BMP4 Promotes Prostate Tumor Growth in Bone through Osteogenesis

Abstract

Induction of new bone formation is frequently seen in the bone lesions from prostate cancer (PCa). However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, two xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from PCa bone metastases. When implanted subcutaneously in SCID mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (“secretome”) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of BMP-4 and several cytokines including IL-8, Gro, and CCL2. We demonstrated that BMP-4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treating with BMP-4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP-4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of PCa in bone.

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

“…Therefore, C4-like antibodies have an important potential for clinical, diagnostic, and therapeutic uses in a subset of colorectal cancers. As BMP4 has also been shown to contribute to carcinogenesis in breast (12), lung (14), prostate (15), and gastric (18) cancers, the oncologic applicability of C4-like antibodies is considerable.…”

“…Most intriguing is the role of BMP4, which presents opposing roles depending on the neoplasm (7,9). In certain malignancies, such as glioblastoma (10) and myeloma (11), high levels of BMP4 are associated with less malignant features while in breast (12), ovarian (13), lung (14), and prostate (15), BMP4 is involved in epithelial-mesenchymal transition (EMT) and metastatic behavior. In gastrointestinal cancers such as pancreas (16), colon (17), and gastric cancer (18), BMP4 has been associated with tumor progression and chemotherapy resistance.…”

“…Neutralization of BMP by several natural antagonists and chemical inhibitors has already been proven successful for the suppression of metastasis in prostate (15), lung (14), as well as breast cancer (20). Albeit significant progress has been made in generating highly specific and less toxic small-molecule inhibitors that target BMP type I receptors (21)(22)(23), these inhibitors are still nonselective.…”

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

“…We hypothesized the existence of a functional role between PCA3 and PRUNE2, and their involvement in prostate cancer progression. To study this possibility, we investigated PRUNE2 as well as the PCA3 intronic antisense transcripts, which we cloned from MDA-PCa-133, a patient-derived xenograft (PDX) of bone metastasis from prostate cancer (11) (Fig. 1 A and B).…”

“…ADAR proteins are key regulatory enzymes for RNA editing and sequestering of noncoding RNA sequences, such as introns and untranslated mRNAs (5,(11)(12)(13), derived from the hybridization of retroinverted Alu elements (5,13), with conversion of adenosine-to-inosine (A-to-I) RNA editing after nuclear dsRNA formation. Thus, we hypothesized that PCA3-PRUNE2 dsRNA may be regulated by ADAR-mediated RNA editing.…”