Croset Martine, Santini Daniele, Iuliani Michele, Fioramonti Marco, Zoccoli Alice, Vincenzi Bruno, Tonini Giuseppe, Pantano Francesco
Institut national de la santé et de la recherche médicale (INSERM), UMR 1033, Lyon F-69008, France.
Medical Oncology, Campus Bio-Medico University of Rome, Rome 00128, Italy.
Molecules. 2014 Jul 11;19(7):10115-28. doi: 10.3390/molecules190710115.
The development of bone metastases requires multistep and multicellular machinery consisting not only of processes shared with any type of metastases (formation of a pre-metastatic niche, chemotaxis of tumor cells into the host tissue, tumor cells escape from the microvasculature), but also biological interactions that are strictly related to the particular bone microenvironment (bone marrow colonization by cancer cells, osteomimicry, deregulation of bone homeostasis). MiRNAs are highly conserved, small RNAs molecules that regulate gene expression. The functional consequence of miRNA deregulation lies in the mRNA targets whose expression is altered. MiRNA networks acting as upstream regulators of these genes interfere with the initial steps of tumor local invasion and cancer cell intravasation, mainly by regulating the epithelial-mesenchymal transition, the motility, invasiveness and survival abilities of these cells. The miRNA-mediated regulation on the steps of bone tropism, anchorage, homing and finally bone colonization is more tissue specific, being dependent on the expression pattern of target miRNAs in bone marrow sinusoids, bone cells and microenvironment. In that, miRNA specific expression signatures that can distinguish between primary tumors from their corresponding bone metastases might be determinants of clinical aggressiveness. In this review, we focus on the current advances on functions and molecular mechanisms by which miRNAs exert their biological roles in regulating bone metastases development.
骨转移的发生需要多步骤、多细胞机制，这不仅包括与任何类型转移所共有的过程（形成前转移微环境、肿瘤细胞向宿主组织的趋化性、肿瘤细胞从微血管系统逸出），还包括与特定骨微环境密切相关的生物学相互作用（癌细胞在骨髓中的定植、骨模拟、骨稳态失调）。微小RNA（miRNA）是高度保守的小RNA分子，可调节基因表达。miRNA失调的功能后果在于其表达发生改变的mRNA靶点。作为这些基因上游调节因子的miRNA网络主要通过调节上皮-间质转化、这些细胞的运动性、侵袭性和生存能力，干扰肿瘤局部侵袭和癌细胞进入血管的初始步骤。miRNA对骨嗜性、锚定、归巢以及最终骨定植步骤的调节更具组织特异性，这取决于骨髓血窦、骨细胞和微环境中靶miRNA的表达模式。就此而言，能够区分原发性肿瘤与其相应骨转移灶的miRNA特异性表达特征可能是临床侵袭性的决定因素。在本综述中，我们重点关注miRNA在调节骨转移发生发展过程中发挥生物学作用的功能及分子机制的当前进展。
