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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 7 of 15

including synovial sarcoma and fibrosarcoma, followed by the approval of tazemetostat, an inhibitor of
[78]
[15]
enhancer of zeste homolog 2 (EZH2) , for advanced or metastatic epithelioid sarcoma . These agents
improved the progression-free and overall survival of soft tissue sarcoma patients but showed little
improvement over conventional anticancer agents. Therefore, identification of new therapeutic targets is
imperative to allow the development of efficient, biologically-based treatments for both sarcoma types.

Recently, we showed the level of pGSK3b Y216 (active form) was higher in human synovial sarcoma and
fibrosarcoma cell lines than in untransformed fibroblast cells, considered to be the normal mesenchymal
counterpart cells. Inhibition of the activity or expression of GSK3b suppressed the survival and proliferation
of sarcoma cells, attenuated their invasion into collagen gel, and induced their apoptosis. These effects of
GSK3b inhibition against sarcoma cells were associated with G0/G1-phase cell cycle arrest and reduced
expression of cyclin D1, CDK4, and matrix metalloproteinase 2. Intraperitoneal administration of GSK3b-
specific inhibitors attenuated the growth of synovial sarcoma SYO-1 and fibrosarcoma HT1080 cell
xenografts in athymic mice, with no obvious side effects. This treatment also suppressed cell proliferation
and induced apoptosis in the xenograft tumors. These results indicate that synovial sarcoma and
fibrosarcoma depend on deregulated activity of GSK3b to enhance the cyclin D1/CDK4-mediated pathway
for cell proliferation and degradation of extracellular matrix for tumor invasion [Table 1]. Our study
therefore provides a biological basis for GSK3b as a new and common therapeutic target for these sarcoma
[79]
types as well as for osteosarcoma [41,45,46] and embryonal/alveolar rhabdomyosarcomas [62,64] .

FUTURE PERSPECTIVES FOR GSK3b IN SARCOMA BIOLOGY AND THERAPY
In order to confirm GSK3b as a relevant and potentially valuable therapeutic target in bone and soft tissue
sarcomas, it is important to broaden the spectrum of targetable tumor types. Moreover, it is important to
explore the mechanistic influence of GSK3b on emerging sarcoma therapies and to clarify the properties of
this kinase in normal cells and tissues affected by sarcoma therapy.

Potential involvement of GSK3b in undifferentiated pleomorphic sarcoma (malignant fibrous
histiocytoma)
Undifferentiated pleomorphic (UP) sarcoma is currently defined as a subset of the sarcoma type previously
designated as malignant fibrous histiocytoma (MFH) that encompassed myxofibrosarcoma, pleiomorphic
[4]
liposarcoma/rhabdomyosarcoma, and UP sarcoma . UP sarcoma is one of the most prevalent soft tissue
sarcomas, accounting for 10% of cases in adults. It frequently affects deep soft tissues in the extremities
and trunk, but rarely occurs in superficial regions such as subcutaneous tissue [80,81] . As with most soft
tissue sarcomas, the mainstay of curative treatment for UP sarcoma is surgical excision of the tumor and
post-surgery irradiation. Optional adjuvant chemotherapy is reported to increase the overall survival
[82]
of patients . The first-line treatment for metastatic UP sarcoma is doxorubicin-based chemotherapy,
occasionally combined with ifosfamide or olaratumab, an anti-PDGF antibody. Although other anti-tumor
agents such as trabectedin and pazopanib have shown some efficacy, the outcome of patients with advanced
UP sarcoma is worse than for other soft tissue sarcoma types .
[83]

[84]
The genetic profile of UP sarcoma has not been fully elucidated , although the inactivation of Rb and
[85]
loss of p53 function are frequently observed in MFH . A previous study showed the side population cells
(hypothetically corresponding to stem-like cells) of UP sarcoma display activation of both Hh- and notch-
mediated pathways responsible for sarcoma cell self-renewal. This study suggested that UP sarcoma cells
share the same molecular pathways as mesenchymal stem cells (MSCs) . Another study demonstrated
[86]
that human MSCs could be transformed via inhibition of Wnt/b-catenin signaling to form UP sarcoma-
[87]
like tumors in athymic mice, thus suggesting MSCs as the origin of UP sarcoma . GSK3b is a negative
regulator of the canonical Wnt/b-catenin pathway [18-20] and of the maintenance of MSCs, as described below.
Therefore, GSK3b may potentially play a role in the tumorigenesis and progression of UP sarcoma and