BMP-2 inhibits lung metastasis of osteosarcoma: an early investigation using an orthotopic model

Abstract

BackgroundBone 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.Methods3×105/20 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.ResultsIn 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.ConclusionOn 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.

Induction of Myogenic Differentiation Improves Chemosensitivity of Chemoresistant Cells in Soft-Tissue Sarcoma Cell Lines

“…e concept of differentiation therapy was proposed as early as the 1970s based on the idea that the malignant cells (perhaps Cancer Stem Cells or Tumor Propagating Cells) could differentiate into less aggressive or benign cells, allowing differentiation to be an alternative or complementary strategy to chemotherapy-mediated cytotoxicity [40][41][42]. It has been shown that differentiation therapy can reduce malignancy by preventing tissue invasion and metastasis [43]. Leukemia is by far the most studied cancer for differentiation therapy and the only cancer with a successful application [44].…”

To B (Bone Morphogenic Protein-2) or Not to B (Bone Morphogenic Protein-2): Mesenchymal Stem Cells May Explain the Protein’s Role in Osteosarcomagenesis

“… Gauthaman et al (2012) found that umbilical cord-derived MSCs from Wharton’s jelly suppressed the proliferation and migration of MG-63 cells (a human OS cell line) in vitro ; in a Kaposi sarcoma model, MSCs also inhibited tumor progression ( Khakoo et al, 2006 ). BMP-2 also has inhibited OS progression, although the potential mechanism was not discussed ( Xiong et al, 2018 ). Given the close link between MSCs and BMP-2 in osteoblastic differentiation and OS etiology, BMP-2 might suppress OS through BMSCs.…”

“…Moreover, BMP-2 has suppressed tumors and promoted bone formation simultaneously: Wang et al (2012) indicated that renal cell cancer was inhibited and bone formation was induced with the application of BMP-2. Furthermore, BMP-2 has reduced tumor volume, attenuated OS-induced pulmonary metastases, and stimulated bone formation ( Xiong et al, 2018 ). Applying 30 μg of BMP-2 to OS-bearing mice also increased the transcription of osteogenic genes and promoted osteogenesis ( Wang et al, 2013 ).…”

“…Whether BMP-2 suppresses or stimulates tumor development remains a contentious issue ( Weiss, 2015 ), and this controversy still challenges researchers ( Kendal et al, 2020 ; Table 1 ). Using an orthotopic mouse model, Xiong et al (2018) revealed that 2.5 μg of recombinant human BMP-2 (rhBMP-2) applied for 14 days not only induced bone formation but also suppressed OS growth and pulmonary metastasis in OS-bearing mice. Similar research also documented that rhBMP-2 constrained the tumorigenicity of cancer stem cells in human OS cell lines in vitro and in vivo ( Wang et al, 2011 ; Gill et al, 2017 ).…”

Global Research on Osteosarcoma, 1999–2019: A Bibliometric and Visual Analysis

“…At present, the clinical treatment of OS is primarily surgical, with adjunctive chemoradiotherapy and biotherapy. In recent years, immunotherapy [4,5], molecular targeted therapy [6,7], and cancer stem cell therapy [8,9] have been used increasingly for the treatment of this disease. Although the 5-year survival rate of patients with OS has increased significantly with the improvement of treatment and clinical management, therapeutic effects remain unsatisfactory in patients with metastatic and recurrent OS [10].…”