Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms. Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival. These results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.

中文翻译：

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原发性肿瘤切除后微转移的自发消退：原发性肿瘤分泌组的关键作用


许多案例研究报告了原发性肿瘤切除后已识别的转移灶的自发消退，但潜在的机制尚不清楚。在这里，我们提出了原发肿瘤切除后转移灶的消退和潜伏期模型，并确定了潜在的潜在机制。使用表达高度敏感荧光素酶的 MDA-MB-231HM 人类乳腺癌细胞，我们监测了 BALB/c nu/nu 小鼠自发转移的早期发展阶段。原发肿瘤的切除引起了微转移的显着消退，但较大的转移没有明显消退，并且体内补充肿瘤分泌组减弱了这种消退，这表明原发肿瘤分泌的因子促进了早期转移生长。相应地，MDA-MB-231HM 条件培养基增加了体外肿瘤增殖和粘附并减少了细胞凋亡。为了确定特定的介导因素，对 MDA-MB-231HM 分泌蛋白组进行了细胞因子阵列和蛋白质组分析。结果发现血管生成、生长因子结合和活性、粘着斑、金属蛋白酶和细胞凋亡调节过程显着富集。 MDA-MB-231HM 分泌的这些过程的关键介质 IL-8、PDGF-AA、丝氨酸蛋白酶抑制剂 E1 (PAI-1) 和 MIF 的中和，每种都会拮抗分泌组诱导的增殖。此外，在原发肿瘤存在的情况下，它们在体内同时阻断，阻止了微转移的发展。有趣的是，在 METABRIC 乳腺癌患者队列中，Serpin E1、IL-8 或这四个因素的表达升高预示着生存率较差。 这些结果表明原发肿瘤切除后微转移的消退和潜伏期以及原发肿瘤分泌组在促进 MDA-MB-231HM 异种移植物早期转移生长中的关键作用。如果推广，这些发现可以提出控制微转移和微小残留病的新方法。