Professional Documents
Culture Documents
ARI
ANNUAL
REVIEWS
9 December 2008
15:4
Further
Key Words
Abstract
Despite elaborate characterization of the risk factors, bladder cancer is
still a major epidemiological problem whose incidence continues to rise
each year. Urothelial carcinoma is now recognized as a disease of alterations in several cellular processes. The more prevalent, less aggressive,
recurrent, noninvasive tumors are characterized by constitutive activation of the Ras-MAPK pathway. The less common but more aggressive
invasive tumors, which have a higher mortality rate, are characterized
by alterations in the p53 and retinoblastoma pathways. Several diagnostic tests have attempted to identify these molecular alterations in
tumor cells exfoliated in the urine, whereas prognostic tests have tried
to identify aberrations so as to predict tumor behavior and identify therapeutic targets. The future of bladder cancer patient management will
rely on the use of molecular tests to reliably diagnose the presence of disease, predict individual tumor behavior, and suggest potential targeted
therapeutics.
251
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252
Mitra
Cote
or a n gi o ge nes
m
Tu
Gene
regulation
Signal
transduction
Cell
growth
on
Cell
death
r ce ll i nv asi
Cell-cycle
regulation
mo
Tu
UC: urothelial
carcinoma
is
INTRODUCTION
Figure 1
Aberrant cellular processes contributing to bladder
tumorigenesis. Malignant transformation of the
bladder urothelium involves alterations in ve
intrinsic cellular processes (central pie) that can
respond to external carcinogenic cues or that can be
affected by genetic alterations. Tumor maintenance,
progression, and metastasis also depend on two
extrinsic processes, angiogenesis and invasion,
which regulate tumor interaction with stromal
elements and adjacent cells.
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Table 1
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Risk factor
Mechanism of carcinogenesis
Primary cellular
process(es) altered
Strength of
association
Reference(s)
Lifestyle
Tobacco smoking
Cell-cycle regulation,
gene regulation
Strong
Cell-cycle regulation
Weak
10
Dyestuff manufacturing
Cell-cycle regulation,
gene regulation
Strong
Rubber manufacturing
Cell-cycle regulation
Strong
14
Painting
Cell-cycle regulation,
gene regulation
Moderate
15
Leather processing
Cell-cycle regulation
Moderate
16
Printing
Cell-cycle regulation,
gene regulation
Weak
16
Hairdressing
Cell-cycle regulation
Weak
10
Aluminum smelting
Cell-cycle regulation
Strong
17, 18
Asphalt paving
Cell-cycle regulation
Inadequate
19
Fireghting
Cell-cycle regulation
Weak
20
Truck driving
Cell-cycle regulation
Moderate
21
Unconrmed
Moderate
22
Cell-cycle regulation,
signal transduction,
gene regulation
Strong
24
Coffee
Unconrmed
Inadequate
27
Articial sweeteners
Unknown in humans
Unconrmed
Inadequate
29
Gene regulation
Moderate
1, 30
Schistosoma haematobium
Gene regulation
Strong
32
Chronic inammation
Moderate
Urinary calculi
Chronic inammation
Weak
Occupation
Diet
(Continued )
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Table 1
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(Continued )
Risk factor
Mechanism of carcinogenesis
Primary cellular
process(es) altered
Strength of
association
Reference(s)
Strong
33
NAT2 polymorphism
Gene regulation
Strong
35
NAT1 polymorphism
Gene regulation
Inadequate
37
GSTM1 polymorphism
Gene regulation
Weak
38
Family history
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FGFR: broblast
growth factor receptor
Loss of
heterozygosity: loss
of an allele from a
heterozygous cell
locus; can result in
tumor-suppressorgene inactivation if the
other allele is mutated
MMP: matrix
metalloproteinase
VEGF: vascular
endothelial growth
factor
ECM: extracellular
matrix
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9Rb
p16
p53
Rb
CIS
p16
p53
?
