Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
Oncogene. 2021 Mar;40(12):2273-2284. doi: 10.1038/s41388-021-01706-8. Epub 2021 Mar 1.
Recent findings suggest that the dissemination of tumor cells occurs at the early stage of breast and pancreatic carcinogenesis, which is known as early dissemination. The evidence of early dissemination has been demonstrated predominantly in the bloodstream and bone marrow; however, limited evidence has revealed the existence and behavior of disseminated cells in distant organs. Here, we show that premalignant pancreatic cells seed distant stealth metastasis that eventually develops into manifest metastasis. By analyzing lineage-labeled pancreatic cancer mouse models (KPCT/TFF1KO; Pdx1-Cre/LSL-KRAS/LSL-p53/LSL-tdTomato/TFF1KO), we found that premalignant pancreatic cells, rather than mature malignant cells, were prone to enter the bloodstream and reside in the bone marrow, liver, and lung. While these metastatic cells exhibited the characteristics of the cells of host organs and did not behave as malignant cells, they underwent malignant transformation and formed distinct tumors. Surprisingly, the manifestation of distant metastasis occurred even before tumor development in the primary site. Our data revealed that disseminated premalignant cells reside stealthily in distant organs and evolve in parallel with the progression of the primary tumor. These observations suggest that we must rebuild a therapeutic strategy for metastatic pancreatic cancer.
最近的研究结果表明，肿瘤细胞的扩散发生在乳腺癌和胰腺癌发生的早期阶段，这被称为早期扩散。早期扩散的证据主要在血液和骨髓中得到证实；然而，有限的证据表明，在远处器官中存在并观察到了播散细胞的行为。在这里，我们展示了癌前胰腺细胞会播种远处的隐匿性转移，这些转移最终会发展为明显的转移。通过分析谱系标记的胰腺癌小鼠模型（KPCT/TFF1KO；Pdx1-Cre/LSL-KRAS/LSL-p53/LSL-tdTomato/TFF1KO），我们发现癌前胰腺细胞，而不是成熟的恶性细胞，更容易进入血液并存在于骨髓、肝脏和肺部。虽然这些转移性细胞表现出宿主器官细胞的特征，而不是恶性细胞的特征，但它们发生了恶性转化并形成了明显的肿瘤。令人惊讶的是，远处转移的表现甚至发生在原发部位肿瘤发展之前。我们的数据揭示了播散的癌前细胞在远处器官中隐匿地存在，并与原发性肿瘤的进展平行演化。这些观察结果表明，我们必须为转移性胰腺癌重建一种治疗策略。
