Cell Biology, Immunology, and Microbiology Graduate Program, Graduate School of Biomedical Sciences, Fort Worth, Texas.
Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, Texas.
Mol Cancer Res. 2018 Nov;16(11):1652-1664. doi: 10.1158/1541-7786.MCR-18-0308. Epub 2018 Jul 13.
Tumor metastatic relapse is the primary cause for cancer-associated mortality. Metastatic relapse is believed to arise from quantities of tumor cells that are below detectable thresholds, which are able to resist radio/chemotherapy by obtaining a dormant state and hiding in certain organs, i.e., tumor reservoirs. The thymus, a central T-cell immune organ, has been suggested to be a premetastatic tumor reservoir for B-lymphoma cells. However, it remains unknown whether the thymus is able to harbor nonlymphoid solid tumor cells, and whether chemotherapy can thoroughly eliminate cancer cells in the thymus. If chemotherapy is not able to eliminate these cells in the thymus, then what processes allow for this? Melanoma cell-inoculated and genotoxic doxorubicin-treated mouse model systems were used to determine that the thymus, particularly the atrophied thymus, was able to harbor blood stream-circulating melanoma cells. In addition, a chemotherapy-induced DNA-damage response triggered activation in nonmalignant thymic cells, which in turn resulted in thymocyte death and thymic epithelial cell senescence to develop an inflammatory thymic microenvironment. This inflammatory condition induced thymic-harbored minimal tumor cells to acquire a chemoresistant state. Here, the thymus serves as a premetastatic reservoir for nonlymphoid solid tumor cells during chemotherapy, which could be a novel target of minimal residual disease in antitumor therapy, thus preventing tumor metastatic relapse. .
肿瘤转移复发是癌症相关死亡的主要原因。转移复发被认为是由数量低于检测阈值的肿瘤细胞引起的，这些细胞能够通过进入休眠状态并隐藏在某些器官（即肿瘤库）中来抵抗放射/化学疗法。胸腺是中央 T 细胞免疫器官，被认为是 B 细胞淋巴瘤细胞的前转移肿瘤库。然而，目前尚不清楚胸腺是否能够容纳非淋巴样实体瘤细胞，以及化疗是否能够彻底清除胸腺中的癌细胞。如果化疗不能彻底清除胸腺中的这些细胞，那么是什么过程允许它们存在呢？使用黑色素瘤细胞接种和遗传毒性阿霉素处理的小鼠模型系统来确定胸腺，特别是萎缩的胸腺，能够容纳血流循环中的黑色素瘤细胞。此外，化疗诱导的 DNA 损伤反应会激活非恶性胸腺细胞，进而导致胸腺细胞死亡和胸腺上皮细胞衰老，从而形成炎症性胸腺微环境。这种炎症状态会诱导胸腺中储存的微量肿瘤细胞获得耐药状态。在这里，胸腺在化疗期间充当非淋巴样实体瘤细胞的前转移肿瘤库，这可能成为抗肿瘤治疗中微小残留病的新靶点，从而防止肿瘤转移复发。
