On The Horizon From The ORS: WNT, Osteosarcoma, and Future Therapy

On the Horizon From the ORS
Wnt, Osteosarcoma, and Future

Therapy
Bang H. Hoang, MD
Topics from the frontiers of basic

research presented by the Orthopaedic
Research Society.
From the Department of Orthopaedic
Surgery, University of California at
Irvine Medical Center, Orange, CA.
Neither Dr. Hoang nor any immediate
family member has received anything of
value from or owns stock in a
commercial company or institution
related directly or indirectly to the
subject of this article.
J Am Acad Orthop Surg 2012;20:58-59
Copyright 2012 by the American
Academy of Orthopaedic Surgeons.
58
Osteosarcoma is the most common

type of primary bone cancer, with
peak incidences in adolescence and
at age >60 years. This tumor has a
very high propensity for local invasion and distant metastasis. Pulmonary metastasis is the most common mode of spread, occurring in
about 80% of patients. Aggressive
treatment with high-dose chemotherapy and surgery leads to cure in
60% to 70% of patients. However,
the long-term survival for patients
with relapse is only 20%.1
The Wnt pathway is comprised of
a family of highly conserved proteins that regulate cell-to-cell interactions during embryogenesis. In
the absence of Wnt binding to cellsurface receptors called Frizzled
and LRP-5/6, a cytoplasmic complex consisting of axin, adenomatous polyposis coli, and glycogen
synthase kinase- phosphorylates
-catenin, thus promoting the ubiquitination and degradation of
-catenin. In addition to Wnt proteins and receptors, several negative
regulators, called Wnt antagonists,
exist. -Catenin, together with
LEF/TCF transcription factors, acts
as a signal transducer for downstream genes involved in cell proliferation and growth.
Using clinical tissue samples, we
examined the relationship between
the Wnt pathway and clinical outcome of patients with osteosarcoma. In this study, RNA from
fresh-frozen osteosarcoma specimens was isolated to characterize
the expression of the Wnt receptor
LRP-5 by polymerase chain reaction. We found a statistically significant correlation between LRP-5
expression and a worse event-free
survival in patients. More importantly, patients whose primary tumors expressed LRP-5 sustained a
higher risk of developing metastasis.
Given the association between
LRP-5 and osteosarcoma, we proceeded to examine whether blocking Wnt signaling by a soluble
LRP-5 receptor affects tumor progression. Our results suggest that
blocking Wnt/LRP-5 signaling halts
tumor invasiveness by reversing the
epithelial-to-mesenchymal transition, confirming the important role
of Wnt in osteosarcoma progression. In contrast, downregulation
of Wnt antagonists is a common
event in osteosarcoma tumors and
cell lines, suggesting that Wnt activation contributes to the tumorigenic phenotypes. Further analysis
suggests that promoter hypermethylation is one of the key mechanisms by which osteosarcoma suppresses Wnt antagonist expression.2
Consistent with this notion, reexpression of Wnt antagonists
slows both tumor growth and the
formation of lung metastasis in
vivo. Therefore, drugs that target
DNA methyltransferase may play
an important role in preventing osteosarcoma progression.
Several strategies have been devised to exploit the Wnt pathway for therapeutic purpose.
DeAlmeida et al3 showed that a secreted Wnt antagonist, consisting
of the ligand-binding domain of
Frizzled-8 fused with human immunoglobulin G, had antitumor efficacy in an animal model. Monoclonal antibodies against Wnt-1 and
-2 have been shown to induce
apoptosis in several cancer cell
Journal of the American Academy of Orthopaedic Surgeons
On the Horizon From the ORS
lines, including sarcoma.4 Another

class of compound takes advantage
of the PDZ-binding domain of Disheveled (Dvl), a Wnt-activating protein.5 Dvl is involved in transducing
the intracellular signal to inhibit
-catenin destruction complex. By
targeting this PDZ domain, researchers hope to turn off Wnt signaling by
preventing Dvl from keeping a high
intracellular level of -catenin. This
class of drug will be able to address
mutations leading to increased expression of Wnt ligand or decreased
expression of negative regulators, or
to mutation in extracellular receptors. However, it would be less effective against tumors harboring downstream mutations of the degradation
complex or mutations of -catenin
itself.
Although strategies that directly
target the Wnt pathway hold great
promise, there may be significant
side effects because this pathway is
critical for tissue regeneration and
for stem cells in the gut and bone
marrow to self-renew. Another approach may involve drugs that specifically block downstream targets of
January 2012, Vol 20, No 1
Wnt. One such target is the hepatocyte growth factor receptor c-Met, a
receptor tyrosine kinase aberrantly
expressed in most human osteosarcomas. It appears that c-Met not only
plays a role in the progression of osteosarcoma but may also be essential
to its initiation. Overexpression of
c-Met can convert primary human
osteoblasts into osteosarcoma cells,
displaying the transformed phenotype both in vitro and in vivo.6 Our
data implicated c-Met as being
tightly regulated by Wnt signaling
and therefore susceptible to the negative effects of Wnt antagonists. Together, these findings suggest that
drugs inhibiting Wnt signaling or
Wnt target genes, such as c-Met,
should exhibit anti-tumor effects
against at least a subset of osteosarcoma.
It is clear that activation of the
Wnt pathway plays an important
role in the biology of osteosarcoma.
Although treatment of osteosarcoma
has improved, there is still much to
gain, especially in the areas of recurrence and metastasis prevention.
Strategies to target the Wnt pathway
have emerged as a viable alternative

to current treatment paradigms.
References
1.
Hayden JB, Hoang BH: Osteosarcoma:

Basic science and clinical implications.
Orthop Clin North Am 2006;37(1):1-7.
2.
Rubin EM, Guo Y, Tu K, Xie J, Zi X,

Hoang BH: Wnt inhibitory factor 1
decreases tumorigenesis and metastasis
in osteosarcoma. Mol Cancer Ther 2010;
9(3):731-741.
3.
DeAlmeida VI, Miao L, Ernst JA, Koeppen H, Polakis P, Rubinfeld B: The

soluble wnt receptor Frizzled8CRD-hFc
inhibits the growth of teratocarcinomas
in vivo. Cancer Res 2007;67(11):53715379.
4.
He B, You L, Uematsu K, et al: A

monoclonal antibody against Wnt-1
induces apoptosis in human cancer cells.
Neoplasia 2004;6(1):7-14.
5.
Grandy D, Shan J, Zhang X, et al:

Discovery and characterization of a
small molecule inhibitor of the PDZ
domain of dishevelled. J Biol Chem
2009;284(24):16256-16263.
6.
Patan S, Avnet S, Coltella N, et al: MET

overexpression turns human primary
osteoblasts into osteosarcomas. Cancer
Res 2006;66(9):4750-4757.
59

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On the Horizon From the ORS

Wnt, Osteosarcoma, and Future

Topics from the frontiers of basic

Osteosarcoma is the most common

Journal of the American Academy of Orthopaedic Surgeons

On the Horizon From the ORS

lines, including sarcoma.4 Another

January 2012, Vol 20, No 1

have emerged as a viable alternative

Hayden JB, Hoang BH: Osteosarcoma:

Rubin EM, Guo Y, Tu K, Xie J, Zi X,

DeAlmeida VI, Miao L, Ernst JA, Koeppen H, Polakis P, Rubinfeld B: The

He B, You L, Uematsu K, et al: A

Grandy D, Shan J, Zhang X, et al:

Patan S, Avnet S, Coltella N, et al: MET

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