The Role of the BMP Signaling Antagonist Noggin in the Development of Prostate Cancer Osteolytic Bone Metastasis

Abstract

Members of the BMP and Wnt protein families play a relevant role in physiologic and pathologic bone turnover. Extracellular antagonists are crucial for the modulation of their activity. Lack of expression of the BMP antagonist noggin by osteoinductive, carcinoma-derived cell lines is a determinant of the osteoblast response induced by their bone metastases. In contrast, osteolytic, carcinoma-derived cell lines express noggin constitutively. We hypothesized that cancer cell-derived noggin may contribute to the pathogenesis of osteolytic bone metastasis of solid cancers by repressing bone formation. Intra-osseous xenografts of PC-3 prostate cancer cells induced osteolytic lesions characterized not only by enhanced osteoclast-mediated bone resorption, but also by decreased osteoblast-mediated bone formation. Therefore, in this model, uncoupling of the bone remodeling process contributes to osteolysis. Bone formation was preserved in the osteolytic lesions induced by noggin-silenced PC-3 cells, suggesting that cancer cell-derived noggin interferes with physiologic bone coupling. Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity. This investigation provides new evidence for a model of osteolytic bone metastasis where constitutive secretion of noggin by cancer cells mediates inhibition of bone formation, thereby preventing repair of osteolytic lesions generated by an excess of osteoclast-mediated bone resorption. Therefore, noggin suppression may be a novel strategy for the treatment of osteolytic bone metastases.

Identification and Diagnostic Performance of a Small RNA within the PCA3 and BMCC1 Gene Locus That Potentially Targets mRNA

“…Noggin is an antagonist of bone morphogenetic proteins (BMP; ref. 31), which has been reported to be downregulated in prostate cancer cells (32,33). Noggin loss leads to the development of osteoblastic bone metastases.…”

Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy

“…These antagonists share a common cysteine knot protein motif with BMPs and inhibit the ligands by direct binding and prevention of ligand-receptor interaction (Groppe et al 2002). Antagonists include Gremlin1, Noggin, Chordin, Ventroptin, and Brorin and play protumorigenic roles in a number of different cancer types (Namkoong et al 2006;Sneddon et al 2006;Hsu et al 2008;Secondini et al 2011;Gao et al 2012;Kim et al 2012;Mulvihill et al 2012). In examining the mRNA expression of several BMP antagonists in CSC and nonstem glioma cell populations, we found robust expression of Gremlin1 in the CSCs, with comparatively modest or absent expression of other antagonists ( Fig.…”

A New Murine Model of Osteoblastic/Osteolytic Lesions from Human Androgen-Resistant Prostate Cancer

“…On the other hand, the expression of DKK1 and Noggin, two osteoblast inhibitors (respectively Wnts and bone morphogenetic protein (BMP) inhibitors), is decreased in PC3c versus PC3 (Figure 1 C-D) [24,25]. Moreover, PC3c similarly to PC3 cells expressed factors known to be implicated in prostate cancer osteomimicry such as OPN and Runx2.…”