Endothelial-to-osteoblast transition in prostate cancer bone metastasis

描述（由申请人提供）：前列腺癌（PCa）具有致命潜力的一个明显特征是肿瘤细胞在去势环境中存活并在骨形成表型中发生骨转移的能力。我们最近证明，pca诱导的异常骨过度生长促进骨肿瘤的生长。因此，PCa细胞与其错误诱导的骨之间的双向相互作用在PCa在骨中的进展中起着关键作用。一般认为，转移性前列腺癌细胞通过刺激骨髓中常驻成骨细胞的增殖来诱导新骨形成。然而，人类骨转移标本的组织病理学分析表明，编织骨并非来自邻近骨表面。因此，由PCa转化为成骨细胞的细胞来源尚未确定。我们的目的是确定PCa骨转移中ca诱导异位骨形成的细胞来源。

DESCRIPTION (provided by applicant): A distinct feature of prostate cancer (PCa) with lethal potential is the ability of tumor cells to survive in a castrated environment and develop metastases in bone with a bone-forming phenotype. We recently demonstrated that PCa-induced aberrant bone overgrowth promotes tumor growth in bone. Thus, bi-directional interaction between the PCa cells and their mis-induced bone plays a critical role in PCa progression in bone. It is generally assumed that the metastatic PCa cells induce new bone formation by stimulating the proliferation of resident osteoblasts in the bone marrow. However, histopathological analyses of human bone metastasis specimens showed that woven bone was not from the adjacent bone surface. Thus, the origin of cells that were converted into osteoblasts by PCa is yet to be determined. Our objective is to identify the cell origin for the PCa-induced ectopic bone formation in PCa bone metastasis. While osteoblastic PCa bone metastasis is prevalent in the clinical setting, there is a lack of osteogenic PCa models for PCa bone metastasis study. Our xenograft core has recently successfully generated a bone forming PCa xenograft MDA-PCa-118b (PCa-118b) from a patient sample, providing us with a model to decipher the mechanism of PCa-induced bone formation. Using this xenograft, our preliminary results showed that (1) PCa-118b recruits mouse stromal cells into the tumors and converts them into osteoblasts; (2) Osteoblasts in PCa-118b also co-express the endothelial cell marker Tie2; (3) PCa-118b secretes factors, including BMP4 and TGF¿2, which have been shown to promote endothelial-to-mesenchyme transition (EndMT); (4) BMP4 or TGF¿2 are able to convert endothelial cells to express osterix (OSX), an osteoblast- specific transcription factor; and (5) In human PCa bone metastasis specimens, we detected stromal cells that co-express osteoblast and endothelial cell markers, osteocalcin and Tie2, respectively. Thus, we hypothesize that mis-induced bone in PCa bone metastasis originates from endothelial cells that were induced by PCa- secreted factors to undergo EndMT and osteoblastogenesis to form osteoblasts (OSB). The EndMT/OSB conversion leads to bone overgrowth that supports PCa progression in bone. The Specific Aims are: Aim 1. Identify tumor-secreted factors that induce EndMT/OSB in PCa bone metastasis. We will determine a minimal set of the secretory factors together with BMP4 and TGF¿2 that are involved in inducing EndMT/OSB. Aim 2. Determine how BMP4 and TGF¿2 regulate the signal transduction and transcriptional program of endothelial cells during EndMT/OSB. RNA-seq and ChIP-seq will be used to identify the transcriptional network. Aim 3. Determine whether blocking PCa-induced EndMT/OSB inhibits osteoblastic bone metastasis in vivo. Aim 4. Examine the clinical relevance of EndMT/OSB in human PCa bone metastasis. Impact. The endothelial origin of osteoblasts will allow for strategies to target the key steps of the EndMT/OSB conversion for suppression of aberrant bone formation and thus, PCa progression in bone.