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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

In vivo growth and progression of chondrosarcoma cell lines. a) This graph plots the injected to non-injected limb volume ratios for the study groups at each time point. Periosteal injected JJ012 developed into tumours most rapidly, followed 2-3 weeks later by intratibial injected JJ012. FS090 did not form tumours in either implantation site. b) Periosteal tumours expanded one area of the limb while intratibial tumours grew in a circumferential manner. On histology both tumours (T) invaded cortex, but leaving the epiphysis (E) largely intact. On radiographs, lytic regions (black arrow), and sclerotic (grey arrow) were noted in both models. c) 5/5 animals injected with periosteal JJ012 demonstrated lung metastases, in contrast with 2/4 animals in the intratibial group. d) Lung metastases (M) were lobular in appearance, and were positive on Alizarin red staining (arrows), indicating calcification.
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Figure 4: In vivo growth and progression of chondrosarcoma cell lines. a) This graph plots the injected to non-injected limb volume ratios for the study groups at each time point. Periosteal injected JJ012 developed into tumours most rapidly, followed 2-3 weeks later by intratibial injected JJ012. FS090 did not form tumours in either implantation site. b) Periosteal tumours expanded one area of the limb while intratibial tumours grew in a circumferential manner. On histology both tumours (T) invaded cortex, but leaving the epiphysis (E) largely intact. On radiographs, lytic regions (black arrow), and sclerotic (grey arrow) were noted in both models. c) 5/5 animals injected with periosteal JJ012 demonstrated lung metastases, in contrast with 2/4 animals in the intratibial group. d) Lung metastases (M) were lobular in appearance, and were positive on Alizarin red staining (arrows), indicating calcification.

Mentions: JJ012 cells implanted within the periosteum developed into tumours by 4 weeks, while intratibial implanted JJ012 cells developed tumours between 6-7 weeks (Fig.4a). The average volume of JJ012 periosteal tumours was 174.2 mm3 just prior to euthanasia at 7 weeks. Intratibial JJ012 tumours had an average volume of 198.5 mm3 just prior to euthanasia at 10 weeks. By contrast, FS090 implanted either within periosteum or within the intramedullary canal did not form any tumours, even at 3 months (Fig.4a). Periosteal JJ012 tumours tended to expand into the soft tissues in one part of the limb, while intratibial tumours grew in a more circumferential manner (Fig.4b). At dissection, new vessels arising from the femoral artery and supplying the tumours were noted, and corresponding with the in vitro angiogenesis activity noted for JJ012. On sectioning of the proximal tibias, tumour tissue invaded the cortex and medulla of the metaphysis, while the epiphysis was largely preserved, consistent with the human disease (Fig.4b). Radiolucencies and opacities consistent with bony erosions and periosteal reactions respectively were found on x-ray (Fig.4b). All JJ012 periosteal tumours (5/5 animals) resulted in spontaneous lung metastases by 7 weeks while JJ012 intratibial tumours gave rise to lung metastases in 50% of animals (2/4) (Fig.4c). One of the original 5 animals in this latter group had been euthanised and excluded from the study due to systemic infection at week 6. Metastases were only visualised on microscopy (rather than macroscopically), and stained positive with Alizarin red, indicating calcification, which is also characteristic of human chondrosarcoma metastases (Fig.4d).


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

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

In vivo growth and progression of chondrosarcoma cell lines. a) This graph plots the injected to non-injected limb volume ratios for the study groups at each time point. Periosteal injected JJ012 developed into tumours most rapidly, followed 2-3 weeks later by intratibial injected JJ012. FS090 did not form tumours in either implantation site. b) Periosteal tumours expanded one area of the limb while intratibial tumours grew in a circumferential manner. On histology both tumours (T) invaded cortex, but leaving the epiphysis (E) largely intact. On radiographs, lytic regions (black arrow), and sclerotic (grey arrow) were noted in both models. c) 5/5 animals injected with periosteal JJ012 demonstrated lung metastases, in contrast with 2/4 animals in the intratibial group. d) Lung metastases (M) were lobular in appearance, and were positive on Alizarin red staining (arrows), indicating calcification.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 4: In vivo growth and progression of chondrosarcoma cell lines. a) This graph plots the injected to non-injected limb volume ratios for the study groups at each time point. Periosteal injected JJ012 developed into tumours most rapidly, followed 2-3 weeks later by intratibial injected JJ012. FS090 did not form tumours in either implantation site. b) Periosteal tumours expanded one area of the limb while intratibial tumours grew in a circumferential manner. On histology both tumours (T) invaded cortex, but leaving the epiphysis (E) largely intact. On radiographs, lytic regions (black arrow), and sclerotic (grey arrow) were noted in both models. c) 5/5 animals injected with periosteal JJ012 demonstrated lung metastases, in contrast with 2/4 animals in the intratibial group. d) Lung metastases (M) were lobular in appearance, and were positive on Alizarin red staining (arrows), indicating calcification.
Mentions: JJ012 cells implanted within the periosteum developed into tumours by 4 weeks, while intratibial implanted JJ012 cells developed tumours between 6-7 weeks (Fig.4a). The average volume of JJ012 periosteal tumours was 174.2 mm3 just prior to euthanasia at 7 weeks. Intratibial JJ012 tumours had an average volume of 198.5 mm3 just prior to euthanasia at 10 weeks. By contrast, FS090 implanted either within periosteum or within the intramedullary canal did not form any tumours, even at 3 months (Fig.4a). Periosteal JJ012 tumours tended to expand into the soft tissues in one part of the limb, while intratibial tumours grew in a more circumferential manner (Fig.4b). At dissection, new vessels arising from the femoral artery and supplying the tumours were noted, and corresponding with the in vitro angiogenesis activity noted for JJ012. On sectioning of the proximal tibias, tumour tissue invaded the cortex and medulla of the metaphysis, while the epiphysis was largely preserved, consistent with the human disease (Fig.4b). Radiolucencies and opacities consistent with bony erosions and periosteal reactions respectively were found on x-ray (Fig.4b). All JJ012 periosteal tumours (5/5 animals) resulted in spontaneous lung metastases by 7 weeks while JJ012 intratibial tumours gave rise to lung metastases in 50% of animals (2/4) (Fig.4c). One of the original 5 animals in this latter group had been euthanised and excluded from the study due to systemic infection at week 6. Metastases were only visualised on microscopy (rather than macroscopically), and stained positive with Alizarin red, indicating calcification, which is also characteristic of human chondrosarcoma metastases (Fig.4d).

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