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New clinically relevant, orthotopic mouse models of human chondrosarcoma with spontaneous metastasis.

Clark JC, Akiyama T, Dass CR, Choong PF - Cancer Cell Int. (2010)

Bottom Line: JJ012 demonstrated significantly higher proliferative capacity, invasion, and colony formation in collagen I gel.JJ012 conditioned medium stimulated endothelial tube formation and osteoclastogenesis with a greater potency than FS090 conditioned medium, perhaps related to the effects of VEGF and MMP-9.All JJ012 periosteal tumours (5/5) resulted in lung micro-metastases, while only 2/4 JJ012 intratibial tumours demonstrated metastases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedics and University of Melbourne Department of Surgery, St Vincent's Health, Melbourne, Australia. sarcoma@bigpond.net.au.

ABSTRACT

Background: Chondrosarcoma responds poorly to adjuvant therapy and new, clinically relevant animal models are required to test targeted therapy.

Methods: Two human chondrosarcoma cell lines, JJ012 and FS090, were evaluated for proliferation, colony formation, invasion, angiogenesis and osteoclastogenesis. Cell lines were also investigated for VEGF, MMP-2, MMP-9, and RECK expression. JJ012 and FS090 were injected separately into the mouse tibia intramedullary canal or tibial periosteum. Animal limbs were measured, and x-rayed for evidence of tumour take and progression. Tibias and lungs were harvested to determine the presence of tumour and lung metastases.

Results: JJ012 demonstrated significantly higher proliferative capacity, invasion, and colony formation in collagen I gel. JJ012 conditioned medium stimulated endothelial tube formation and osteoclastogenesis with a greater potency than FS090 conditioned medium, perhaps related to the effects of VEGF and MMP-9. In vivo, tumours formed in intratibial and periosteal groups injected with JJ012, however no mice injected with FS090 developed tumours. JJ012 periosteal tumours grew to 3 times the non-injected limb size by 7 weeks, whereas intratibial injected limbs required 10 weeks to achieve a similar tumour size. Sectioned tumour tissue demonstrated features of grade III chondrosarcoma. All JJ012 periosteal tumours (5/5) resulted in lung micro-metastases, while only 2/4 JJ012 intratibial tumours demonstrated metastases.

Conclusions: The established JJ012 models replicate the site, morphology, and many behavioural characteristics of human chondrosarcoma. Local tumour invasion of bone and spontaneous lung metastasis offer valuable assessment tools to test the potential of novel agents for future chondrosarcoma therapy.

No MeSH data available.


Related in: MedlinePlus

Tumour histology and osteoclast involvement. a) Pleomorphic, ovoid cells (*) with an additional spindle cell population (arrows) were noted for JJ012 tumours. b) Dedifferentiated chondrosarcoma from a human de novo tumour demonstrated some similar ovoid cells without a spindle cell component. c) In periosteal and intratibial tumours, TRAP staining (arrows) revealed prominent osteoclasts at the interface between tumour (T) and bone cortex (C), and this was associated with bone matrix erosion and a mass of dead cellular material (D). d) An osteoclastogenesis assay demonstrated higher osteoclasts formed by JJ012 media (CM) compared with FS090 media (CM) (* p < 0.05), and the same relationship for chondrosarcoma and mouse monocyte (RAW 246.7) co-culture (* p < 0.05).
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Figure 5: Tumour histology and osteoclast involvement. a) Pleomorphic, ovoid cells (*) with an additional spindle cell population (arrows) were noted for JJ012 tumours. b) Dedifferentiated chondrosarcoma from a human de novo tumour demonstrated some similar ovoid cells without a spindle cell component. c) In periosteal and intratibial tumours, TRAP staining (arrows) revealed prominent osteoclasts at the interface between tumour (T) and bone cortex (C), and this was associated with bone matrix erosion and a mass of dead cellular material (D). d) An osteoclastogenesis assay demonstrated higher osteoclasts formed by JJ012 media (CM) compared with FS090 media (CM) (* p < 0.05), and the same relationship for chondrosarcoma and mouse monocyte (RAW 246.7) co-culture (* p < 0.05).

Mentions: JJ012 histology (either intratibial or periosteal) demonstrated an undifferentiated, high-grade appearance (Fig.5a) with pleomorphism and frequent nucleoli similar to a patient biopsy sample of dedifferentiated chondrosarcoma (Fig.5b). The main difference noted in the animal model was the addition of a spindle cell population of cells. TRAP staining of the JJ012 tumour tissue revealed TRAP-positive, osteoclast-like cells at the bone-tumour interface, which were associated with erosions of the cortex (Fig.5c). There were none of these cells in the cortex when tumour was not adjacent. These TRAP-positive cells were thought to be osteoclasts activated by the adjacent tumour.