Ta
(HG
)
T1
p21
T2a
p16INK4a
G)
Ta (L
T2b
al
rm ium
No thel
o
ur
9qHRAS
T3a
Lamina
propria
T3b
Epithelium
T4a
3
FGFR3
Musculariss
propria
Perivesical fat
Pros
ostate
Urethra
ret
ECM
remodeling
genes
Figure 2
Composite model for urothelial tumorigenesis and progression. Noninvasive and invasive tumors are
characterized by distinct molecular alterations. Although noninvasive tumors have constitutive activation of
the Ras-MAPK (mitogen-activated protein kinase) pathway, at carcinoma in situ (CIS) and invasive lesions
have alterations in p53 and other cell-cycle-regulatory molecules. Loss of heterozygosity of 9q is more
common in low-grade papillary carcinomas (Ta), although deletions of chromosome 9 are also seen in
progressive CIS. Locations of molecules indicate characteristic alterations that pose a risk for progression of
a particular phenotype. The thickness of the arrows is approximately proportionate to the relative frequency
of occurrence. Locations of the arrow tails and heads correspond to the tumor stage(s) before and after
alteration(s) of the denoted molecule(s), respectively. Abbreviations: ECM, extracellular matrix; FGFR3,
broblast growth factor receptor 3; HG, high-grade; HRAS, protein of the Harvey rat sarcoma viral
oncogene homolog gene; LG, low-grade; Rb, retinoblastoma protein.
In addition to the differences in molecular alterations between noninvasive and invasive UC, there are also marked contrasts in
epidemiology, chromosomal alterations, clinical outcome, and therapeutic management be256
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PROGNOSTIC IMPACT OF
FUNCTIONAL ALTERATIONS IN
BLADDER CANCER
Tumorigenesis involves multiple alterations in
several tightly controlled pathways that otherwise interact normally within a molecular circuitry to maintain cellular homeostasis
(Figure 4). Alterations within many of these
molecular pathways have been identied in UC.
However, it is their net effect on the deregulation of key cellular processes that establishes
the tumor and controls its fate. More importantly, alterations in key molecular markers are
important predictors of outcome and therapeutic response (Table 2), and they may also act as
druggable targets (52).
function (54, 55). However, loss of heterozygosity on chromosome 17 occurs during the later
stages of UC and is usually associated with a
more aggressive phenotype (56).
Normally, the short half-life of p53 (630
min) prevents its accumulation in the nucleus
(57). However, TP53 mutations result in an altered protein that is resistant to normal regulatory ubiquitin-mediated degradation. This
causes increased intranuclear accumulation of
the protein, which can be detected by immunohistochemistry (58). We and others have
shown that p53 nuclear immunoreactivity is
predictive of outcome particularly for patients
with invasive, organ-conned, node-negative
(T12bN0) UC (5961). From a therapeutic
standpoint, although conventional chemotherapy has limited benets in UC patients, and although cisplatin-based combination therapies
show mixed to modest benets in the adjuvant
and neoadjuvant settings (45), evidence suggests that patients with locally advanced UC
who harbor p53 alterations respond benecially
to adjuvant chemotherapy that contains DNAdamaging agents such as cisplatin (62). The
plausible explanation is that DNA damage to
p53-altered urothelial cells might cause an uncoupling of the S and M phases of the cell cycle,
resulting in apoptosis (63). This led to the institution of the rst international multicenter clinical trial in UC that targeted molecular lesions,
to identify organ-conned invasive UC patients
with the greatest risk of progression (i.e., patients with p53-altered tumors) who would respond best to cisplatin-containing chemotherapy (64).
Although p53 nuclear accumulation is correlated with TP53 mutations (65, 66), a significant discordance does exist. Our studies examining p53 immunoreactivity with the corresponding TP53 mutations in primary UC suggest that although both nuclear accumulation
and gene mutations are independent prognostic indicators, those tumors with a mutated
TP53 and an altered protein phenotype exhibit
the worst prognosis and those with a wild-type
gene and an unaltered protein perform the best
(Figure 5) (67). Furthermore, it appears that
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Superficial
Invasive
Noninvasive
Relative risk of bladder cancer
(compared to nonsmokers)
7
6
5
4
3
2
1
0
Average frequency
of alterations
Ta
16
14
12
10
8
6
4
2
0
Muscle-invasive
T1
T2
T3
T4
Chromosomal loss
Chromosomal gain
Chromosomal amplification
80
70
60
50
HRAS-activating mutation
FGFR3-activating mutation
p53 alteration
p21 alteration
Rb alteration
p16 alteration
40
30
20
10
0
Relative risk
High
Moderate
Low
Recurrence
Progression
Mortality
Minimal
None
Mitra
Recommended therapy
258
Tumor stage
Cote
Yes
Yes
Yes
Palliative
(select
T4aN0)
Radical cystectomy
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Supplemental Material
Figure 3
Differences between noninvasive and invasive bladder tumors. Supercial bladder tumors are lesions that do
not invade the muscularis propria (Ta, T1). However, noninvasive tumors refer to those that do not invade
the basement membrane (Ta). (a) The relative risk of developing invasive bladder cancer is higher in smokers
than in nonsmokers. (b) Invasive tumors also have a higher frequency of chromosomal losses, gains, and
amplications. (c) Although mutations in HRAS and FGFR3 decrease with invasion, the opposite is true for
p53, p21, Rb, and p16 alterations. (d ) Invasive tumors have a lower chance for recurrence, but they are more
prone to progression and increased risk of death. (e) Transurethral tumor resection and intravesical Bacille
Calmette-Guerin instillation are generally recommended for supercial tumors (TaT1), and radical
cystectomy is advocated for the invasive (T1T3) tumors. However, transurethral resection may also be
employed in patients with muscle-invasive tumors with extensive comorbid disease or poor performance
status (orange bar), and palliative radical cystectomy may be performed in select T4a patients without
metastatic lymph nodes who are responsive to chemotherapy ( pink bar). Abbreviations: FGFR3, broblast
growth factor receptor 3 gene; HRAS, Harvey rat sarcoma viral oncogene homolog gene; Rb, retinoblastoma
protein.
