Abstract
Giant cell tumor of bone(GCTB) is a special benign tumor with variable aggressiveness and recurrence rate. Increasing evidences suggest that a subset of cells called cancer stem cells (CSCs) are present as cancer-initiating cells in a range of malignant tumors. However, the role of CSCs in benign tumor such as GCTB remains unknown, and the connection between the presence of CSCs and biological characteristics of GCTB is unclear. To investigate this issue, we screened a panel of markers of normal stem cells and CSCs and found ALCAM+ stromal cells possessed characteristics of stem-like cells. Subsequently a series of experiments such cell proliferation, migration and invasion assays were performed to investigate the biological characteristics of ALCAM+ stromal cells in vivo and in vitro. The clinical significance of ALCAM expression were further evaluated using Kaplan-Meier analyses. The ALCAM+ GCTB cells showed the stem cell properties of self renewal and had the capacity to differentiate in vitro. The ALCAM+ GCTB cells showed increased resistance for chemotherapy- or radiation-induced cell death. ALCAM knockdown reduced stem/progenitor characteristics in GCTB Cells. Furthermore, ALCAM expression was associated with outcome in GCTB patients. Our work demonstrates for the first time ALCAM+ tumorigenic sub-population within stromal GCTB cells and may represent a potential therapeutic target in aggressive and recurrent GCTBs.
Highlights
Giant cell tumor of bone (GCTB) is a special primary bone tumor with distinctive biological characteristics, exhibiting three histological different cell types: osteoclast-like multinucleated giant cells, the spindleshaped, fibroblast-like mesenchymal stromal cell, a round morphology called macrophage-like cells[1]
20 candidate cell surface markers in GCTB28 sphere cells and parental cells were expressed and of these, only ALCAM was significantly different between parental cells and spheres (Fig. 1d and Table S1). qRT-PCR data showed that OCT4, NANOG, SOX2, and BMI1 expression in ALCAM+ subsets was significantly higher than in ALCAM subsets in GCTB cells (Fig. 1e, f)
ALCAM expression in GCTB28 cells after 10 Gy radiotherapy data appear in Figure S1A, and compared to before therapy ALCAM expression increased after radiation
Summary
Giant cell tumor of bone (GCTB) is a special primary bone tumor with distinctive biological characteristics, exhibiting three histological different cell types: osteoclast-like multinucleated giant cells, the spindleshaped, fibroblast-like mesenchymal stromal cell, a round morphology called macrophage-like cells[1]. Classified as a benign tumor by WHO, GCTB is known for its high local aggressiveness, propensity for local recurrence especially in spine, and infrequent metastases[2]. Since Cooper first described this tumor in 1818, our understanding of GCTB has progressed, and many attempts have been made to define prognostic parameters for GCTB. In spite of available histological system or clinicoradiological system of GCTB used by some pathologists and surgeons, the prognostic significance is still controversially discussed[6,7,8,9,10]. More works should be carried out to further reveal the biological characterization of GCTB and to search for new factors related to GCTB progression that may predict the clinical outcome of GCTB patients
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