Abstract
Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, the tumor stromal cells of these lesions are responsible for the recruiting of multinucleated giant cells which ultimately lead to bone disruption. In this regard, the underlying pathological mechanism of osteoclastogenesis processes in GCTB and DF is still poorly understood. Although current therapeutic strategy involves surgery, radiotherapy and chemotherapy, the benefit of the latter is still debated. Thus, in order to shed light on these poorly investigated diseases, we focused on the molecular biology of GCTB and DF. The expression of bone-vicious-cycle- and neoangiogenesis-related genes was investigated. Moreover, combining patient-derived primary cultures with 2D and 3D culture platforms, we investigated the role of denosumab and levantinib in these diseases. The results showed the upregulation of RANK-L, RANK, OPN, CXCR4, RUNX2 and FLT1 and the downregulation of OPG and CXCL12 genes, underlining their involvement and promising role in these neoplasms. Furthermore, in vitro analyses provided evidence for suggesting the combination of denosumab and lenvatinib as a promising therapeutic strategy in GCTB and DF compared to monoregimen chemotherapy. Furthermore, in vivo zebrafish analyses corroborated the obtained data. Finally, the clinical observation of retrospectively enrolled patients confirmed the usefulness of the reported results. In conclusion, here we report for the first time a molecular and pharmacological investigation of GCTB and DF combining the use of translational and clinical data. Taken together, these results represent a starting point for further analyses aimed at improving GCTB and DF management.
Highlights
First reported in 1953 by Jaffe [1], giant cell tumor of bone (GCTB). known as osteoclastoma, is described in the latest WHO version as an osteolytic bone tumor characterized by the presence of osteoclast-like multinucleated giant cells [2]
Due to a minimal residual disease shown in the postsurgery computed tomography (CT) scan (Supplementary Figure S1), the Multidisciplinary Board suggested indication to continue the treatment with denosumab
We aimed to explore the role of new molecular targets and treatments for poorly explored bone sarcoma histotypes, including lesions which are considered benign but exhibit a locally aggressive behaviour, such as GCTB and desmoplastic fibroma (DF)
Summary
First reported in 1953 by Jaffe [1], giant cell tumor of bone (GCTB). known as osteoclastoma, is described in the latest WHO version as an osteolytic bone tumor characterized by the presence of osteoclast-like multinucleated giant cells [2]. Known as osteoclastoma, is described in the latest WHO version as an osteolytic bone tumor characterized by the presence of osteoclast-like multinucleated giant cells [2] This locally aggressive and rarely metastasizing tumor is generally considered a benign neoplasm due to its indolent behavior, it often causes severe bone resorption as a result of RANK signaling promotion of multinuclear osteoclast generation [3]. GCTB occurs in young adults in epiphyseal–metaphyseal regions of the long bones, such as distal femur (26%), proximal tibia (20%) and distal radius (11%), while in iliac bone, spine and hand bones, cases are rarely reported [5,6,7,8] The incidence of this bone sarcoma is estimated in almost 5% of all primary bone tumors, with a slight female predilection [9].
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