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EGFR
ErbB-2
VEGFR2
EGFR
Src
Grb2
Sos
Ras
VEGFR2
PIP3
PI3K
JAK
Cytoplasm
RASSF1a
PKC Raf
PLC
PTEN
E-cadherin
PDK1
MEK
Akt
ERK
-catenin
DAPK
Cytokine
receptor
STAT1
STAT3
STAT1
STAT3
ERK
Nucleus
MSK1
RSK
Bad
CDKN2A
Cyclin E
p27 CDK2
Rb
E2F
p21 p53
Mdm2 p14
E2F
pRb
c-Fos
Caspase-6
Apaf-1
Caspase-9
Caspase-7
Caspase-10
Caspase-8
Caspase-3
FADD
ASK1
MKK7
JNK
TRADD
FADD
Apoptosis
Bid
TNFR
Cyclin D1
CDK4
Bax
Cytochrome c
Fas
p16
c-Myc
Cdc25a
Bcl-2
Bcl-X L
Mitochondrion
FGFR3
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c--Jun
c-Jun
c-Ju
c-J
Jun
HIF
cIAP
NF-B
HIF VEGF
TP
MMP-2
MMP-9
Hyp
ypoxia
Tumor blood
vessell
260
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Cote
uPA plasmiin
n bFGF
bFGF
aFGF
SF
64
integrin
TSP-1 IL-8
ECM
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(77). This provides the biologic basis for constitutive Rb inactivation in the presence of an
intact gene through Rb hyperphosphorylation.
Rb phosphorylation is facilitated by the cyclin/CDK complexes. The specic complexes
that phosphorylate Rb are cyclin D1/CDK4/6
and cyclin E/CDK2. Although a rare event in
UC, the frequency of CDK4 amplication is
signicantly linked to higher grade and invasive potential (70). Negative regulation of the
CDKs is achieved by CDKIs such as p21, p16,
and p27, which act as tumor suppressors. Low
p27 levels have been associated with shortened disease-free and overall survival in UC
(78).
Studies investigating the combined effect of
p53 and Rb pathway alterations on UC prognosis have also shown promising results. Early
studies on combined Rb and p53 expression revealed that abnormal expression of either or
both proteins was signicantly associated with
an increased risk of progression in T1 tumors
(79). Our studies examining the combined effects of p53, p21, and Rb alterations have shown
that an incremental increase in the number
of altered markers is associated with poorer
recurrence-free and overall survival (80). Other
studies have conducted similar analyses using
various marker combinations of p53, p21, Rb,
p16, and Mdm2 to generate prognostic panels
(8185) and have demonstrated a synergism between these markers in bladder tumorigenesis,
progression, and outcome prediction.
ROLE OF METHYLATION
DNA methylation exerts its effects on the human genome
through the mutational burden of 5-methylcytosine, epigenetic
effects of promoter methylation, and induction of chromosomal
instability by DNA hypomethylation. The covalent addition of a
methyl group to cytosine at CpG palindromes by DNA methyltransferase results in the formation of 5-methylcytosine. This increases the probability of C T transition mutations by a deamination reaction; when this occurs in the coding regions of genes,
it can result in a nonfunctional protein. Further, aberrant hypermethylation of CpG islands in the promoter regions of tumorsuppressor genes is a frequent, heritable, yet potentially reversible
mechanism of transcriptional suppression in UC (Supplemental Table 1; follow the Supplemental Material link from the
Annual Reviews home page at http://www.annualreviews.org).
