Hydrodynamic shear stress promotes epithelial-mesenchymal transition by downregulating ERK and GSK3β activities

Hye Yeon Choi, Gwang Mo Yang, Ahmed Abdal Dayem, Subbroto Kumar Saha, Kyeongseok Kim, Youngbum Yoo, Kwonho Hong, Jin Hoi Kim, Cassian Yee, Kyung Mi Lee, Ssang Goo Cho

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)


Background: 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. Methods and results: 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 middle /CD44 high /CD133 middle /CXCR4 low /ALDH1 low primary patient epithelial tumor cells into specific high sphere-forming CD24 low /CD44 low /CD133 high /CXCR4 high /ALDH1 high 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. Conclusion: 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.

Original languageEnglish
Article number6
JournalBreast Cancer Research
Issue number1
Publication statusPublished - 2019 Jan 16


  • ERK-GSK3β
  • Hydrodynamic shear stress
  • ROS/NO
  • Tumor-initiating cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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