Abstract
Osteosarcoma is the most common primary malignant bone cancer, with high rates of pulmonary metastasis. Osteosarcoma patients with pulmonary metastasis have worse prognosis than those with localized disease, leading to dramatically reduced survival rates. Therefore, understanding the biological characteristics of metastatic osteosarcoma and the molecular mechanisms of invasion and metastasis of osteosarcoma cells will lead to the development of innovative therapeutic intervention for advanced osteosarcoma. Here, we identified that osteosarcoma cells commonly exhibit high platelet activation-inducing characteristics, and molecules released from activated platelets promote the invasiveness of osteosarcoma cells. Given that heat-denatured platelet releasate maintained the ability to promote osteosarcoma invasion, we focused on heat-tolerant molecules, such as lipid mediators in the platelet releasate. Osteosarcoma-induced platelet activation leads to abundant lysophosphatidic acid (LPA) release. Exposure to LPA or platelet releasate induced morphological changes and increased invasiveness of osteosarcoma cells. By analyzing publicly available transcriptome datasets and our in-house osteosarcoma patient-derived xenograft tumors, we found that LPA receptor 1 (LPAR1) is notably upregulated in osteosarcoma. LPAR1 gene KO in osteosarcoma cells abolished the platelet-mediated osteosarcoma invasion in vitro and the formation of early pulmonary metastatic foci in experimental pulmonary metastasis models. Of note, the pharmacological inhibition of LPAR1 by the orally available LPAR1 antagonist, ONO-7300243, prevented pulmonary metastasis of osteosarcoma in the mouse models. These results indicate that the LPA–LPAR1 axis is essential for the osteosarcoma invasion and metastasis, and targeting LPAR1 would be a promising therapeutic intervention for advanced osteosarcoma.
Highlights
Osteosarcoma is a tumor of mesenchymal origin that constitutes the most common primary malignant bone cancer, exhibiting heterogeneous histological, genetic, and molecular features [1]
Osteosarcoma cells commonly exhibit high platelet activationinducing characteristics, and their invasiveness is promoted by the platelet releasate Platelet–cancer cell interactions and the release of bioactive molecules from activated platelets are critical for the hematogenous metastasis of carcinomas [15,16,17,18,19], but they are unrecognized in sarcomas
To investigate the effects of bioactive molecules released from activated platelets on osteosarcoma cell invasion, we harvested the reaction mixture used in the platelet aggregation assay and employed the centrifugation supernatants following the experiments as the platelet releasate (Supplementary Fig. S1)
Summary
Osteosarcoma is a tumor of mesenchymal origin that constitutes the most common primary malignant bone cancer, exhibiting heterogeneous histological, genetic, and molecular features [1]. Given that osteosarcoma is a rare malignant tumor that is highly heterogeneous, the patient survival rate has not improved in the last 40 years, especially for metastatic osteosarcomas. The first line of chemotherapy, including high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide, has been introduced [12]; there is no consensus on either the optimal combination or the therapeutic options for patients with metastatic or recurrent osteosarcoma [13, 14]. Understanding the mechanisms of invasion and metastasis common to osteosarcoma is essential for developing more effective therapeutic approaches for treating these patients
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