However, variations in the prevalence of methylation levels of
genes reported by various studies in UC hinder their applicability as potential prognostic indicators. This is notable in the case
of DAPK (death-associated protein kinase), which encodes for the
protein that prevents ERK (extracellular signalregulated kinase)
translocation from the cytoplasm to the nucleus, thereby inhibiting signaling via the Ras-MAPK pathway. A similar scenario is
observed with methylation reports on p14ARF and p16INK4a . However, RASSF1A, which encodes for a protein that can inhibit Ras
function, has shown more consistent methylation levels across
studies and holds promise as a reliable prognostic marker.
The series of cell death events that occur throughout normal development and in
Figure 4
Intra- and intercellular circuitry contributing to bladder tumorigenesis. A complex network of molecular signaling is involved in
malignant transformation and tumor progression. Mitogenic signals from growth receptors ( gray) on the cell surface are conducted
along signal transduction pathways (molecules in black) to affect cell-cycle regulation (molecules in purple) and apoptosis (molecules in blue).
This leads to gene-expression changes that are controlled by key transcription factors ( yellow). The tumor cell also interacts with factors
controlling angiogenesis ( green) and invasion (orange). Abbreviations: aFGF, acidic broblast growth factor; ASK1, activator of S phase
kinase 1; bFGF, basic broblast growth factor; DAPK, death-associated protein kinase; ECM, extracellular matrix; ERK, extracellular
signalregulated kinase; FADD, Fas-associated protein with death domain; HIF, hypoxia-inducible factor; JAK, Janus kinase; JNK,
c-Jun N-terminal kinase; MEK, mitogen-activated protein kinase (MAPK)/ERK kinase; MMP, matrix metalloproteinase; MSK1,
mitogen- and stress-activated kinase 1; PDK, 3 -phosphoinositide-dependent kinase; PI3K, phosphatidylinositol 3kinase; PIP3 ,
phosphatidylinositol (3,4,5)trisphosphate; PKC, protein kinase C; PLC, phospholipase C; pRb, phosphorylated retinoblastoma
protein; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RSK, ribosomal S6 kinase; SF, scatter factor; TRADD,
tumor necrosis factor (TNF) receptorassociated death domain; TRAF, TNF receptorassociated factor; TSP, thrombospondin; uPA,
urokinase-type plasminogen activator; VEGFR2, vascular endothelial growth factor receptor 2.
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Table 2
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Marker/
expression
in urothelial
carcinoma
Molecular
pathway(s)
involved
Normal function
Prognostic impact
Cell-cycle regulation
p53a
Inhibits G1 -S progression
p53
p21b
p53
Mdm2c
p53
p14b
Inhibits MDM2
p53
Decreased survival
p16b
Rb
Rbd
Rb
CDK4c
Rb
p27b
Rb
Decreased survival
Fasb
Extrinsic apoptotic
Bcl-2c
Intrinsic apoptotic
Baxb
Intrinsic apoptotic
Caspase-3b
Promotes apoptosis
Common apoptosis
effector
Increased recurrence
FGFR3e
Ras-MAPK
Increased recurrence
EGFRc
Ras-MAPK,
PI3K-Akt
ErbB-2c
Ras-MAPK,
PI3K-Akt
Decreased survival
VEGFR2c
Ras-MAPK,
PI3K-Akt
Cell death
Cell growth
Signal transduction
HRASc
Ras-MAPK
PKCf
PLC/PKC
Increased recurrence
PTENb
PI3K-Akt
Gene regulation
STAT3c
JAK-STAT
NF-Bg
NF-B
c-Fosc
MAPK
c-Junc
MAPK
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(Continued )
Marker/
expression in
urothelial
carcinoma
Molecular
pathway(s)
involved
Normal function
Prognostic impact
Tumor angiogenesis
HIFc
VEGFc
TPc
uPAc
bFGFc
Ras-MAPK
aFGFc
Ras-MAPK
SFc
TSP-1b
Inhibits angiogenesis
p53
E-cadherinb
Cadherin
-cateninb
Wnt/-catenin
64
integrinh
Cytoskeletal
signaling
Decreased survival
MMP-2c
MMP-9c
TIMP-2i
Invasion
Altered.
Underexpressed/lost.
c
Overexpressed.
d
Lost/hyperphosphorylated.
e
Overactivated.
f
Overexpressed in membrane.
g
Polymorphic insertion/deletion in promoter region.
h
Lost/overexpressed.
i
Uncertain.
