Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany.
Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany.
Int J Cancer. 2020 Jul 15;147(2):519-531. doi: 10.1002/ijc.32933. Epub 2020 Mar 4.
Disseminated tumor cells (dTCs) can frequently be detected in the bone marrow (BM) of colorectal cancer (CRC) patients, raising the possibility that the BM serves as a reservoir for metastatic tumor cells. Identification of dTCs in BM aspirates harbors the potential of assessing therapeutic outcome and directing therapy intensity with limited risk and effort. Still, the functional and prognostic relevance of dTCs is not fully established. We have previously shown that CRC cell clones can be traced to the BM of mice carrying patient-derived xenografts. However, cellular interactions, proliferative state and tumorigenicity of dTCs remain largely unknown. Here, we applied a coculture system modeling the microvascular niche and used immunofluorescence imaging of the murine BM to show that primary CRC cells migrate toward endothelial tubes. dTCs in the BM were rare, but detectable in mice with xenografts from most patient samples (8/10) predominantly at perivascular sites. Comparable to primary tumors, a substantial fraction of proliferating dTCs was detected in the BM. However, most dTCs were found as isolated cells, indicating that dividing dTCs rather separate than aggregate to metastatic clones-a phenomenon frequently observed in the microvascular niche model. Clonal tracking identified subsets of self-renewing tumor-initiating cells in the BM that formed tumors out of BM transplants, including one subset that did not drive primary tumor growth. Our results indicate an important role of the perivascular BM niche for CRC cell dissemination and show that dTCs can be a potential source for tumor relapse and tumor heterogeneity.
肿瘤播散细胞（dTCs）可在结直肠癌（CRC）患者的骨髓（BM）中频繁检测到，这增加了 BM 可能是转移性肿瘤细胞库的可能性。在 BM 抽吸物中鉴定 dTCs 具有评估治疗效果并通过有限的风险和努力指导治疗强度的潜力。尽管如此，dTCs 的功能和预后相关性尚未完全确定。我们之前曾表明，CRC 细胞克隆可以追溯到携带患者来源异种移植物的小鼠的 BM 中。然而，dTCs 的细胞相互作用、增殖状态和致瘤性在很大程度上仍然未知。在这里，我们应用了一种模拟微血管龛的共培养系统，并使用免疫荧光成像对小鼠 BM 进行了研究，结果表明原发性 CRC 细胞向内皮管迁移。BM 中的 dTCs 很少见，但可以从大多数患者样本（8/10）的异种移植物小鼠中检测到，主要位于血管周围部位。与原发性肿瘤类似，在 BM 中检测到大量增殖的 dTCs。然而，大多数 dTCs 被发现为孤立细胞，这表明分裂的 dTCs更倾向于分离而不是聚集形成转移性克隆，这是在微血管龛模型中经常观察到的现象。克隆追踪确定了 BM 中自我更新的肿瘤起始细胞亚群，这些细胞可以从 BM 移植中形成肿瘤，其中一个亚群不会驱动原发性肿瘤生长。我们的研究结果表明，血管周围 BM 龛在 CRC 细胞扩散中起着重要作用，并表明 dTCs 可能是肿瘤复发和肿瘤异质性的潜在来源。
