Transcript FGFR3 and Bladder Cancer

FGFR3 and Bladder
Cancer
Amy Fair
March 29, 2005
Biol 169
Overview
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Family of receptor tyrosine kinases.
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FGF’s enhance proliferation of
both epithelial and mesenchymal cells
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Also regulate cell migration & differentiation,
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Mutations can lead to constitutive activation
of the receptor in the absence of a ligand.
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
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The receptors are tissue specific with
epithelial receptors and mesenchymal
receptors.
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This specificity is then further refined by
the herapan sulfate interactions.
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Allows for local signaling of proliferation,
migration, and differentiation.
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
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Analysis of mouse bone development of both gain-offunction and loss-of-function showed that this
receptor ultimately limits chondrocyte proliferation.
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Mice with an activating mutation in FGFR3 had
decreased expression of Ihh, Ptc, and Bmp4 and
resulted in dwarfism.
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Mice lacking FGFR3 showed up regulation of Ihh, Ptc,
and Bmp4 and overgrowth of long bones.
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FGFR3 is a NEGATIVE regulator of bone growth.
Dwarfism
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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.
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?
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Bladder cancer accounts for about 90% of
urinary tract cancer cases.
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Bladder cancer originates in the bladder
lining, these cells can expand and deflate
(transitional epithelial cells), smooth muscle,
and a fibrous layer.
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Tumors are categorized as low-stage
(superficial) or high-stage (muscle invasive).
Symptoms and Diagnosis
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Symptoms include blood in the urine, frequent
urination, and pain upon urinating.
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Urological and imaging test are required to
diagnose bladder cancer.
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The urine test checks for elevated levels of
protein in the urine.
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If detected, cytoscopy and biopsy are
performed.
Incidence
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Incidence of bladder cancer increases with
age.
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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.
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2 to 3 times more common in men than women.
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
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Not much is known about FGFR3’s complete
role in bladder and cervical tissues.
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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.
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More work will be required to find FGFR3’s
complete role in cancer but we now know it is
an important target.
Refrences
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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.