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Figure 1. Reported mechanisms by which GSK3b promotes (→) the development of osteosarcoma and rhabdomyosarcoma, while
suppressing (—|) osteogenesis and skeletal musculogenesis. →: promoting; —|: suppressive; GSK3b: glycogen synthase kinase 3b; NF-
κB: nuclear factor kappa-light-chain-enhancer of activated B cells; FOXO1: forkhead box O-subfamily 1; PAX3: paired box 3

and alveolar; in total nearly 80%) of rhabdomyosarcoma.

Synovial sarcoma and fibrosarcoma
In addition to rhabdomyosarcoma, the major soft tissue sarcoma types include synovial sarcoma,
fibrosarcoma, and undifferentiated pleomorphic sarcoma [1,2,65] . Synovial sarcoma accounts for 5%-10% of all
soft tissue sarcomas. Although it can arise at almost any anatomical site and at any age, synovial sarcoma
[66]
frequently affects the extremities, particularly the popliteal fossa, in adolescents and young adults .
Histologically, this sarcoma is characterized by biphasic tumor cells comprising epithelioid and spindle-
shaped cellular components, thereby mimicking synovial tissue. However, unlike its nomenclature, this
[67]
sarcoma does not arise from synovial tissue and does not express synovial cell markers . Genetically,
more than 90% of synovial sarcoma tumors show a pathognomonic t(X;18)(p11.2;q11.2) translocation
that generates a fusion of the synovial sarcoma 18 (SS18) and SSX genes, encoding a pro-oncogenic
[68]
transcription factor . Despite the standard approach of wide radical surgery combined with radiation of
[70]
[69]
the primary tumor , local recurrence and distant metastasis are frequently encountered , resulting in
[71]
poor patient outcome . Although synovial sarcoma is relatively chemosensitive compared to other soft
[72]
tissue sarcomas , there is only limited survival benefit from anthracycline-based adjuvant chemotherapy
[73]
for high-risk patients with metastatic and/or residual tumor .
Fibrosarcoma is defined as a malignant neoplasm of fibroblast origin and characterized histologically by
a “herringbone” architecture formed by the tumor cells and stromal deposition of collagen within the
tumor [4,74] . Fibrosarcomas are divided into the congenital-type that rarely metastasizes, and the adult-
[75]
type that is highly malignant . The incidence of adult-type fibrosarcoma has declined over the years as
the diagnostic criteria has become more strict and other mesenchymal tumors that mimic fibrosarcoma
are more accurately defined. Most fibrosarcomas arise from the fascia and tendon of soft tissue, with rare
occurrences in the medullary canal and periosteum of bones. Adult-type fibrosarcoma affects the deep
soft tissues of the extremities, trunk, head, and neck in middle- and older-aged adults. The mainstay of
treatment is surgical removal of the tumor, occasionally followed by radiation for high-grade tumors and
cases with insufficient surgical margin. Although chemotherapy is not recommended for the management
of fibrosarcoma patients, anthracycline-based chemotherapy is the first-line regimen. However,
fibrosarcoma is characterized by low sensitivity to chemotherapy and frequent tumor recurrence. This
results in poor overall prognosis, with a 10-year survival rate of 60% and 30% for patients with low- and
[76]
high-grade tumors, respectively .
During the past decade, several targeted agents have been developed for soft tissue sarcomas [14-17] , together
with a new generation of chemotherapeutic agents (e.g., trabectedin and eribulin) [9,10] . Recently, the multi-
[56]
[77]
target kinase inhibitors pazopanib and anlotinib were approved for multiple soft tissue sarcoma types