von Alten Julia, Fister Stefanie, Schulz Hiltrud, Viereck Volker, Frosch Karl-Heinz, Emons Günter, Gründker Carsten
Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, D-37075 Göttingen, Germany.
Breast Cancer Res Treat. 2006 Nov;100(1):13-21. doi: 10.1007/s10549-006-9222-z. Epub 2006 Jun 7.
Bone, besides lung and liver, is one of the most preferential metastatic target sites for breast cancers. Although the precise molecular mechanisms underlying this preference need to be elucidated, it appears that bone microenvironments possess unique biological features that enable circulating cancer cells to home, survive and proliferate, and destroy bone. The majority of human breast cancers and in addition most breast cancer cell lines express GnRH receptors. Their proliferation is time- and dose-dependently reduced by GnRH-I and GnRH-II agonists by counteracting of the mitogenic signal transduction.
We have established a coculture system of different breast cancer cell lines stable transfected with red fluorescence (DS-Red) and human primary osteoblasts (hOB) or MG63 human osteosarcoma cells to analyze tumor cell invasion to bone.
We could show that breast cancer cell invasion was increased when cocultured with hOB or MG63. Treatment with GnRH-I and GnRH-II analogs reduced the ability to invade a reconstituted basement membrane (Matrigel) and to migrate in response to the cellular stimulus. Searching for the molecular mechanisms we found that GnRH treatment reduces expression of the osteoblast derived chemokine SDF-1 by hOB or MG63 cells cocultured with breast cancer cells.
These data represent the first report that the activation of tumor GnRH receptors reduces the metastatic potential of breast cancer cells. The crosstalk between metastatic breast cancer cells and bone is critical to the development and progression of bone metastases. Disruption of this interaction will allow us to design mechanism-based effective and specific therapeutic interventions for bone metastases.
除肺和肝脏外，骨是乳腺癌最常见的转移靶器官之一。尽管这种偏好背后的确切分子机制有待阐明，但骨微环境似乎具有独特的生物学特性，使循环中的癌细胞能够归巢、存活和增殖，并破坏骨骼。大多数人类乳腺癌以及大多数乳腺癌细胞系均表达促性腺激素释放激素（GnRH）受体。GnRH-I和GnRH-II激动剂通过抵消有丝分裂信号转导，以时间和剂量依赖的方式降低其增殖。
我们建立了一种共培养系统，将稳定转染红色荧光（DS-Red）的不同乳腺癌细胞系与人类原代成骨细胞（hOB）或MG63人骨肉瘤细胞共培养，以分析肿瘤细胞对骨的侵袭。
我们发现，与hOB或MG63共培养时，乳腺癌细胞的侵袭能力增强。用GnRH-I和GnRH-II类似物处理可降低侵袭重组基底膜（基质胶）的能力以及对细胞刺激作出迁移反应的能力。在寻找分子机制时，我们发现GnRH处理可降低与乳腺癌细胞共培养的hOB或MG63细胞中成骨细胞衍生趋化因子SDF-1的表达。
这些数据首次表明，肿瘤GnRH受体的激活可降低乳腺癌细胞的转移潜能。转移性乳腺癌细胞与骨之间的相互作用对于骨转移的发生和发展至关重要。破坏这种相互作用将使我们能够设计基于机制的有效且特异性的骨转移治疗干预措施。
