An association between successful engraftment of osteosarcoma patient-derived xenografts and clinicopathological findings.

Although osteosarcoma is a rare disease, with a global incidence rate estimated at 5.0/million/year, it is the most frequent primary bone sarcoma in children and adolescents. In translational research, the patient-derived xenograft (PDX) model is considered an authentic in vivo model for several types of cancer, as tumorgrafts faithfully retain the biological characteristics of the primary tumors. Our goal was to investigate the association between PDX formation and clinical findings of osteosarcoma patients and the ability of the model to preserve in immunocompromized mice the characteristics of the parental tumor. A fresh sample of the patient tumor obtained from a representative biopsy or from surgical resection was implanted into nude mice. When tumor outgrowths reached ~1,500mm³, fresh PDX fragments were re-transplanted into new hosts. Engraftment in mice was obtained after a latency period of 19-225 days (median 92 days) in 40.54% of the implanted samples. We confirmed the histopathological fidelity between the patient tumor and their respective established PDXs, including the expression of biomarkers. PDX take rate was higher in surgical resection samples, in post-chemotherapy surgical samples and in samples from patients with metastatic disease at presentation. In conclusion, we have shown that the osteosarcoma PDX model reliably recapitulates the morphological aspects of the human disease after serial passage in mice. The observation that more aggressive forms of osteosarcoma, including those with metastatic disease at presentation, have a higher efficiency to generate PDXs provides a promising scenario to address several unanswered issues in clinical oncology.

PATIENT-DERIVED XENOGRAFTS AS A PRECLINICAL MODEL FOR BONE SARCOMAS.

OBJECTIVE: The purpose of this study was to reproduce a mouse model of bone sarcomas for use in cancer research. METHODS: A fresh sample of the tumor tissue was implanted subcutaneously into nude mice. When the patient-derived xenograft (PDX) reached a volume of 1500 mm3, it was harvested for re-implantation into additional mice. Histology was used to compare the morphological characteristics of different generations of sarcoma xenografts with the primary tumor. RESULTS: Sixteen sarcoma tissue samples were engrafted into nude mice. Nine patients were diagnosed with osteosarcoma, two with chondrosarcoma, two with malignant peripheral nerve sheath tumor, one with synovial sarcoma, one with pleomorphic sarcoma, and one with Ewing's sarcoma. PDX tumors were generated in 11 of the 16 implanted specimens (69% success rate in P1). Six P1 tumors grew sufficiently for transfer into additional mice, producing the P2 generation, and three P2 tumors established the P3 generation. CONCLUSION: PDX tumors generated from bone sarcomas were successfully established in immunodeficient mice and reproduced the characteristics of the primary tumor with a high degree of fidelity. The preclinical PDX model described herein may represent an important tool for translational oncology research and for evaluating therapeutic strategies for bone sarcomas. Level of Evidence I; Experimental study.

OBJETIVO: O propósito deste estudo foi reproduzir em camundongos um modelo de sarcomas ósseos para uso em pesquisa oncológica. MÉTODO: Amostras frescas de tecido tumoral foram implantadas por via subcutânea em camundongos Nude. Quando o xenoenxerto derivado do paciente (PDX) alcançava 1500 mm3, ele era retirado do animal e reimplantado em outros camundongos. Estudos histológicos foram realizados para comparar as características morfológicas de diferentes gerações de xenoenxertos com o tumor primário. RESULTADOS: Dezesseis amostras de tecido sarcomatoso foram enxertadas em camundongos. Nove pacientes foram diagnosticados com osteossarcoma, dois com condrossarcoma, dois com tumor maligno de bainha de nervo periférico, um com sarcoma sinovial, um com sarcoma pleomórfico e um com sarcoma de Ewing. Foram gerados tumores PDX em 11 das 16 amostras enxertadas (taxa de sucesso de 69% em P1). Destes, seis tumores P1 cresceram o suficiente para serem transferidos para outros camundongos, dando origem à geração P2 e três dos tumores P2 estabeleceram a geração P3. CONCLUSÕES: Os tumores PDX de sarcomas ósseos foram estabelecidos com sucesso em camundongos imunodeficientes e reproduziram com alta precisão as características do tumor primário. O modelo pré-clínico de PDX descrito pode representar uma ferramenta importante para a pesquisa oncológica translacional e para avaliar estratégias terapêuticas para sarcomas ósseos. Nível de Evidência I; Estudo experimental.

Patient-derived xenografts as a preclinical model for bone sarcomas / Xenoenxertos derivados de pacientes como modelo pré-clínico de sarcomas ósseos

ABSTRACT Objective: The purpose of this study was to reproduce a mouse model of bone sarcomas for use in cancer research. Methods: A fresh sample of the tumor tissue was implanted subcutaneously into nude mice. When the patient-derived xenograft (PDX) reached a volume of 1500 mm3, it was harvested for re-implantation into additional mice. Histology was used to compare the morphological characteristics of different generations of sarcoma xenografts with the primary tumor. Results: Sixteen sarcoma tissue samples were engrafted into nude mice. Nine patients were diagnosed with osteosarcoma, two with chondrosarcoma, two with malignant peripheral nerve sheath tumor, one with synovial sarcoma, one with pleomorphic sarcoma, and one with Ewing's sarcoma. PDX tumors were generated in 11 of the 16 implanted specimens (69% success rate in P1). Six P1 tumors grew sufficiently for transfer into additional mice, producing the P2 generation, and three P2 tumors established the P3 generation. Conclusion: PDX tumors generated from bone sarcomas were successfully established in immunodeficient mice and reproduced the characteristics of the primary tumor with a high degree of fidelity. The preclinical PDX model described herein may represent an important tool for translational oncology research and for evaluating therapeutic strategies for bone sarcomas. Level of Evidence I; Experimental study.

RESUMO Objetivo: O propósito deste estudo foi reproduzir em camundongos um modelo de sarcomas ósseos para uso em pesquisa oncológica. Método: Amostras frescas de tecido tumoral foram implantadas por via subcutânea em camundongos Nude. Quando o xenoenxerto derivado do paciente (PDX) alcançava 1500 mm3, ele era retirado do animal e reimplantado em outros camundongos. Estudos histológicos foram realizados para comparar as características morfológicas de diferentes gerações de xenoenxertos com o tumor primário. Resultados: Dezesseis amostras de tecido sarcomatoso foram enxertadas em camundongos. Nove pacientes foram diagnosticados com osteossarcoma, dois com condrossarcoma, dois com tumor maligno de bainha de nervo periférico, um com sarcoma sinovial, um com sarcoma pleomórfico e um com sarcoma de Ewing. Foram gerados tumores PDX em 11 das 16 amostras enxertadas (taxa de sucesso de 69% em P1). Destes, seis tumores P1 cresceram o suficiente para serem transferidos para outros camundongos, dando origem à geração P2 e três dos tumores P2 estabeleceram a geração P3. Conclusões: Os tumores PDX de sarcomas ósseos foram estabelecidos com sucesso em camundongos imunodeficientes e reproduziram com alta precisão as características do tumor primário. O modelo pré-clínico de PDX descrito pode representar uma ferramenta importante para a pesquisa oncológica translacional e para avaliar estratégias terapêuticas para sarcomas ósseos. Nível de Evidência I; Estudo experimental.