AP-1 as a Regulator of MMP-13 in the Stromal Cell of Giant Cell Tumor of Bone.
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ABSTRACT:
SUBMITTER: Mak IW
PROVIDER: S-EPMC3065034 | biostudies-literature | 2011
REPOSITORIES: biostudies-literature
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AP-1 as a Regulator of MMP-13 in the Stromal Cell of Giant Cell Tumor of Bone.
Mak Isabella W Y IW Turcotte Robert E RE Popovic Snezana S Singh Gurmit G Ghert Michelle M
Biochemistry research international 20110227
Matrix-metalloproteinase-13 (MMP-13) has been shown to be an important protease in inflammatory and neoplastic conditions of the skeletal system. In particular, the stromal cells of giant cell tumor of bone (GCT) express very high levels of MMP-13 in response to the cytokine-rich environment of the tumor. We have previously shown that MMP-13 expression in these cells is regulated, at least in part, by the RUNX2 transcription factor. In the current study, we identify the expression of the c-Fos a ...[more]
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Project description:Giant cell tumor of bone (GCTB) is a very rare tumor entity, which is little examined owing to the lack of established cell lines and mouse models and the restriction of available primary cell lines. The stromal cells of GCTB have been made responsible for the aggressive growth and metastasis, emphasizing the presence of a cancer stem cell population. To identify and target such tumor-initiating cells, stromal cells were isolated from eight freshly resected GCTB tissues. Tumorigenic properties were examined by colony and spheroid formation, differentiation, migration, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, immunohistochemistry, antibody protein array, Alu in situ hybridization, FACS analysis and xenotransplantation into fertilized chicken eggs and mice. A sub-population of the neoplastic stromal cells formed spheroids and colonies, differentiated to osteoblasts, migrated to wounded regions and expressed the metastasis marker CXC-chemokine receptor type 4, indicating self-renewal, invasion and differentiation potential. Compared with adherent-growing cells, markers for pluripotency, stemness and cancer progression, including the CSC surface marker c-Met, were enhanced in spheroidal cells. This c-Met-enriched sub-population formed xenograft tumors in fertilized chicken eggs and mice. Cabozantinib, an inhibitor of c-Met in phase II trials, eliminated CSC features with a higher therapeutic effect than standard chemotherapy. This study identifies a c-Met(+) tumorigenic sub-population within stromal GCTB cells and suggests the c-Met inhibitor cabozantinib as a new therapeutic option for targeted elimination of unresectable or recurrent GCTB.
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Project description:Purpose of reviewGiant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However, there is much discussion regarding the optimal applied treatment strategy.Recent findingsNeoadjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence postsurgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated.SummaryFor the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB, this could be a promising treatment option for selected patients with advanced disease.
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Project description:Giant-cell tumor of bone (GCTB) is a rare osteolytic tumor of the bone. Although classified as a benign tumor, GCTB is characterized by local aggressiveness and risk of local recurrence. In addition, GTCB can in some cases lead to the development of so-called 'benign' chest metastases. Surgical resection by intralesional curettage with high-speed burring and polymethylmethacrylate cement is the standard treatment for resectable tumors. In cases of metastatic or unresectable disease (when planned surgical procedure is impossible or would result in severe morbidity), medical treatments such as cytotoxic chemotherapy or interferon-α have limited efficacy. Bisphosphonates have been proposed as a therapeutic option to reduce osteoclast activity. In bone, various pathological states may result from an imbalance in the RANK (receptor activator of nuclear factor kappa-B)/RANKL (receptor activator of nuclear factor kappa-B ligand)/OPG (osteoprotegerin) pathway. Involvement of the RANKL pathway in pathogenesis of GCTB was first proposed in 2000. Denosumab is a fully human monoclonal antibody that binds and inhibits RANKL, thereby preventing the activation of the RANK pathway. As it showed the possibility to counteract osteoclast activation in GCTB and prevent the known physiopathological role of RANKL, denosumab has been under evaluation in the clinic as a treatment for GCTB since 2005. Results of a first Phase II trial demonstrate the therapeutic potential of denosumab to inhibit progressive bone destruction and metastatic progression in patients with unsalvageable giant-cell tumor (GCT), and have also provided key insights into the biology of GCT. Denosumab is currently a therapeutic option for patients with unresectable GCTB but its place in the global therapeutic strategy has not yet been defined.
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Project description:Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.
| S-EPMC8460728 | biostudies-literature