Background: Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, are known to regulate cell proliferation, differentiation, apoptosis, chemotaxis, and angiogenesis. BMPs also participate in the development of most tissues and organs in vertebrates. Recombinant human (rh) BMPs, such as rhBMP-2, rhBMP-4, and rhBMP-7, have been recently approved to augment spinal fusion and recalcitrant long-bone non-unions because of their equivalent or superior efficacy to autogenous bone graft in enhancing bony fusion. Nonetheless, the use of BMPs is contraindicated in surgery for bone tumors because of concerns that this anabolic growth factor may cause tumor proliferation. However, we have repeatedly reported that BMP-2 is effective in inducing osteogenic differentiation of a subpopulation of osteosarcoma (OSA) cells that acquire stem cell attributes and are capable of reconstituting tumor masses, which in turn suppress the malignancy of the bone tumor.
Methods: 3×105/20 µL human OSA 143B cells were inoculated into 5-6 weeks old BABL/c nude mice to establish orthotopic OSA. X-ray device was used to monitor the developed tumors in animals. Necropsy was performed and the pathology of lung metastasis were tested by Haemotoxylin and Eosin. Moreover, bone formation induced by rhBMP-2 was investigated through micro-computed tomography. In addition, immunohistochemistry staining was used to evaluate the tumorigenicity and growth of OSA cells after rhBMP-2 treatment.
Results: In the present study, we established an orthotopic model of OSA by inoculating 143B cells into BABL/c mice, which resulted in a tumor occurrence rate of 100%. Following the treatment with rhBMP-2, lung metastasis, which contributes to poor prognosis, was significantly restricted, indicating an additional aspect of rhBMP-2 to suppress expansion of OSA. Concurrently, our micro-computed tomography and radiographic analyses showed that rhBMP-2 reduced the invasion of tumor cells into adjacent bone tissue, which in turn helped to preserve the integrity of the affected bone tissue. Finally, the growth of Ki-67-positive cells and those cells that express high levels of aldehyde dehydrogenase (ALDHbr) was found to be inhibited in the developed tumors.
Conclusion: On the basis of these results, we conclude that rhBMP-2 can impede the malignancy of OSA by reducing lung metastasis of the tumor. Induction of the tumor cells by rhBMP-2 also helps to preserve the impaired skeleton. These results imply that BMP-2 or BMP-2-mimetic drugs, if properly combined with traditional therapies, may provide a new therapeutic option for the treatment of OSA.
Keywords: cancer stem cell; lung metastasis; orthotopic tumor model; osteosarcoma; recombinant human bone morphogenetic protein-2.