Related Experiment Videos
Multidrug resistance and malignancy in human osteosarcoma
K Scotlandi1, M Serra, G Nicoletti
1Dipartimento di Oncologia, Istituti Ortopedici Rizzoli, Bologna, Italy.
Abstract:
In osteosarcoma, resistance to chemotherapy and metastatic spread are the most important mechanisms responsible for the failure of current multimodal therapeutic programs. We have shown previously that overexpression of the MDR1 gene product P-glycoprotein is the most important predictor of an adverse clinical course in patients with osteosarcoma. treated with chemotherapy. In this study, we analyzed the relationship between P-glycoprotein expression and local aggressiveness and systemic dissemination of multidrug-resistant (MDR) human osteosarcoma cells. Compared to parental sensitive cells, MDR cells showed a decreased tumorigenicity,and metastatic ability in athymic mice, together with a reduced migratory and invasive ability and a lower homotypic adhesion ability in vitro, suggesting that P-glycoprotein overexpression is associated with a less malignant phenotype. These experimental observations were confirmed by clinical data. In fact, the time of appearance of lung metastases in a series of osteosarcoma patients treated with chemotherapy was significantly shorter in the group of cases with no expression of P-glycoprotein in the primary lesion compared to the group with P-glycoprotein overexpression. Moreover, the incidence of P-glycoprotein overexpression was found to be higher among patients with localized disease at the clinical onset than in patients with evidence of metastasis at the time of diagnosis. These data indicate that, in osteosarcoma, the MDR phenotype is not associated with a more aggressive behavior both in vitro and in clinical settings, suggesting that the previously shown association of the MDR phenotype with a worse outcome in osteosarcoma is not related to a higher metastatic ability of cells with P-glycoprotein overexpression but is more likely due to their lack of responsiveness to cytotoxic drugs.
Insights
Multidrug-resistant (MDR) osteosarcoma cells expressing P-glycoprotein show reduced metastasis. This suggests MDR phenotype
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osteosarcoma treatment failure is linked to chemotherapy resistance and metastasis.
- P-glycoprotein (encoded by MDR1 gene) overexpression predicts poor outcomes in osteosarcoma patients.
- The relationship between P-glycoprotein expression and osteosarcoma aggressiveness requires further investigation.
Purpose of the Study:
- To investigate the association between P-glycoprotein expression and the local aggressiveness and metastatic potential of multidrug-resistant (MDR) human osteosarcoma cells.
- To correlate in vitro findings with clinical data from osteosarcoma patients.
Main Methods:
- In vitro studies using multidrug-resistant (MDR) and parental sensitive osteosarcoma cell lines to assess migratory, invasive, and adhesion abilities.
- In vivo studies in athymic mice to evaluate tumorigenicity and metastatic potential.
- Clinical data analysis correlating P-glycoprotein expression in primary tumors with metastasis timing and disease stage at diagnosis.
Main Results:
- MDR osteosarcoma cells overexpressing P-glycoprotein exhibited decreased tumorigenicity and metastatic ability in mice.
- In vitro, these cells showed reduced migration, invasion, and homotypic adhesion.
- Clinical data revealed a longer time to lung metastasis in patients with P-glycoprotein overexpression and a higher incidence of overexpression in localized disease.
- P-glycoprotein overexpression was more frequent in patients with localized disease than in those with existing metastases.
Conclusions:
- P-glycoprotein overexpression in osteosarcoma is associated with a less aggressive phenotype in vitro and in vivo.
- Clinical findings support that the MDR phenotype in osteosarcoma is not linked to increased metastatic ability.
- The adverse clinical outcome associated with MDR osteosarcoma is likely due to drug resistance rather than enhanced metastatic potential.