Expressional Analysis of GFP-Tagged Cells in an In Vivo Mouse Model of Giant Cell Tumor of Bone

Singh, Shalini; Singh, Mohini; Mak, Isabella W. Y.; Ghert, Michelle

doi:10.2174/1874325001307010109

Cited by 10 publications

(7 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results are consistent with previous studies in which GFP-labeled GCTB stromal cells were injected into the tibia of immunodeficient Balb/c nu/nu mice. 43 That study demonstrated the presence of green fluorescent, single stromal cells 1 year after injection. The latter scenario supports the notion and possibility that GCTB stromal cells survive in mice for a long time without forming large tumors.…”

Section: Discussionmentioning

confidence: 91%

Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 91%

Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Therefore, additional studies are required to evaluate the survival and tumorigenicity of the various cell types or combinations. Previously, it has been reported that GCTB stromal cells transfected with green fluorescence protein survived 52 weeks in vivo (24). However, isolation of stromal cells from GCTB in vitro results in the rapid loss of expression of receptor activator of nuclear factor-κB ligand (44).…”

Section: Discussionmentioning

confidence: 99%

“…Although several in vivo GCTB models are available, studies on this tumor are restricted as the development of the in vivo model is incomplete, associated with a short survival time or does not induce osteolytic lesion (22)(23)(24). Stromal cells injected subcutaneously into immunocompromised mice do not produce giant cells (22,24,25). Furthermore, tumor tissues grown on chick chorioallantoic membranes do not appear to recruit chicken monocytes to synthesize new giant cells despite increased vascularization from the membrane, and the survival time is typically 10 days (23).…”

Section: Introductionmentioning

confidence: 99%

Intratibial injection of patient‑derived tumor cells from giant cell tumor of bone elicits osteolytic reaction in nude mouse

Zhou

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

There have been various reports in the literature of an model for giant cell tumor of bone (GCTB). However, few suitable animal models of GCTB have been established, due to the fact that GCTB contains three histologically different cell types. To the best of our knowledge, injection of patient-derived GCTB cells into bone environment has not been reported until now. In the present study, the biological behavior of GCTB cells in nude mice was investigated through intratibial injection of patient-derived GCTB cells. Patient-derived GCTB cells were obtained from 5 patients who had not undergone chemo- and radiotherapy. Once isolated, the cell suspension was injected into the tibias of nude mice. The growth process was monitored by weekly observation and photographic documentation using X-ray. Four months after injection, nude mice were sacrificed and the injected tibial samples were fixed, and further analyzed using micro-computed tomography (micro-CT), standard histology, tartrate-resistant acid phosphatase (TRAP) staining and mitochondrial immunofluorescence staining. X-ray, micro-CT and standard histology revealed osteolytic destruction in the proximal end of the tibia. TRAP staining identified TRAP-positive, osteoclast-like cells distributed in the bone marrow interface of the lesion area. Anti-human mitochondrial immunofluorescence staining confirmed that the surviving cells in the osteolytic destruction were of human GCTB cell origin. These findings indicate that intratibial injection of patient-derived GCTB cells may elicit osteolytic destruction in nude mice. The results of the current study present a novel animal model for GCTB, opening new perspectives to investigate this disease and develop therapeutic agents.

show abstract

“…Although several in vivo GCTB models are available, studies on tumor therapeutics are hampered because in vivo development was either incomplete or had short survival time or did not induce osteolytic lesion. Stromal cells injected subcutaneously into immunocompromised mice do not produce giant cells (44)(45)(46). Moreover, tumor tissues grown on chick chorioallantoic membranes do not appear to recruit chicken monocytes to synthesize new giant cells and are unsuitable for drug administration, despite increased vascularization from the membrane, but only survive for 10 days (5,31).…”

Section: Discussionmentioning

confidence: 99%

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

Luo

Jin

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-kB signaling-related cytokines, including TNFa, MCP-1, IL1a, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-kB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cellinduced bone destruction in vivo. As a result, bortezomib suppressed NF-kB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-kB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB.

show abstract

Expressional Analysis of GFP-Tagged Cells in an In Vivo Mouse Model of Giant Cell Tumor of Bone

Cited by 10 publications

References 16 publications

Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib

Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib

Intratibial injection of patient‑derived tumor cells from giant cell tumor of bone elicits osteolytic reaction in nude mouse

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

Contact Info

Product

Resources

About