies have shown that it is mutated in 30% of cases.mutated in 30% of cases.

Future of Bladder CancerFuture of Bladder Cancer Not much is known about FGFR3’s Not much is known about FGFR3’s

complete role in bladder and cervical complete role in bladder and cervical tissues.tissues.

Studies have shown that FGFR3 seems to Studies have shown that FGFR3 seems to mediate opposite signals, acting as a mediate opposite signals, acting as a negative regulator of bone growth and an negative regulator of bone growth and an oncogene of several tumor types.oncogene of several tumor types.

More work will be required to find FGFR3’s More work will be required to find FGFR3’s complete role in cancer but we now know complete role in cancer but we now know it is an important target.it is an important target.

RefrencesRefrences Bladder CancerBladder Cancer. The Urology Channel Online. . The Urology Channel Online.

http://www.urologychannel.com/bladdercancer/index.shtmlhttp://www.urologychannel.com/bladdercancer/index.shtml Frequent activating mutations of FGFR3 in human bladder Frequent activating mutations of FGFR3 in human bladder

and cervix carcinomas. and cervix carcinomas. Jerome Bourdin, Xavier Sastre-Jerome Bourdin, Xavier Sastre-Garau, Dominique Chopin, Jean Paul Thiery& Francois Garau, Dominique Chopin, Jean Paul Thiery& Francois Radvanyi. Radvanyi. Correspondence; Nature America, Inc.Correspondence; Nature America, Inc., 1999; , 1999; http://genetics.nature.comhttp://genetics.nature.com

FGF Signaling pathways in endochondral and FGF Signaling pathways in endochondral and intramembranous bone development and human genetic intramembranous bone development and human genetic disease. disease. David M. Ornitz and Pierre J. Marie; David M. Ornitz and Pierre J. Marie; Genes and Genes and DevelopmentDevelopment; 16:1446-1465. 2002; Cold Spring Harbor ; 16:1446-1465. 2002; Cold Spring Harbor Press Laboratory Press. Press Laboratory Press. www.genesdev.comwww.genesdev.com. .

FGFsignaling in Skeletal DevelopmentFGFsignaling in Skeletal Development. Michael Naski and . Michael Naski and David M. Ornitz. David M. Ornitz. Frontiers in Bioscience3, Frontiers in Bioscience3, d781-794. August d781-794. August 1, 1998.1, 1998.