Bendre Manali S, Gaddy-Kurten Dana, Mon-Foote Thetsu, Akel Nisreen S, Skinner Robert A, Nicholas Richard W, Suva Larry J
Center for Orthopaedic Research, Department of Orthopaedic Surgery, Barton Research Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Cancer Res. 2002 Oct 1;62(19):5571-9.
Metastasis is the process by which tumor cells spread from their site of origin to distant sites after gaining access to the circulatory system. An understanding of the factors contributing to the metastatic potential of breast cancer cells to bone will enhance the prospect of developing new therapies that impede metastasis. In this study, we have used an in vivo selection scheme involving left cardiac ventricle injection into nude mice to identify a highly metastatic human breast cancer cell line (MDA-MET) from a less metastatic (MDA-231) parental cell line. In this model, tumor-bearing mice exhibit features similar to those associated with human metastatic bone disease such as osteolytic bone destruction. After inoculation, MDA-MET cells form devastating lesions within 4 weeks, whereas the parental cells do not, even after 10 weeks. In vitro, the MDA-MET cells have a similar growth rate to the parental MDA-231 cells yet demonstrate distinct adhesive and invasive phenotypes. MDA-MET cells show increased early adhesion to type IV collagen and are significantly more invasive through Matrigel than MDA-231 cells. Analysis of the gene expression profile in the metastatic MDA-MET versus poorly metastatic MDA-231 cells identified relatively few genes whose expression was altered >2-fold. Of particular interest was the lack of parathyroid hormone-related protein (PTHrP) mRNA expression, which was supported at the protein level by immunoradiometric assay. These data support the idea that PTHrP is not predictive of the metastasis of human breast cancer to bone. Another important difference between the two cell lines was the elevated expression by MDA-MET cells of the cytokine IL-8. Reverse transcriptase-PCR and ELISA confirmed the increased expression of IL-8 in MDA-MET cells. In addition, IL-8 mRNA expression is also elevated in a variety of human cancer cell lines with different metastatic potential in vivo. These experiments suggest that the elevated expression of IL-8 (and not PTHrP) by MDA-MET cells is a phenotypic change that may be related to their enhanced ability to metastasize to the skeleton.
转移是肿瘤细胞在进入循环系统后从其起源部位扩散到远处部位的过程。了解促成乳腺癌细胞向骨转移潜能的因素，将提高开发阻碍转移的新疗法的前景。在本研究中，我们采用了一种体内筛选方案，即将细胞注射到裸鼠的左心室，从转移能力较低的（MDA-231）亲代细胞系中鉴定出一种高转移性人乳腺癌细胞系（MDA-MET）。在这个模型中，荷瘤小鼠表现出与人类转移性骨病相关的特征，如溶骨性骨破坏。接种后，MDA-MET细胞在4周内形成破坏性病变，而亲代细胞即使在10周后也不会形成。在体外，MDA-MET细胞的生长速率与亲代MDA-231细胞相似，但表现出不同的黏附及侵袭表型。MDA-MET细胞对IV型胶原的早期黏附增加，并且通过基质胶的侵袭能力明显强于MDA-231细胞。对转移性MDA-MET细胞与低转移性MDA-231细胞的基因表达谱分析发现，表达改变超过2倍的基因相对较少。特别值得关注的是甲状旁腺激素相关蛋白（PTHrP）mRNA表达的缺失，免疫放射分析在蛋白水平也证实了这一点。这些数据支持PTHrP不能预测人类乳腺癌向骨转移这一观点。这两种细胞系的另一个重要差异是MDA-MET细胞中细胞因子IL-8的表达升高。逆转录聚合酶链反应和酶联免疫吸附测定证实了MDA-MET细胞中IL-8表达增加。此外，在体内具有不同转移潜能的多种人类癌细胞系中，IL-8 mRNA表达也升高。这些实验表明，MDA-MET细胞中IL-8（而非PTHrP）表达升高是一种表型变化，可能与其向骨骼转移能力增强有关。