Abbreviations: aFGF, acidic broblast growth factor; bFGF, basic broblast growth factor; CDK, cyclin-dependent kinase; EGFR, epidermal growth
factor receptor; FGFR3, broblast growth factor receptor 3; HIF, hypoxia-inducible factor; HRAS, protein of the Harvey rat sarcoma viral oncogene
homolog gene; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-B, nuclear factorkappa B; PI3K,
phosphatidylinositol 3-kinase; PIP3 , phosphatidylinositol trisphosphate; PKC, protein kinase C; PLC, phospholipase C; PTEN, phosphatase and tensin
homolog deleted on chromosome 10; Rb, retinoblastoma protein; SF, scatter factor; STAT, signal transducer and activator of transcription; TIMP-2, tissue
inhibitor of metalloproteinase 2; TP, thymidine phosphorylase; TSP-1, thrombospondin-1; uPA, urokinase-type plasminogen activator; VEGF, vascular
endothelial growth factor; VEGFR2, VEGF receptor 2.
b
Apoptosis can be initiated by two alternative pathways. The extrinsic pathway involves
activation of death receptors on the cell surface, whereas the intrinsic pathway is mediated
by mitochondria (Figure 4). Both pathways activate caspases that cleave cellular substrates
and lead to the characteristic biochemical
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1.00
Wt gene, wt protein (n=85)
0.75
0.50
10
15
20
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of the same pathway by either event. Approximately 82% of grade 1 tumors and Ta tumors
have mutations in either a Ras gene or FGFR3,
suggesting that activation of the MAPK pathway may be an obligate event in most of these
cases.
The epidermal growth factor receptor
(EGFR) family consists of four closely related
receptors that homo- or heterodimerize after
ligand activation and transmit signals via the
Ras-MAPK or phosphatidylinositol 3kinase
(PI3K)-Akt signal transduction pathways, regulating cell-cycle progression, mitogenic signaling, and other processes crucial to cancer progression (Figure 4). Among the best-studied
receptors in this family are EGFR (ErbB-1)
and ErbB-2 (Her2/neu). Unlike FGFR3, however, these receptors are also overexpressed in
invasive tumors (107, 108). Increased EGFR
expression has been associated with increased
probability of progression and death (109111).
Similarly, increased ErbB-2 expression has been
associated with worse disease-specic survival
(108, 112, 113). Interestingly, the combined
expression prole of EGFR and ErbB-2 has
been suggested to be a better predictor of outcome than each individual marker alone (114),
although this nding was not supported by another study (115).
VEGF is an important signaling protein involved in both vasculogenesis (formation of the
embryonic circulatory system) and angiogenesis (growth of blood vessels from preexisting
vasculature). All VEGF family members stimulate cellular responses by binding to VEGF
receptors (VEGFRs). VEGFR2 (KDR/Flk-1)
mediates most of the known cellular responses
to VEGF. VEGFR2 expression has been correlated with increasing disease stage and tumor
invasion into the muscle (116). Our studies have
also shown that VEGFR2 may be an important
determinant for prediction of nodal metastasis
in UC patients (117).
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transcription factors in the nuclei. Deregulations in these pathways can alter signal conduction, thereby leading to abnormal regulation of genes. In UC, the most important signaling pathways identied to date include, but
may not be limited to, the Ras-MAPK pathway, the phospholipase C (PLC)protein kinase
C (PKC) signaling cascade, the Janus kinase
( JAK)signal transducer and activator of transcription (STAT) pathway, the PI3K-Akt pathway, and the nuclear factorkappa B (NF-B)
pathway.
Most low-grade papillary tumors show constitutive activation of the Ras-MAPK pathway, generally through activating FGFR3 mutations (45). Activating Ras mutations are found
in approximately 13% of Ta tumors and are
not as common as FGFR3 mutations in this
tumor stage (106). Nevertheless, constitutive
Ras-MAPK pathway activation does represent
a dominant alteration in noninvasive tumors.
HRAS mutations have been observed in exfoliated cells in the urine of patients with low-grade
bladder tumors (118). Recent studies from our
group show that HRAS is signicantly overexpressed in nonprogressing Ta tumors, compared with those that progress to an invasive
phenotype (119). Transduction of mitogenic
signals along the pathway induces MYC, a gene
that encodes the transcription factor c-Myc
(Figure 4) (45). c-Myc regulates cyclin expression and inhibits the activity of CDKIs, thereby
controlling the cell cycle. To date, however, cMyc has not proved to be a good prognostic
indicator for UC (120, 121).