New clinically relevant, orthotopic mouse models of human chondrosarcoma with spontaneous metastasis.

Clark JC, Akiyama T, Dass CR, Choong PF - Cancer Cell Int. (2010)

Tumour histology and osteoclast involvement. a) Pleomorphic, ovoid cells (*) with an additional spindle cell population (arrows) were noted for JJ012 tumours. b) Dedifferentiated chondrosarcoma from a human de novo tumour demonstrated some similar ovoid cells without a spindle cell component. c) In periosteal and intratibial tumours, TRAP staining (arrows) revealed prominent osteoclasts at the interface between tumour (T) and bone cortex (C), and this was associated with bone matrix erosion and a mass of dead cellular material (D). d) An osteoclastogenesis assay demonstrated higher osteoclasts formed by JJ012 media (CM) compared with FS090 media (CM) (* p < 0.05), and the same relationship for chondrosarcoma and mouse monocyte (RAW 246.7) co-culture (* p < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902463&req=5

Figure 5: Tumour histology and osteoclast involvement. a) Pleomorphic, ovoid cells (*) with an additional spindle cell population (arrows) were noted for JJ012 tumours. b) Dedifferentiated chondrosarcoma from a human de novo tumour demonstrated some similar ovoid cells without a spindle cell component. c) In periosteal and intratibial tumours, TRAP staining (arrows) revealed prominent osteoclasts at the interface between tumour (T) and bone cortex (C), and this was associated with bone matrix erosion and a mass of dead cellular material (D). d) An osteoclastogenesis assay demonstrated higher osteoclasts formed by JJ012 media (CM) compared with FS090 media (CM) (* p < 0.05), and the same relationship for chondrosarcoma and mouse monocyte (RAW 246.7) co-culture (* p < 0.05).
Mentions: JJ012 histology (either intratibial or periosteal) demonstrated an undifferentiated, high-grade appearance (Fig.5a) with pleomorphism and frequent nucleoli similar to a patient biopsy sample of dedifferentiated chondrosarcoma (Fig.5b). The main difference noted in the animal model was the addition of a spindle cell population of cells. TRAP staining of the JJ012 tumour tissue revealed TRAP-positive, osteoclast-like cells at the bone-tumour interface, which were associated with erosions of the cortex (Fig.5c). There were none of these cells in the cortex when tumour was not adjacent. These TRAP-positive cells were thought to be osteoclasts activated by the adjacent tumour.

Bottom Line: JJ012 demonstrated significantly higher proliferative capacity, invasion, and colony formation in collagen I gel.JJ012 conditioned medium stimulated endothelial tube formation and osteoclastogenesis with a greater potency than FS090 conditioned medium, perhaps related to the effects of VEGF and MMP-9.All JJ012 periosteal tumours (5/5) resulted in lung micro-metastases, while only 2/4 JJ012 intratibial tumours demonstrated metastases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedics and University of Melbourne Department of Surgery, St Vincent's Health, Melbourne, Australia. sarcoma@bigpond.net.au.

ABSTRACT

Background: Chondrosarcoma responds poorly to adjuvant therapy and new, clinically relevant animal models are required to test targeted therapy.

Methods: Two human chondrosarcoma cell lines, JJ012 and FS090, were evaluated for proliferation, colony formation, invasion, angiogenesis and osteoclastogenesis. Cell lines were also investigated for VEGF, MMP-2, MMP-9, and RECK expression. JJ012 and FS090 were injected separately into the mouse tibia intramedullary canal or tibial periosteum. Animal limbs were measured, and x-rayed for evidence of tumour take and progression. Tibias and lungs were harvested to determine the presence of tumour and lung metastases.

Results: JJ012 demonstrated significantly higher proliferative capacity, invasion, and colony formation in collagen I gel. JJ012 conditioned medium stimulated endothelial tube formation and osteoclastogenesis with a greater potency than FS090 conditioned medium, perhaps related to the effects of VEGF and MMP-9. In vivo, tumours formed in intratibial and periosteal groups injected with JJ012, however no mice injected with FS090 developed tumours. JJ012 periosteal tumours grew to 3 times the non-injected limb size by 7 weeks, whereas intratibial injected limbs required 10 weeks to achieve a similar tumour size. Sectioned tumour tissue demonstrated features of grade III chondrosarcoma. All JJ012 periosteal tumours (5/5) resulted in lung micro-metastases, while only 2/4 JJ012 intratibial tumours demonstrated metastases.

Conclusions: The established JJ012 models replicate the site, morphology, and many behavioural characteristics of human chondrosarcoma. Local tumour invasion of bone and spontaneous lung metastasis offer valuable assessment tools to test the potential of novel agents for future chondrosarcoma therapy.

No MeSH data available.


Related in: MedlinePlus