| Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 9, Number 7, July 2008
Contents
Wnt Signaling
Guest Editor: Rashna D. Balsara
Editorial Pp. 511-512
Wnt Signaling in Development, Disease and Translational
Medicine Pp. 513-531
G.S. Coombs, T.M. Covey and D.M.
Virshup
[Abstract]
The Potential for Targeting Oncogenic WNT/β-Catenin
Signaling in Therapy Pp. 532-547
K.B.R. Ewan and T.C. Dale
[Abstract]
Targeting the Most Upstream Site of Wnt Signaling
Pathway Provides a Strategic Advantage for Therapy in Colorectal
Cancer Pp. 548-557
J. Qi and Y-Q. Zhu
[Abstract]
Wnt Signaling in Angiogenesis Pp. 558-564
N.L. Parmalee and J. Kitajewski
[Abstract]
WNT Signaling in Stem Cell Biology and Regenerative
Medicine Pp. 565-570
M. Katoh
[Abstract]
Wnt Signaling and Prostate Cancer Pp.
571-580
D.R. Robinson, C.R. Zylstra and B.O.
Williams
[Abstract]
Wnt Signaling and Potential Applications in Bone
Diseases Pp. 581-590
G. Rawadi
[Abstract]
Wnt Signaling in Renal Cancer Pp. 591-600
H. Guillén-Ahlers
[Abstract]
Abstracts
[Back to top]
Editorial
Signaling pathways are ubiquitously present in organisms ranging
from the simple metazoan Hydra to vertebrates. These pathways
play a pivotal role in tightly regulating cell-cell communication
that coordinates various biological activities, such as embryogenesis,
development, tissue homeostasis and regeneration. Among the
myriad signaling pathways elucidated, the Wnt signaling pathway
has made a tremendous impact by not only increasing our understanding
of development, but also towards understanding cellular perturbations
that promote human degenerative diseases and cancer. Components
of the Wnt signaling pathway have a rich evolutionary history,
pre-dated about 650 million years ago. Investigators have
identified several bilaterian Wnt gene subfamilies
in cnidarians, drosophila, C. elegans and mammals
indicating a common ancestral cluster of Wnt genes.
There is extensive amount of conservation of the Wnt
gene cluster making orthologous recognition easy, suggesting
similar biological and biochemical activities.
The Wnts are composed of a large family of highly conserved
growth factors or ligands that bind to the Frizzled/LRP receptor
complex, and relays their signals to the nucleus via
several transduction intermediates. One of the most focused
aspects of Wnt signaling has been the canonical pathway in
which the cytoplasmic stabilization of β-catenin
is controlled by a destruction complex, and its subsequent
nuclear translocation and activity plays a central role. This
well-defined model of Wnt signaling is also referred to as
the β-catenin-dependent
pathway. In the absence of Wnt, the destruction complex, which
consists of Axin/Adenomatous Polyposis Coli (APC)/Glycogen
Synthase Kinase-3 (GSK3) degrades β-catenin.
Presence of Wnt ligands in association with the signaling
intermediate Dishevelled blocks the activity of the destruction
complex causing stabilization and accumulation of β-catenin.
In the nucleus β-catenin
interacts with the TCF/LEF-1 transcriptional activators resulting
in the expression of specific Wnt target genes. However, the
Wnt ligands are pleiotropic, and participate in signaling
cascade events that are β-catenin-independent
or the noncanonical pathway(s) that operates through a network
of intermediates that are calcium-dependent or require GTPases.
Depending on the interaction of Wnts with different surface
receptors various cellular outcomes have been observed. Some
atypical members of the receptor tyrosine kinase family, such
as RYK can associate with Wnt, and elicit axon repulsion providing
directional guidance to extending axons during mammalian central
nervous system development. Another noncanonical pathway,
now known as the planar cell polarity (PCP) pathway utilizes
both Frizzled and Dishevelled, along with c-Jun N-terminal
kinase, and a number of novel signaling molecules to regulate
PCP. Paradoxically in this pathway the specific role of Wnt
is not fully understood. Furthermore, the Wnt/PCP pathway
via Frizzled7 and Dishevelled can regulate convergent extension
(CE) movements in Xenopus embryos. Both the Wnt pathways
have been presented in considerable details in the ensuing
articles. Though in a given cell only a subset of Wnts can
stimulate the canonical signaling pathway there is cross-talk
between the two pathways, whereby the noncanonical pathway
can directly antagonize the canonical pathway to regulate
signals critical for vertebrate body axis determination, limb
development, and possibly oncogenesis.
