Abstract
Bone morphogenetic protein 2 (BMP2) signaling had significant roles in diverse pathological processes, such as cancer. Nevertheless, the interaction between BMP2 and carcinoma development remained largely unknown. In particular, the roles that BMP2 play in the development of liver cancer remained controversial, and mechanisms were unclear. BMP2 with strong osteogenic potential had been manufactured into various bone materials. However, cancer risk concerns were raised in recent years. Thus, we focused on analyzing the effects of exogenous BMP2 on the growth of liver cancer and the detailed mechanisms. We found that both intravenous injection of rhBMP2 and in vivo implantation of rhBMP2 materials could lead to the expansion of myeloid-derived suppressor cells (MDSCs) in peripheral blood and subsequently enhanced the infiltration of MDSCs into tumor in vivo. Furthermore, BMP2 signaling-activated MDSCs could secrete IL6 to enhance cell proliferation of liver cancer cells in vitro and facilitate liver cancer growth in vivo. Our study indicated that increased concentration of BMP2 within the peripheral blood could enhance liver cancer growth via the activation of MDSCs. In this study, the roles that BMP2 played in liver cancer growth were further confirmed and the detailed mechanisms about how BMP2 enhanced liver cancer growth were also elucidated.
Highlights
Bone morphogenetic protein (BMP), which belonged to the transforming growth factor β family, was discovered by Urist in 1965 [1]
We demonstrated that implantation of Recombined human bone morphogenetic protein 2 (rhBMP2) collagen gels promoted the activation of Bone morphogenetic protein 2 (BMP2) signaling in myeloid-derived suppressor cells (MDSCs) and the infiltration of MDSCs into liver cancer tissues of ICR mice (Figures 4J,K and Supplementary Figures 2A,B)
From the public clinical microarray database of TCGA, we found that the expression of BMP2 in liver cancer tissues was associated with Arg1 and IL6, the activation marker of MDSCs (Figures 6I,J)
Summary
Bone morphogenetic protein (BMP), which belonged to the transforming growth factor β family, was discovered by Urist in 1965 [1]. Recombined human bone morphogenetic protein 2 (rhBMP2), as a type of BMP molecule, displayed strong osteogenic potential, which could induce bone formation even in ectopic sites. Many studies had reported the satisfactory outcomes of rhBMP2 in the induction of new bone regeneration, several complications of rhBMP2, such as postoperative radiculitis, ectopic bone formation, edema, and especially carcinogenesis [2], raised some concerns on safety issues. In 2010, the US Food and Drug Administration reported a notably increased cancer rate (4-fold) among patients in the rhBMP2-treated group compared with the control group at the second year [2]. The interaction between rhBMP2 and heterotopic tumors remained largely unknown, which might potentially threaten the patients’ health. We focused on the roles of exogenous BMP2 playing in carcinoma progression
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