PKC,
a
ubiquitous,
phospholipiddependent enzyme, is involved in signal
transduction associated with cell proliferation,
differentiation, and apoptosis. The binding
of a ligand to a tyrosine kinase receptor
activates PLC and diacylglycerol, subsequently
leading to PKC activation (122). In addition to
regulating transcription factors such as c-Fos
and NF-B, PKC can inhibit Bad activity
and promote Raf, a molecule upstream in the
Ras-MAPK pathway (Figure 4). Studies have
reported that the expressions of PKC isozymes
and decrease with increasing UC grade
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ammation, autoimmune response, cell proliferation, and apoptosis by regulating the expression of genes involved in these processes.
Bacille Calmette-Guerininduced interleukin6 expression by UC occurs as an immediateearly gene pathway that requires NF-B (136).
A study examining a functional insertion/
deletion polymorphism in the promoter region
of NFKB1 showed that supercial UC patients
with the homozygous deletion had a higher risk
of recurrence than those with the homozygous
insertion (137).
c-Fos and c-Jun are a pair of transcription factors that, in combination with other
related proteins, form the AP-1 (activating
protein 1) transcription factor complex (138).
c-Fos and c-Jun are strong transactivators that
control basal and inducible transcription of several genes involved in proliferation, differentiation, apoptosis, and transformation. c-Fos
expression has been correlated with increasing tumor grade (139), whereas c-Jun expression has been correlated with increasing tumor
stage in UC (140). Our recent studies also indicate that increased JUN expression is associated
with poorer recurrence-free and overall survival
in UC (135).
Microvessel density
(MVD): mean
number of blood
vessels over a number
of randomly selected
areas or in the densest
areas of
neovascularization
(known as hot spots)
Tumor Angiogenesis
Angiogenesis involves production of factors
by tumor cells that interact with stromal elements to recruit endothelial cells to the site
of malignancy and establish a vascular supply,
which can provide the required nutrients for
the rapid clonal expansion of the cancer cells.
Angiogenesis is measured histologically by microvessel density (MVD) estimations. We have
shown that MVD is signicantly associated with
disease-free and overall survival in UC (141).
The hypoxia-inducible factors (HIF-1 and
HIF-2) are heterodimeric transcription factors
that are regulated by oxygen concentrations and
that bind to DNA-upregulating neighboring
genes (53). Although hypoxia itself does not
upregulate the transcription of the protein, it
inhibits the oxygen-dependent degradation of
the subunits. HIF-1 overexpression has been
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survival in UC patients (162165). Furthermore, loss of immunoreactivity of both Ecadherin and -catenin is a strong predictor
of poor progression-free and overall survival in
UC (166).
Integrins are transmembrane glycoprotein
heterodimers that regulate cellular processes,
which, if altered, can promote tumor progression, invasion, and metastasis. They are receptors for ECM proteins such as laminin and
collagen, and they maintain normal tissue architecture (167). The intracellular domains also
connect to the actin cytoskeleton, thus linking
the cytoskeleton to the ECM. The 64 integrin is the most commonly studied in bladder
tumorigenesis. In normal urothelial cells, the
64 integrin has a close relationship to collagen VII, a component of the hemidesmosomal
anchoring complex, and it restricts cell migration by anchoring contacts with laminin. Loss
of polarity of 64 expression has been noted in
supercial UC, and muscle-invasive UCs show
either a loss of 64 and/or collagen VII expression or a lack of colocalization of the two
proteins (168). Patients with tumors that exhibit
weak 64 immunoreactivity perform signicantly better than do those with either no expression or strong overexpression (169).
The tumors ability to degrade the matrix
and invade the basement membrane is facilitated by the actions of several protease families, especially the uPAs and MMPs. High levels
of MMP-2 and MMP-9 have been associated
with increasing stage and grade of UC (170,
171), and MMP-2 overexpression can predict
poor relapse-free and disease-specic survival
(172). Additionally, the MMP-9:E-cadherin ratio is prognostic for disease-specic survival
(173). Tissue inhibitors of metalloproteinases
(TIMPs), proteins produced by the host or
the tumor itself, antagonize MMP function,
thereby inhibiting tumor cell invasion. Although studies have reported poor prognosis
in patients with high MMP-2:TIMP-2 ratios
(174, 175), this nding is not consistent (176).
