Department of Stem Cell & Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
Department of Surgery, Konkuk University School of Medicine, Seoul, 05030, Republic of Korea.
Breast Cancer Res. 2019 Jan 16;21(1):6. doi: 10.1186/s13058-018-1071-2.
Epithelial-mesenchymal transition (EMT) occurs in the tumor microenvironment and presents an important mechanism of tumor cell intravasation, stemness acquisition, and metastasis. During metastasis, tumor cells enter the circulation to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood.
Here, we present both in vivo and in vitro evidence that EMT-like transition also occurs in circulating tumor cells (CTCs) as a result of hydrodynamic shear stress (+SS), which promotes conversion of CD24/CD44/CD133/CXCR4/ALDH1 primary patient epithelial tumor cells into specific high sphere-forming CD24/CD44/CD133/CXCR4/ALDH1 cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) with elevated tumor progression and metastasis capacity in vitro and in vivo. We demonstrate that conversion of CSLCs/TICs from epithelial tumor cells via +SS is dependent on reactive oxygen species (ROS)/nitric oxide (NO) generation, and suppression of extracellular signal-related kinase (ERK)/glycogen synthase kinase (GSK)3β, a mechanism similar to that operating in embryonic stem cells to prevent their differentiation while promoting self-renewal.
Fluid shear stress experienced during systemic circulation of human breast tumor cells can lead to specific acquisition of mesenchymal stem cell (MSC)-like potential that promotes EMT, mesenchymal-epithelial transition, and metastasis to distant organs. Our data revealed that biomechanical forces appeared to be important microenvironmental factors that not only drive hematopoietic development but also lead to acquisition of CSLCs/TIC potential in cancer metastasis. Our data highlight that +SS is a critical factor that promotes the conversion of CTCs into distinct TICs in blood circulation by endowing plasticity to these cells and by maintaining their self-renewal signaling pathways.
上皮-间质转化（EMT）发生在肿瘤微环境中，是肿瘤细胞浸润、获得干细胞特性和转移的重要机制。在转移过程中，肿瘤细胞进入循环系统以进入远处组织，但这种流体微环境如何影响癌细胞生物学尚不清楚。
在这里，我们提供了体内和体外的证据，表明 EMT 样转化也发生在循环肿瘤细胞（CTC）中，这是由于流体切应力（+SS）的作用，促进了 CD24/CD44/CD133/CXCR4/ALDH1 原发性上皮肿瘤细胞向特定的高球体形成 CD24/CD44/CD133/CXCR4/ALDH1 癌症干细胞样细胞（CSLCs）或肿瘤起始细胞（TICs）的转化，从而提高了体外和体内的肿瘤进展和转移能力。我们证明，通过 +SS 从上皮肿瘤细胞向 CSLCs/TICs 的转化依赖于活性氧（ROS）/一氧化氮（NO）的产生，以及细胞外信号相关激酶（ERK）/糖原合成酶激酶（GSK）3β的抑制，这一机制类似于在胚胎干细胞中起作用的机制，防止其分化，同时促进自我更新。
在人乳腺癌细胞的全身循环过程中经历的流体切应力可以导致特定的间充质干细胞（MSC）样潜能的获得，从而促进 EMT、间质-上皮转化和转移到远处器官。我们的数据表明，生物力学力似乎是重要的微环境因素，不仅驱动造血发育，而且导致癌症转移中 CSLCs/TIC 潜能的获得。我们的数据强调，+SS 是通过赋予这些细胞可塑性并维持其自我更新信号通路，将 CTCs 转化为血液中不同的 TICs 的关键因素。
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