Given the diverse functions of Wnt ligands it is not surprising
Wnt function gone awry would lead to dire consequences in
humans. Some of the disorders associated with dysfunctional
Wnt signaling are cancers, bone density defects, and defects
in retinal angiogenesis. In this special issue dedicated to
Wnt signaling, all articles illustrate in detail the multifaceted
functions potentiated by the Wnt ligands. The first article
by Coombs and colleagues gives a lucid description on the
history of Wnt signaling. It also introduces the reader on
the role of Wnts in development, cancers, bone diseases and
neuropsychiatric disorders. The article by Ewan and Dale focuses
on cellular events triggered by ligand/receptor interaction
with a view to exploit different players of this pathway for
therapeutic purposes in oncogenic therapy. Aberrant Wnt signaling
in colorectal cancer and associated genetic changes have been
addressed by Qi and Zhu. They have also described structured
therapeutic intervention at different levels of the Wnt pathway.
Parmalee and Kitajewski have explained the role of Wnt through
Frizzled4 on the newly discovered angiogenic factor Norrin
with respect to retinal angiogenesis. The article by Katoh
describes the role of Wnt signaling along with different signaling
partners on a variety of stem cells, such as embryonic, neural,
mesenchymal, hematopoietic and intestinal stem cells. Thus,
enabling investigators to gain insights towards developing
tissue engineering and regeneration technology. Robinson and
colleagues have reviewed the role of the canonical Wnt pathway
in the initiation and development of prostate cancer with
emphasis on skeletal metastasis. They have also discussed
the cross-talk between Wnt signaling and other pathways, such
as the PI3K/AKT and the dihydrotestosterone/Androgen receptor
pathway. The complex function of Wnt signaling in bone homeostasis
has been reviewed by Rawadi, with a discussion on the involvement
of the Wnt inhibitor DKK1 in skeletal diseases. The article
also highlights the possibility of targeting different components
of the Wnt pathway for treating bone diseases. The emerging
role of Wnt signaling in renal cell carcinoma is covered by
Guillén, which discusses the involvement of the newly
identified von Hippel-Lindau (VHL) tumor suppressor gene and
hypoxia inducible factors. Additionally, the correlation between
hypermethylation of Wnt antagonist genes, aberrant alternative
splicing of TCF-4 and kidney tumor formation has been highlighted.
It is apparent that the Wnt signaling pathway is intriguing,
complex, and multifunctional. In the past two decades it has
gained prominence as it has been demonstrated to play a crucial
role in numerous aspects of developmental biology and diseases.
Considerable research insights and investments have accrued
towards exploiting different components of the Wnt pathway
for developing therapeutical and remedial drugs. Several articles
in this issue have given in-depth information on potential
drug intervention against different Wnt-directed diseases,
however outlined briefly are some drug developmental strategies
employed towards fighting cancers. Large-scale screening programs
based on rational drug design, as well as drugs that are currently
in the market are being evaluated for treatment of cancers
involving aberrant Wnt signaling. Prime examples are the non-steroidal
anti-inflammatory drugs (NSAIDS), such as asprin, indomethacin,
and sulindac sulphone developed as Exisulind by OSI Pharmacuticals,
have been reported to effectively reduce colon tumor growth
or polyps, and reduce β-catenin
levels. Other drugs which include the new generation nitric
oxide-NSAIDS, and retinoids effectively inhibit colon cancer
growth by reducing the formation of Tcf-β-catenin
complex. Another therapeutic approach is development of monoclonal
antibodies against Wnt and Frizzled proteins that are overexpressed
in several cancers. Monoclonal antibodies against Wnt1, Wnt2,
and Frizzled 1/2 have been known to induce apoptosis and effectively
block tumor growth. The search for small molecule inhibitors
by high throughput screening to selectively block Dishevelled/Frizzled
or Tcf-β-catenin
complex formation, thereby preventing its interaction downstream
with transcriptional co-activators, and expression of Wnt-regulated
genes is an attractive tool for developing drugs against cancers,
and diseases associated with aberrant Wnt signaling.
As in all drug discovery efforts, apart from the efficacy
of the drug its safety and toxicological potential is of paramount
importance. More so since the Wnt pathways play a significant
role in development, and side effects from therapeutically
targeting the Wnt/β-catenin
pathway is unknown especially when long-term treatment is
involved. Though several of the NSAIDS, and small molecule
inhibitors show promising results in clinical trials and mouse
studies, their use as long term drugs are accompanied by severe
side effects, such as abdominal pain, liver problems, and
have yet to gain FDA approval. The challenging race is to
identify small molecules that selectively interfere with cancer-specific
Tcf-β-catenin
complex formation without disrupting other β-catenin
complexes essential of maintaining normal cellular duties
in non-cancer cells.