In fact, increased TIMP-2 expression has also
been associated with worse prognosis (177). Although such paradoxical TIMP behavior may
MOLECULAR DIAGNOSTIC
TESTS FOR BLADDER CANCER
Although most of the above discussion focuses
on the identication and use of markers for disease prognosis, molecular diagnostics have only
recently forayed into the eld of UC detection. This has stemmed from the need to provide rapid, reliable, noninvasive, and inexpensive diagnostic tests for UC, as hematuria detection lacks specicity, and routine cystoscopies
are both invasive and expensive (6). Although
development of prognostic markers is based
on a pathway- and process-specic approach,
diagnostic markers can identify more general
molecular characteristics of tumors; however,
these need to be very sensitive and specic in
detecting UC.
Advantages of Urine
as a Marker Source
Diagnosis of UC should preferably be made
using noninvasive procedures, and urine functions as an excellent source of surrogate molecular markers for the disease because very few
organs are exposed to it (as opposed to blood).
Furthermore, although the harsh urinary pH
degrades most proteases, those proteins that do
survive are very specic for the urologic tract,
and many are exclusive to UC. The collection
of exfoliated cells from voided urine that can
identify tumor markers is the basis for cytologic
examination and for various diagnostic molecular assays.
269
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271
272
Mitra
Qualitative immunoassay;
detects NMP22
Qualitative immunoassay;
detects brin and FDP
NMP22
BladderCheka,b
(Matritech, Inc.,
Newton, MA)
Cote
Accu-Dxa
(PerImmune Inc.,
Rockville, MD)
Quantitative ELISA;
detects hCFHrp
Quantitative microplate
sandwich ELISA; detects
NMP22
Immunoblot, quantitative
ELISA
Quantitative solid-phase
sandwich monoclonal
assay
Quantitative ELISA;
detects HA and HAase
BTA TRAKa,b
(Polymedco, Inc.,
Cortlandt Manor,
NY)
NMP22a,b
(Matritech, Inc.,
Newton, MA)
BLCA-4
UBC II ELISAb ,
UBC IRMAb
(IDL Biotech,
Bromma, Sweden)
HA-HAase
91100
48.770
8096.4
48100
5283
6870
55.7
9.389
7088.8
7295
87100
7091
5090
6886
85.7
5090
Specificity
(%)
No urine stabilization
required
Sensitive in detecting
high-stage and
bilharzial-related tumors
Sensitive in detecting
high-grade/-stage and
bilharzial-related tumors
Sensitive in detecting
high-stage and
bilharzial-related tumors
Sensitive in detecting
high-grade/-stage
tumors
Advantages
UTI
Microhematuria,
bladder inammation,
radiation cystitis,
urogenital
tuberculosis
False positives
Requires urine
stabilization before
transportation
Antibodies cross-react
with hCFH
Lacks quantitation
Antibodies cross-react
with hCFH
Disadvantages
9 December 2008
Specialized
Qualitative immunoassay;
detects hCFHrp
BTA stata,b
(Polymedco, Inc.,
Cortlandt Manor,
NY)
Point-of-care
Principle
Detection
Sensitivity
(%)
ARI
Test
Table 3
ANRV368-PM04-11
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RT-PCR; measures
hTERT mRNA levels
PCR
Multitarget, multicolor
uorescent in situ
hybridization assay
Immunocytochemistry;
detects Lewis X antigen
Immunocytouorescence;
detects a glycosylated
form of
carcinoembryonic
antigen and mucin
glycoproteins
TRAP
hTERT
Microsatellite
analysis
UroVysiona,b
(Abbott Molecular,
Inc., Des Plaines,
IL)
Lewis X
ImmunoCyta,b
(DiagnoCure, Inc.,
Quebec, Canada)
6070
36.986.4
8996
80100
Sensitive in detecting
high-grade/-stage
tumors
Advantages
False positives
Microhematuria, UTI,
BPH
Reactive urothelial
lesions
UTI, BPH
Disadvantages
Sensitivity affected by
hTERT degradation in
urine and by sample
collection and processing
errors
Needs at least 50
telomerase-expressing
cells to yield a positive
result. Sensitivity
affected by TRAP
degradation in urine and
by sample collection and
processing errors
Approved by the U.S. Food and Drug Administration for bladder cancer diagnosis/management.
Commercially available.
