Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone
Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone
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DOI：
10.1038/sj.onc.1210694
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发表时间：
2008-01-24
期刊：
影响因子：
8
通讯作者：
Navone, N. M.
中科院分区：
文献类型：
--
作者：
Li, Z. G.;Yang, J.;Navone, N. M.
前列腺癌产生成骨细胞骨转移的倾向表明癌细胞和成骨细胞以有助于癌症进展的方式相互作用。为了确定介导这些相互作用的因素，我们比较了两种骨源性前列腺癌细胞系（产生成骨细胞（MDA PCa 2b）或溶骨性病变（PC-3））之间的基因表达模式。两种细胞系均表达Wnt配体，包括WNT 7 b，一种与骨生成有关的典型Wnt。PC-3细胞表达的Dickkopf-1（DKK 1）是MDA PCa 2b细胞的50倍，DKK 1是Wnt通路的抑制剂。对这些因子的功能作用的评估（在前列腺癌细胞与原代小鼠成骨细胞（PMO）的共培养物中或在骨器官培养物中）表明，MDA PCa 2b细胞激活PMO中的Wnt经典信号传导，DKK 1阻断由MDA PCa 2b细胞诱导的成骨细胞增殖和新骨形成。MDA PCa 2b细胞在缺乏Wnt共受体Lrp 5的小鼠的颅骨中不诱导骨形成。在人类样本中，WNT 7 b在正常前列腺中不表达，但在高级别前列腺上皮内瘤变区域、9个原发性前列腺肿瘤样本中的3个以及38个前列腺癌骨转移样本中的16个中表达。DKK 1在正常或癌组织中不表达，但在溶骨性骨转移瘤标本中有2例表达（P = 0.0119）。我们得出结论，MDA PCa 2b通过Wnt经典信号诱导新骨形成，LRP 5介导这种效应，DKK 1参与骨形成和骨吸收之间的平衡，决定病变表型。
The tendency of prostate cancer to produce osteoblastic bone metastases suggests that cancer cells and osteoblasts interact in ways that contribute to cancer progression. To identify factors that mediate these interactions, we compared gene expression patterns between two bone-derived prostate cancer cell lines that produce osteoblastic (MDA PCa 2b) or osteolytic lesions (PC-3). Both cell lines expressed Wnt ligands, including WNT7b, a canonical Wnt implicated in osteogenesis. PC-3 cells expressed 50 times more Dickkopf-1 (DKK1), an inhibitor of Wnt pathways, than did MDA PCa 2b cells. Evaluation of the functional role of these factors (in cocultures of prostate cancer cells with primary mouse osteoblasts (PMOs) or in bone organ cultures) showed that MDA PCa 2b cells activated Wnt canonical signaling in PMOs and that DKK1 blocked osteoblast proliferation and new bone formation induced by MDA PCa 2b cells. MDA PCa 2b cells did not induce bone formation in calvaria from mice lacking the Wnt co-receptor Lrp5. In human specimens, WNT7b was not expressed in normal prostate but was expressed in areas of high-grade prostate intraepithelial neoplasia, in three of nine primary prostate tumor specimens and in 16 of 38 samples of bone metastases from prostate cancer. DKK1 was not expressed in normal or cancerous tissue but was expressed in two of three specimens of osteolytic bone metastases (P = 0.0119). We conclude that MDA PCa 2b induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption that determines lesion phenotype.