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Abe et al. J Cancer Metastasis Treat 2020;6:51 I http://dx.doi.org/10.20517/2394-4722.2020.117 Page 3 of 15

vital activities and homeostasis in normal cells in response to endogenous and exogenous stimuli [18,19] .
Aberrant expression and activation of GSK3b contribute to the pathogenesis and progression of common
diseases including glucose intolerance, neurodegenerative disorders with cognitive disturbance, and
chronic inflammatory diseases [20,21] . Such differential functions in healthy and diseased cells have
highlighted GSK3b as a potential drug target in various diseases and have stimulated the development of
pharmacological GSK3b inhibitors [22-24] .

In the field of oncology, GSK3b has long been hypothesized to suppress tumorigenesis. This is based on
S9
its inactivation, as indicated by pGSK3b , in major pro-oncogenic pathways mediated by Wnt/b-catenin,
hedgehog (Hh), notch, and c-Myc signaling, as well as in the process of epithelial-to-mesenchymal transition
(EMT) [25,26] . However, few studies have shown that active GSK3b suppresses tumor development and
progression by disrupting these pro-oncogenic pathways. In contrast to the hypothesis that GSK3b is a
tumor suppressor, a growing number of experimental studies over the past 15 years have demonstrated
that deregulated expression and activity of GSK3b contributes to the pathogenesis and progression of
various cancer types. The notion that GSK3b has pro-tumorigenic properties is supported by observations
that tumor cells depend mechanistically on GSK3b for their survival, proliferation, and invasion, and
that GSK3b renders them unresponsive to chemotherapy, radiation, and some molecular targeted agents
in refractory cancer types. A tumor-promoting role for GSK3b is also supported by evidence of specific
and strong therapeutic effects of various GSK3b inhibitors against at least 25 different cancer types, while
sparing the normal cells and tissues [27-30] . This increasing experimental evidence supports the notion of
GSK3b as a promising therapeutic target in cancer, thereby encouraging the screening and identification of
GSK3b-specific inhibitors for treatment of cancer [24,31,32] .

GSK3b INVOLVEMENT IN BONE AND SOFT TISSUE SARCOMAS
Among the many bone and soft tissue sarcoma types, the tumor-promoting role of GSK3b has been
reported in osteosarcoma, rhabdomyosarcoma (alveolar and embryonal types), synovial sarcoma, and
fibrosarcoma [Table 1].

Osteosarcoma
Although rare, osteosarcoma is the most prevalent primary malignant bone tumor, followed by
chondrosarcoma and Ewing sarcoma. It typically affects the long bone of the limbs in children, adolescents,
[33]
and young adults . The anatomical site of the primary tumor, clinical characteristics, treatment response,
and patient prognosis distinguish high-grade osteosarcoma (accounting for 80% to 90% of cases) from
[34]
low/moderate-grade osteosarcoma (10% to 20%) . The current standard of care for the treatment of
patients with no detectable metastasis at initial diagnosis (accounting for 80% to 85% of cases) sequentially
combines surgery with pre-operative (neoadjuvant) and post-operative (adjuvant) chemotherapy. The
remaining 15% to 20% of patients have metastasis at diagnosis and undergo multi-agent chemotherapy. The
most effective chemotherapy regimen combines high-dose methotrexate, doxorubicin, and cisplatin [7,33,35,36] .
Beginning in the 1970s, the use of multi-agent chemotherapy in patients with localized disease increased
[33]
their survival rate from less than 20% to almost 70% . However, no further substantial improvement has
been achieved over the past 25 years. In contrast to the survival benefits obtained with chemotherapy for
localized primary tumors, little improvement has been achieved in the 5-year survival rate for patients
with concurrent metastasis or post-operative recurrence. This highlights the need for new therapeutic
approaches against metastatic progression in osteosarcoma [37,38] .

During the last decade, comprehensive genomics studies have revealed the highly heterogeneous
nature of genetic alterations in high-grade osteosarcoma. Although several studies suggested candidate
genetic biomarkers for future clinical translation, no actionable genes for targeted therapy have yet been
[13]
identified . Based on studies of the biological and immunological characteristics of osteosarcoma,
nearly 30 clinical trials involving osteosarcoma patients have tested several agents that target receptor-