Mechanism of pro‐tumorigenic effect of BMP‐6: Neovascularization involving tumor‐associated macrophages and IL‐1α

Abstract

INTRODUCTION. Overexpression of bone morphogenetic protein-6 (BMP-6) has been reported in human prostate cancer tissues. Previously we have demonstrated that BMP-6 enhances prostate cancer growth in mice and not in tissue culture. Herein, we have investigated the mechanism of BMP-6’s pro-tumorigenic effect in prostate cancer. METHODS. Tramp C2 murine and LNCaP human prostate cancer cell lines were co-cultured with RAW 264.7 and THP-1 cells, respectively. IL-1a knockout mice were used to confirm the role of BMP-6/IL-1a loop in vivo. Lastly, conditional macrophage null mice cd11b-DTR was used. RESULTS. The results demonstrated that BMP-6 induced the expression of IL-1a in macrophages via a cross-talk between NF-kB1 p50 and Smad1. When endothelial cells were treated with conditioned media harvested from macrophages incubated with BMP-6, tube formation was detected. In the presence of IL-1a neutralizing antibody, endothelial tube formation was blocked. In vivo, tumor growth and neovascularization decreased significantly when BMP-6 was expressed in IL-1a knockout and conditional macrophage-null mice. CONCLUSIONS. Prostate cancer-derived BMP-6 stimulates tumor-associated macrophages to produce IL-1a through a crosstalk between Smad1 and NF-kB1; IL-1a, in turn, promotes angiogenesis and prostate cancer growth.

Antibody Array Revealed PRL-3 Affects Protein Phosphorylation and Cytokine Secretion

“…Recently, a report showed BMP-6 stimulates tumor-associated macrophages to produce IL-1α through a crosstalk between Smad1 and NF-kB1 [45]. In the present study, we found PRL-3 increased the production of IL-1α in HCT116 and LoVo cells (Fig 4).…”

“…Both NF-κB and Stat3 could function as transcriptional factors when they regulate cytokines’ expression such as IL-1β, and they share the same binding site on the promoter of IL-1β [56], so we propose that they might regulate IL-1α mainly through transcriptional regulation as previous report described [45]. Blocking IL-1 signaling by IL-1RN inhibited cell migration of both the control cell and PRL-3overexpressing cells, suggesting either IL-1α or IL-1β was associated with PRL-3 increased cell migration.…”

Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis

“…Elevated expression of TP is correlated with a poor prognosis in breast cancer and pancreatic cancer, and uPA expression is correlated with a poor prognosis in breast cancer (Takao et al, 1998; Toi et al, 1999; Harbeck et al, 2002). Macrophage-derived IL1α directly stimulated endothelial tube formation and neovascularization, as well as growth of mouse prostate tumors (Kwon et al, 2013). TAM-derived ADM was shown to induce angiogenesis and tumor growth in a mouse model of melanoma, and can potentially be implicated in human melanoma angiogenesis (Chen et al, 2011).…”

Opposing roles of TGFβ and BMP signaling in prostate cancer development

“…With respect to BMP signaling, various BMP ligands can exert differential biological impacts on PCa tumorigenesis. For example, BMP6, which is overexpressed in some human PCa cases, has been shown to promote migration and invasion (Darby et al 2008) and stimulate PCa growth and resistance to androgen receptor (AR) antagonists (Kwon et al 2014). In contrast, BMP7 inhibits PCa cell proliferation (Kobayashi et al 2011), although experimental evidence also supports an anti-apoptotic role (Yang et al 2005).…”