Abstract
Osteosarcoma is the most common primary malignant bone tumor. The cause of death due to osteosarcoma is typically a consequence of metastasis to the lung. Controlling metastasis leads to improved prognosis for osteosarcoma patients. The cell stiffness of several tumor types is involved in metastatic potential; however, it is unclear whether the metastatic potential of osteosarcoma depends on cell stiffness. In this study, we analyzed the cell stiffness of the low metastatic Dunn cell line and its highly metastatic LM8 subline, and compared actin organization, cell proliferation, and metastasis. Actin cytoskeleton, polymerization, stiffness, and other cellular properties were analyzed. The organization of the actin cytoskeleton was evaluated by staining F-actin with Alexa Fluor 488 phalloidin. Cell stiffness was measured using Atomic Force Microscopy (AFM). Cell proliferation, migration, invasion, and adhesion were also evaluated. All experiments were performed using mouse osteosarcoma cell lines cultured in the absence and presence of cytochalasin. In LM8 cells, actin polymerization was strongly suppressed and actin levels were significantly lower than in Dunn cells. Stiffness evaluation revealed that LM8 cells were significantly softer than Dunn. Young’s modulus images showed more rigid fibrillar structures were present in Dunn cells than in LM8 cells. LM8 cells also exhibited a significantly higher proliferation. The migration and invasion potential were also higher in LM8 cells, whereas the adhesion potential was higher in Dunn cells. The administration of cytochalasin resulted in actin filament fragmentation and decreased actin staining intensity and cell stiffness in both LM8 and Dunn cells. Cells with high metastatic potential exhibited lower actin levels and cell stiffness than cells with low metastatic potential. The metastatic phenotype is highly correlated to actin status and cell stiffness in osteosarcoma cells. These results suggest that evaluation of actin dynamics and cell stiffness is an important quantitative diagnostic parameter for predicting metastatic potential. We believe that these parameters represent new reliable quantitative indicators that can facilitate the development of new drugs against metastasis.
Highlights
Osteosarcoma is the most common primary malignant tumor of bone
Metastasis by malignant cells is a common and critical phenomenon that has been studied extensively; the is underlying mechanisms involved remain to bethat fullyhas been
Flexibility, and compliance are important factors enabling thebetween passage of tumor cells through the extracellular
Summary
Osteosarcoma is the most common primary malignant tumor of bone. Lung metastasis occurs in approximately 50% of patients with osteosarcoma and is a major cause of death. Since metastases of osteosarcoma are detectable in only 10 to 20% of patients at diagnosis [3], the prediction of metastasis holds promise for improving prognosis. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. Classical prognostic factors among patients with osteosarcoma include tumor size, primary site, histological grade and the histological response to preoperative chemotherapy. Despite successful surgical resection, is critical for the prognosis of osteosarcoma; the determinant factors of metastasis remain to be identified. The ability to predict and control metastasis is expected to improve prognosis for osteosarcoma patients
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