I end the editorial by gratefully acknowledging Professor
Francis J. Castellino, chief editor of CDT for bullying me
into accepting the task of guest editor for this issue, an
experience that has proved to be intellectually enlightening
and enjoyable. I also take this opportunity to profusely thank
all the authors for reviewing different aspects of Wnt signaling
in their areas of expertise as thoughtfully and well-written
manuscripts.
Rashna D. Balsara
[Back to top]
Wnt Signaling in Development, Disease and Translational Medicine
G.S. Coombs, T.M. Covey and D.M.
Virshup
Wnt signaling regulates a multitude of critical processes
in development and tissue homeostasis. The wingless (wg)
gene product was first identified in Drosophila in
1973. Subsequently, the proto-oncogene INT-1 was identified
in mice in 1984 when its activation by mouse mammary tumor
virus’ proviral insertion was found to induce tumor
formation. The discovery in 1987 that wg and INT-1 are orthologues
contributed to an appreciation of the intimate connection
between oncogenic and developmental processes. Diverse diseases
including cancer, diabetes, osteoporosis and psychiatric disorders
may be amenable to treatment via modulation of Wnt-mediated
signaling pathways. There are a number of attractive targets
that are the object of ongoing drug development studies aiming
to capitalize on these opportunities. In this review, we present
a historical overview of key events in this field that have
elucidated the known signaling cascades associated with Wnt
ligands and shaped our understanding of the roles of these
cascades in physiological and pathological processes.
[Back to top]
The Potential for Targeting Oncogenic WNT/β-Catenin
Signaling in Therapy
K.B.R. Ewan and T.C. Dale
There has been a surge of interest in the therapeutic
targeting of the Wnt pathway following the demonstration that
it is activated in a wide variety of tumors and that blocking
aberrant signaling promoted tumor cell apoptosis or differentiation.
This review describes recent therapeutic approaches and discusses
potential opportunities for intervention at multiple levels
within the Wnt pathway.
[Back to top]
Targeting the Most Upstream Site of Wnt Signaling
Pathway Provides a Strategic Advantage for Therapy in Colorectal
Cancer
J. Qi and Y-Q. Zhu
The Wnt signaling pathway has important functions in
development, tissue homeostasis, and regeneration. Deregulation
of canonical Wnt/β-catenin
signaling is frequently found in various human cancers, particularly
in colorectal cancer, and non-canonical Wnt signaling pathways
also have been implicated in neoplasia. Colorectal cancer
is a multipathway disease. Activation of Wnt signaling by
both genetic and epigenetic alterations has been found to
be important for both, initiation and progression of colorectal
cancer. In addition, since Wnt signaling results in diverse
downstream intracellular events, targeted inhibition of Wnt/β-catenin
signaling at the most upstream site of this pathway is a rational
and an advantageous new approach for the therapy of colorectal
cancer.
[Back to top]
Wnt Signaling in Angiogenesis
N.L. Parmalee and J. Kitajewski
Although progress has been made in understanding the role
of growth factors and their receptors in angiogenesis, little
is known about how the Wnt family of growth factors function
in the vasculature. Wnts are multifunctional factors that
act through the frizzled receptors to regulate proliferation,
apoptosis, branching morphogenesis, inductive processes, and
cell polarity. All of these processes must occur as developing
vascular structures are formed and maintained. Recent evidence
has linked the Wnt/Frizzled signaling pathway to proper vascular
growth in murine and human retina. Here we review the literature
describing the angiogenic functions for Wnt signaling and
focus on a newly discovered angiogenic factor, Norrin, which
acts through the Wnt receptor, Frizzled4.
[Back to top]
WNT Signaling in Stem Cell Biology and Regenerative
Medicine
M. Katoh
WNT family members are secreted-type glycoproteins to
orchestrate embryogenesis, to maintain homeostasis, and to
induce pathological conditions. FZD1, FZD2, FZD3, FZD4, FZD5,
FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, and ROR2 are transmembrane
receptors transducing WNT signals based on ligand-dependent
preferentiality for caveolin- or clathrin-mediated endocytosis.
WNT signals are transduced to canonical pathway for cell fate
determination, and to non-canonical pathways for regulation
of planar cell polarity, cell adhesion, and motility.
MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 and Glucagon
are target genes of canonical WNT signaling cascade,
while CD44, Vimentin and STX5 are target
genes of non-canonical WNT signaling cascades. However, target
genes of WNT signaling cascades are determined in a context-dependent
manner due to expression profile of transcription factors
and epigenetic status. WNT signaling cascades network with
Notch, FGF, BMP and Hedgehog signaling cascades to regulate
the balance of stem cells and progenitor cells. Here WNT signaling
in embryonic stem cells, neural stem cells, mesenchymal stem
cells, hematopoietic stem cells, and intestinal stem cells
will be reviewed. WNT3, WNT5A and WNT10B are
expressed in undifferentiated human embryonic stem cells,
while WNT6, WNT8B and WNT10B in endoderm
precursor cells. Wnt6 is expressed in intestinal
crypt region for stem or progenitor cells. TNFα-WNT10B
signaling is a negative feedback loop to maintain homeostasis
of adipose tissue and gastrointestinal mucosa with chronic
inflammation. Recombinant WNT protein or WNT mimetic (circular
peptide, small molecule compound, or RNA aptamer) in combination
with Notch mimetic, FGF protein, and BMP protein opens a new
window to tissue engineering for regenerative medicine.
[Back to top]
Wnt Signaling and Prostate Cancer
D.R. Robinson, C.R. Zylstra and B.O.
Williams
Canonical Wnt signaling has emerged as an important pathway
that underlies the initiation of prostate cancer. Both human
cancers and mouse models have confirmed that mutations or
altered expression of components of this pathway are associated
with prostate tumors. Additionally, several reports suggest
that this pathway plays a key role in the establishment of
skeletal metastasis. This review discusses our current knowledge
of the Wnt signaling pathway in the development of prostate
cancer. First, we will overview the Wnt signaling pathway
to provide background for the rest of the discussion. We will
then review the literature on the role of this pathway and
the downstream effector, β-catenin,
in the development and progression of prostate cancer and
skeletal metastasis. We will also discuss reports that suggest
that β-catenin
can directly interact with the androgen receptor to modulate
its activity. These recent developments may provide insight
into how tumor growth can be achieved under androgen deprivation.
Finally, we speculate on how the pathway may be targeted for
therapeutic treatment and what agents may be available to
achieve this goal.
[Back to top]
Wnt Signaling and Potential Applications in Bone Diseases
G. Rawadi
In the United States, it is estimated that $10-15 billion
is spent annually for the treatment of osteoporotic fracture.
The worldwide annual incidence of osteoporotic hip fracture
exceeds 1.7 million cases. Bone loss leading to osteoporosis
and osteoporotic fractures are caused by an imbalance between
osteoblast-mediated bone formation and osteoclast-mediated
bone resorption and numerous factors have been implicated
in the development of osteoporosis. The prevention and treatment
of osteoporosis traditionally involves the use of anti-resorptive
agents, which target osteoclast function, but do not lead
to a significant increase in bone mass and therefore only
partially reduce risk of fractures. For these reasons, the
search for anabolic agents, which target osteoblast function,
represents an urgent medical need. Genetic studies have firmly
established a link between bone mass in humans and Wnt signaling.
Multiple genetic and pharmacological manipulations of Wnt
signaling in mice have since then confirmed the central role
of this pathway in regulating bone formation. The existence
of many potential pharmacological targets in this pathway
makes it attractive for bone anabolic drug discovery.
[Back to top]
Wnt Signaling in Renal Cancer
H. Guillén-Ahlers
About one fourth of people diagnosed with kidney cancer in
2007, are expected to die of this disease within 5 years from
the date of diagnosis. Recent years have produced novel drugs,
some with FDA approval, and many in clinical trials, all showing
very discrete results. Failure in finding effective treatments
to improve survival with drugs mainly targeting VEGF and its
downstream effectors, urges to shift the drug development
targets to other unexploited pathways shown to be also involved
in renal cancer. Several studies show alterations in the Wnt
signaling pathway, many of which differ from those implicated
in other human cancers. Unlike colorectal or hepatocellular
carcinomas, where APC and axin mutations, respectively, are
the main Wnt signaling deregulating event, renal carcinomas
seem to be affected by other factors. Recent studies have
presented VHL, a tumor suppressor gene strongly associated
with renal cell carcinoma, as a beta-catenin target. This
confirms that Wnt signaling is likely playing a central role
during renal carcinoma development, which needs to be considered
and addressed to treat this disease. This review outlines
briefly the molecular biology of the most common renal cancers
and the drug treatments currently used to treat the disease.
The canonical Wnt pathway is reviewed more carefully adding
specific features in a renal carcinoma context, which present
potential targets for drug development and biomarker use.
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