Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5

Abstract

Morphogenetic protein 2 (BMP-2) is normally expressed in the embryo promoting the development of several organs. Aberrant expression of BMP-2 occurs in approximately 98% of lung carcinomas, however, its role in regulating tumor growth is poorly understood. We show that BMP-2 induces Id-1 expression in lung cancer cell lines through its activation of Smad-1/5, which is dependent on cell culture conditions. A549 cells in DMEM/5% FCS BMP-2 activated Smad-1/5 and caused a transient increase in proliferation. In serum-free medium, BMP-2 induced significantly less Smad-1/5 activation and Id-1 expression, and produced significant growth inhibition. The affect of BMP-2 on tumor growth in vivo was substantially more significant. Recombinant BMP-2 coinjected with A549 cells, into nude mice increased proliferation and produced an increase in Id-1 expression. Forced expression of BMP-2 in A549 cells significantly enhanced tumor growth in the lungs following intravenous injection but not of subcutaneous tumors. Tumors in the lung were found to have an activated Smad-1/5 and expressed Id-1. Subcutaneous tumors expressed less activated Smad-1/5 and Id-1 than that of controls. Human lung carcinomas were also found to express an activated Smad-1/5 and Id-1. We provide evidence that BMP-2 promotes tumor growth. This paper highlights that cell culture experiments may not reveal the full biological affects of BMP-2, and its activity varies depending of the local environment.

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

“…In endothelial cells it has been shown that BMP-6 stimulated migration and tube formation via Id1 up-regulation [8]. The functional effects of BMP-2 in a lung cancer cell line were also related to Smad1-dependent up-regulation of Id1 [6]. Id proteins are known to negatively regulate another class of HLH proteins, the E-proteins, by inhibiting these proteins' ability to bind DNA.…”

“…Several studies have pointed toward members of the inhibitor of DNA binding (Id) protein family, a class of helix-loop-helix (HLH) proteins, as important targets for BMP signalling [5][6][7][8]. HLH proteins act as transcriptional regulators and are essential factors for lymphoid development and function [9][10][11].…”

Serum BMP-2 Up-regulation as an Indicator of Poor Survival in Advanced Non-small Cell Lung Cancer Patients

“…BMP-2 is reported to be highly expressed in approximately 98% of human lung carcinomas, but little expression of BMP-2 has been reported in normal lung tissues. In addition, recombinant BMP-2 stimulated the migration and invasiveness of the A549 and H7249 human lung cancer cell lines in vitro, and enhanced the growth of tumors grown from A549 cells by subcutaneous injection into nude mice in vivo (Langenfeld et al, 2006). Hsu et al found that BMP-2 in the bone matrix cooperated in an enhanced effect on lung cancer epithelial-to-mesenchymal transition (EMT) and migration via activation of the MAPK/ Runx2/Snail signaling pathway .…”

Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1

“…In an in vivo breast cancer to bone metastasis model, the presence of BMP-2 in a scaffold increased the metastatic frequency of the breast cancer cell line SUM1315 (Moreau et al, 2007). On the other hand, treatment with BMP-2 in the breast cancer cell line C2C12 resulted in increased expression of Id-1 (Katagiri et al, 1994;Nobta et al, 2005;Raida et al, 2005;Langenfeld et al, 2006), while BMP-2 also positively regulated the expression of Id-1 in certain cell contexts (Locklin et al, 2001;Takeda et al, 2004). Because BMPs have very important roles in the development of bone metastasis in prostate cancer cells (Feeley et al, 2005(Feeley et al, , 2006, it might be possible that BMP-2 in the bone environment promotes metastasis of cancer cells to bone through upregulation of the intrinsic expression of Id-1 in cancer cells.…”