Prostate Cancer Cells and Bone Stromal Cells Mutually Interact with Each Other through Bone Morphogenetic Protein-mediated Signals
Prostate Cancer Cells and Bone Stromal Cells Mutually Interact with Each Other through Bone Morphogenetic Protein-mediated Signals
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DOI：
10.1074/jbc.m112.353094
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发表时间：
2012-06-08
影响因子：
4.8
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Nishimori, Hikaru;Ehata, Shogo;Miyazono, Kohei
癌细胞和骨微环境之间的功能相互作用有助于骨转移的发展。虽然前列腺癌骨转移的特点是骨化增加，但这一过程中涉及的分子机制尚未完全了解。在这里，骨形态发生蛋白（BMPs）在前列腺癌细胞和骨基质细胞之间的相互作用的作用进行了研究。在人前列腺癌LNCaP细胞中，BMP-4通过Smad依赖性途径诱导产生Sonic hedgehog（SHH）。在小鼠基质MC 3 T3-E1细胞中，SHH上调激活素受体IIB（ActR-IIB）和Smad 1的表达，这反过来又增强了这些细胞中BMP反应性报告基因的活性。用BMP-4和SHH联合刺激MC 3 T3-E1细胞协同诱导成骨细胞标志物的表达，包括碱性磷酸酶、骨唾液蛋白、II型胶原α 1和骨钙素。当MC 3 T3-E1细胞与LNCaP细胞共培养时，LNCaP细胞的SHH可促进BMP-4诱导的MC 3 T3-E1细胞的成骨分化。此外，LNCaP细胞和BMP-4协同诱导生长因子的产生，包括成纤维细胞生长因子（FGF）-2和表皮生长因子（EGF）在MC 3 T3-E1细胞中，并且这些可能促进LNCaP细胞的增殖。总之，我们的研究结果表明，骨形成蛋白为前列腺癌细胞的生存和骨基质细胞在骨微环境中的分化提供了有利的环境，可能导致前列腺癌的成骨转移。
Functional interactions between cancer cells and the bone microenvironment contribute to the development of bone metastasis. Although the bone metastasis of prostate cancer is characterized by increased ossification, the molecular mechanisms involved in this process are not fully understood. Here, the roles of bone morphogenetic proteins (BMPs) in the interactions between prostate cancer cells and bone stromal cells were investigated. In human prostate cancer LNCaP cells, BMP-4 induced the production of Sonic hedgehog (SHH) through a Smad-dependent pathway. In mouse stromal MC3T3-E1 cells, SHH up-regulated the expression of activin receptor IIB (ActR-IIB) and Smad1, which in turn enhanced BMP-responsive reporter activities in these cells. The combined stimulation with BMP-4 and SHH of MC3T3-E1 cells cooperatively induced the expression of osteoblastic markers, including alkaline phosphatase, bone sialoprotein, collagen type II alpha 1, and osteocalcin. When MC3T3-E1 cells and LNCaP cells were co-cultured, the osteoblastic differentiation of MC3T3-E1 cells, which was induced by BMP-4, was accelerated by SHH from LNCaP cells. Furthermore, LNCaP cells and BMP-4 cooperatively induced the production of growth factors, including fibroblast growth factor (FGF)-2 and epidermal growth factor (EGF) in MC3T3-E1 cells, and these may promote the proliferation of LNCaP cells. Taken together, our findings suggest that BMPs provide favorable circumstances for the survival of prostate cancer cells and the differentiation of bone stromal cells in the bone microenvironment, possibly leading to the osteoblastic metastasis of prostate cancer.