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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 9 of 15

Figure 2. Causative involvement of GSK3b in upfront sarcoma therapies and in the adverse events associated with therapy. →:
promoting; —|: suppressive; dotted line: hypothetical effect; NKT: natural killer T; MSCs, mesenchymal stem cells; CAR: chimeric
antigen receptor; CNS: central nervous system; GSK3b: glycogen synthase kinase 3b

prodrug combinations [e.g. cytosine deaminase (CD) combined with 5-fluorocytosine (FC)] [108,109] . Recent
preclinical studies [109] have evaluated the safety and therapeutic efficacy of transduced MSCs loaded with
TRAIL, combined CD/5-FC, IL-12, and osteoprotegerin (OPG) [110] . OPG is a soluble proteoglycan and
member of the TNF receptor superfamily that inhibits tumor-promoting osteoclastogenesis and bone
resorption by acting as a decoy receptor for the receptor activator of NF-κB ligand (RANKL)-mediated
pathway [110] . Previous studies on tissue regeneration and repair have demonstrated the effects of GSK3b
inhibitors on sustaining the stemness phenotype and proliferation of MSCs from different origins, as well
as inducing their transdifferentiation into mature mesenchymal cells [111-115] . These preliminary observations
warrant further investigations to clarify whether GSK3b inhibition enhances the therapeutic efficacy of
MSCs against bone sarcomas [Figure 2].

GSK3b and normal tissue damage associated with sarcoma treatment
Although the mainstay treatments for bone and soft tissue sarcomas remain to be surgery and
[7,8]
chemotherapy , they are inevitably associated with post-surgery tissue defects and adverse events related
to the chemotherapeutics, respectively. This section focuses on the beneficial effects that targeting GSK3b
has on the undesirable events associated with sarcoma treatment.

Normal tissue defect and repair following surgery
Defects in the constitutive normal tissue adjacent to the tumor are an unavoidable consequence of
surgery and are particularly serious for patients with musculoskeletal tumors. As discussed earlier,
adjuvant chemotherapy, radiation, and targeted therapies are usually combined with surgery to optimize
resection of the tumor and to minimize the resulting defect in tumor-adjacent, healthy tissues. There
is strong evidence for a critical role of the Wnt/b-catenin pathway in bone formation and homeostasis
through induction of osteoblastogenesis and differentiation of the osteogenic cell lineage [116-120] while also
suppressing osteoclastogenesis and the resultant bone resorption [121,122] [Figure 1]. Osteoclasts within
[40]
bone sarcoma lesions have been shown to facilitate the progression of osteosarcoma , thereby partially
supporting the tumor-suppressive function of the Wnt/b-catenin pathway [47,48] . Moreover, GSK3b inhibition
protects skeletal muscle cells from apoptosis, promotes their maturation [123,124] , and sustains proliferation
and the stemness phenotype (both self-renewal and transdifferentiation capacity) of MSCs from various
tissues [111-115] as discussed above. Considering its therapeutic effects against the major sarcoma types [Table