Reduced Latency in the Metastatic Niche Contributes to the More Aggressive Phenotype of LM8 Compared to Dunn Osteosarcoma Cells.
Reduced Latency in the Metastatic Niche Contributes to the More Aggressive Phenotype of LM8 Compared to Dunn Osteosarcoma Cells.
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作者：
Arlt MJ;Banke IJ;Bertz J;Ram Kumar RM;Muff R;Born W;Fuchs B
转移是骨肉瘤患者死亡的主要原因，其诊断仍然很困难。然而，在临床前研究中，骨肉瘤细胞中报告基因的强制表达显著提高了微转移的检测，从而提高了研究的质量。我们最近发现，携带lacZ报告基因的Dunn细胞从皮下原发肿瘤中播散的频率与其高转移亚群LM8一样高，但只有LM8细胞生长为大转移。在本时间过程研究中，尾静脉注射的Dunn和LM8细胞在24小时内以相同的频率在小鼠的肺、肝和肾中沉淀。此外，Dunn细胞也生长为大转移瘤，但与LM8相比，在肺组织中延迟两周，在肝脏和肾脏组织中延迟一周，与小鼠的存活时间延长一致。Dunn和lm8细胞来源的卵巢和脊柱转移发生率较低。在体外，与LM8细胞相比，Dunn细胞表现出更低的侵袭性，更强的接触抑制和细胞间粘附，并且几种与癌症和休眠相关的基因存在差异表达。综上所述，与LM8相比，Dunn细胞具有相似的能力，但形成大转移的潜伏期更长，为研究肿瘤细胞休眠提供了一个有趣的新实验系统。
Metastasis is the major cause of death of osteosarcoma patients and its diagnosis remains difficult. In preclinical studies, however, forced expression of reporter genes in osteosarcoma cells has remarkably improved the detection of micrometastases and, consequently, the quality of the studies. We recently showed that Dunn cells equipped with a lacZ reporter gene disseminated from subcutaneous primary tumors as frequently as their highly metastatic subline LM8, but only LM8 cells grew to macrometastases. In the present time-course study, tail-vein-injected Dunn and LM8 cells settled within 24 h at the same frequency in the lung, liver, and kidney of mice. Furthermore, Dunn cells also grew to macrometastases, but, compared to LM8, with a delay of two weeks in lung and one week in liver and kidney tissue, consistent with prolonged survival of the mice. Dunn- and LM8-cell-derived ovary and spine metastases occurred less frequently. In vitro, Dunn cells showed less invasiveness and stronger contact inhibition and intercellular adhesion than LM8 cells and several cancer- and dormancy-related genes were differentially expressed. In conclusion, Dunn cells, compared to LM8, have a similar capability but a longer latency to form macrometastases and provide an interesting new experimental system to study tumor cell dormancy.