Necrosis-mediated circulating tumor cell dissemination

摘要 循环肿瘤细胞（CTC）引起转移，这是癌症患者死亡的主要原因。尽管 尽管反恐委员会的传播具有长期的重要性，但人们仍然不完全了解是什么促成了反恐委员会的传播。一个阻挡 CTC在患者中非常罕见，在小鼠模型中更是如此。最近，我开发了一种 使用大鼠的CTC的体内转移模型。与老鼠相比，我可以收集到10到20倍的信息， 使用大鼠的血液并获得更多的CTC。重要的是，我观察到高CTC负荷与以下因素相关： 肿瘤内坏死，一种炎性细胞死亡形式。此外，我还发现了时间相关性 在肿瘤内坏死增加和CTC扩散之间， CTC计数与原发性肿瘤中坏死的增加一致。我推测原发灶的坏死 肿瘤诱导高CTC播散状态。我将通过以下方式来检验这一假设：1）确定 原发肿瘤对于高CTC扩散状态是充分和必要的2）研究CTC是否 播散优先发生在原发肿瘤的坏死区域，和3）识别坏死的 与高CTC播散状态相关的肿瘤微环境标志物。揭开关系 坏死和CTC播散之间的关系可以选择坏死肿瘤或替代肿瘤的患者 坏死的血清标志物，用于更积极的治疗以破坏转移过程，从而减少 癌症患者死亡率。

ABSTRACT Circulating tumor cells (CTCs) give rise to metastases, the major cause of cancer patient mortality. Despite its long-standing importance, what mediates CTC dissemination remains incompletely understood. One barrier has been the rarity of CTCs in patients and even more so in mouse models. Recently, I have developed an in vivo metastasis model for CTCs using rats. Compared with mice, I can robustly collect 10 to 20 times more blood using rats and obtain many more CTCs. Importantly, I observed that high CTC burden is associated with intratumoral necrosis, a form of inflammatory cell death. Furthermore, I have found temporal correlation between increase in intratumoral necrosis and CTC dissemination where there is a sudden 380-fold increase in CTC counts coinciding with increase in necrosis in the primary tumor. I hypothesize that necrosis in the primary tumor induces a high CTC dissemination state. I will test this hypothesis by 1) determining whether necrosis in the primary tumor is sufficient and necessary for a high CTC dissemination state 2) investigating whether CTC dissemination preferentially occurs in the necrotic regions of the primary tumor and 3) identifying necrotic tumor microenvironment markers associated with high CTC dissemination states. Uncovering the relationship between necrosis and CTC dissemination could enable selecting patients with necrotic tumors or surrogate serum markers of necrosis for more aggressive therapy to disrupt the metastatic process, thereby decreasing cancer patient mortality.