Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases
Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases
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DOI：
10.2353/ajpath.2007.051276
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发表时间：
2007-01-01
影响因子：
6
通讯作者：
Cecchini, Marco G.
中科院分区：
文献类型：
--
作者：
Schwaninger, Ruth;Rentsch, Cyrill A.;Cecchini, Marco G.
前列腺癌和乳腺癌的骨转移可以是成骨的，也可以是溶骨的，但决定这些特征的机制尚不清楚。骨形态发生蛋白和WRIT蛋白是骨诱导分子。它们的活性受Noggin和Dickkopf-1等拮抗剂的调节。骨形态发生和Wnt蛋白拮抗剂在人前列腺癌和乳腺癌细胞系中的差异表达分析表明，溶骨细胞系在体外结构性地表达noggin和Dickkopf-1以及至少一种溶骨细胞因子甲状旁腺激素相关蛋白、集落刺激因子-1和白介素8。相反，骨诱导细胞系在体外既不表达noggin，也不表达Dickkopf-1，也不表达溶骨细胞因子。体外观察到的noggin差异表达谱在体内证实了移植到骨中的前列腺癌细胞系和临床骨转移样本。在骨诱导前列腺癌细胞系中强制表达noggin可以消除其异种骨内移植体内诱导的成骨细胞反应。基底骨吸收和肿瘤生长动力学受到轻微影响。肿瘤细胞缺乏noggin和Dickkopf-1的表达可能是骨转移中成骨细胞反应的相关机制。随之而来的是缺乏溶骨细胞因子；可能允许这种作用。Noggin是骨转移死亡辅助治疗的候选药物。
Prostate and mammary cancer bone metastases can be osteoblastic or osteolytic, but the mechanisms determining these features are unclear. Bone morphogenetic and Writ proteins are osteoinductive molecules. Their activity is modulated by antagonists such as noggin and dickkopf-1. Differential expression analysis of bone morphogenetic and Wnt protein antagonists in human prostate and mammary cancer cell lines showed that osteolytic cell lines constitutively express in vitro noggin and dickkopf-1 and at least one of the osteolytic cytokines parathyroid hormone-related protein, colony-stimulating factor-1, and interleukin-8. in contrast, osteoinductive cell lines express neither noggin nor dickkopf-1 nor osteolytic cytokines in vitro. The noggin differential expression profile observed in vitro was confirmed in vivo in prostate cancer cell lines xenografted into bone and in clinical samples of bone metastasis. Forced noggin expression in an osteoinductive prostate cancer cell line abolished the osteoblast response induced in vivo by its intraosseous xenografts. Basal bone resorption and tumor growth kinetics were marginally affected. Lack of noggin and possibly dickkopf-1 expression by cancer cells may be a relevant mechanism contributing to the osteoblast response in bone metastases. Concomitant lack of osteolytic cytokines; may be permissive of this effect. Noggin is a candidate drug for die adjuvant therapy of bone metastasis.