Abbreviations: BPH, benign prostatic hyperplasia; ELISA, enzyme-linked immunosorbent assay; FDP, brin degradation product; HA, hyaluronic acid; HAase, hyaluronidase; hCFH, human
complement factor H; hCFHrp, hCFH-related protein; hTERT, human telomerase reverse transcriptase; RT-PCR, reverse transcriptase polymerase chain reaction; TRAP, telomeric repeat
amplication protocol; UTI, urinary tract infection.
7080
79.894.4
6987
7297
6070
6070
Specificity
(%)
9 December 2008
70100
70100
Sensitivity
(%)
ARI
Principle
Test
Detection
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CONCLUSION
Scientists and clinicians now have an increased
understanding of the risk factors and molecular
alterations that contribute to bladder tumorigenesis and progression. This has led to the
identication and characterization of individ-
ual markers and marker panels that can diagnose UC and predict prognosis. Recent studies have adopted pathway-specic approaches
to identify alterations in cellular processes in
UC that, in turn, can predict clinical outcome in
individual patients. The availability of sophisticated genomic, proteomic, computational, and
statistical tools now offer us the possibility of assimilating existing data to establish diagnostic
and prognostic marker panels that can then be
validated in retrospective and prospective studies. Although we have tried to review the most
signicant pathways that control critical cellular process in urothelial cells, there are several
other lesser-known and uncharacterized cellular pathways that may also contribute towards
UC development. Future studies will aim to
identify these molecules and pathways and their
impact on tumor behavior and prognosis.
SUMMARY POINTS
1. UC is the most common type of bladder tumor, and it is as much of an economic problem
as it is a public health problem.
2. Exposure to tobacco smoke, aromatic amines, and aniline dyes are the most important
risk factors for UC. Arsenic exposure and Schistosoma haematobium infestation are also
important factors in endemic areas.
3. Noninvasive bladder tumors generally have a more distinct set of molecular alterations
and clinical behavior than the more aggressive invasive tumors.
4. Interaction of molecular pathways involved in the ve intrinsic cellular processes
cell-cycle regulation, cell death, cell growth, signal transduction, and gene regulationis
important in maintaining homeostasis of urothelial cells. Aberrations in one or more of
these processes are responsible for malignant transformation of the urothelium.
5. The extrinsic processes of angiogenesis and tumor cell invasion are also responsible
for tumor maintenance and progression.
6. In addition to the individually prognostic markers that have been identied in several
pathways involved in bladder tumorigenesis, recent studies have identied prognostic
panels comprising markers across multiple tumorigenic pathways.
7. Molecular diagnostic tests for UC are able to detect tumors using urine as a noninvasive
marker source. However, reaching optimal levels of sensitivity and specicity for most
clinically approved tests is still a challenge, thus necessitating intense and often expensive
surveillance and patient follow-up.
274
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FUTURE ISSUES
1. Although many individual prognostic markers have been identied in UC, there is still a
lack of consensus on which markers can be employed clinically. Reasons include differences in study designs and patient cohorts, inconsistent immunohistochemical staining
criteria, different cut-off points for determination of positivity, and variable outcome parameters. Future studies need to validate the markers identied thus far in large prospective clinical cohorts by employing standardized study and analysis protocols.
2. Studies have already started identifying prognostic panels that consist of multiple markers. However, efforts must made to generate concise prognostic marker panels that are
pathway based, rather than combining markers without biologic rationale. Such panels will serve as robust clinical predictors while also providing further insight into the
biologic mechanisms behind UC progression.
3. Molecular tests currently employed for UC detection either lack portability or suffer
from lack of sensitivity and specicity. Concerted efforts must be made to identify reliable
diagnostic markers that can be assessed by rapid, economical, and noninvasive point-ofcare tests.
4. Identication of new diagnostic and prognostic markers is concomitantly generating a
vast library of druggable targets in UC, many of which are already targets for novel
therapeutics. This provides an impetus for initiation of clinical trials targeting patients
with tumors that harbor specic molecular lesions with such therapeutics, and will spur
discovery of other novel compounds that can target additional molecular alterations.
DISCLOSURE STATEMENT
The authors are not aware of any biases that might be perceived as affecting the objectivity of this
review.
ACKNOWLEDGMENTS
Research on bladder cancer in the authors laboratory is supported by National Institutes
of Health/National Cancer Institute grant numbers CA86871, CA7192109, CA123027, and
EB008275; the L.K. Whittier Foundation; the Dhont Family Foundation; and the Candy Foundation. The authors apologize to the investigators whose studies could not be appropriately cited
due to space limitations.
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Contents
Annual Review of
Pathology:
Mechanisms of
Disease
Volume 4, 2009
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Contents