Abstract
BackgroundEpithelial-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 resultsHere, 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 CD24middle/CD44high/CD133middle/CXCR4low/ALDH1low primary patient epithelial tumor cells into specific high sphere-forming CD24low/CD44low/CD133high/CXCR4high/ALDH1high 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.ConclusionFluid 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.
Highlights
Epithelial-mesenchymal transition (EMT) occurs in the tumor microenvironment and presents an important mechanism of tumor cell intravasation, stemness acquisition, and metastasis
We hypothesized that SS applied to tumor cells during systemic blood circulation may trigger the transition of epithelial tumor cells into Tumor-initiating cell (TIC), similar to that observed in hematopoietic stem cells (HSCs)
Elevated green fluorescent protein (GFP) signals were observed on day 28 after the injection, suggesting that Circulating tumor cell (CTC) remaining in blood circulation had undergone proliferation
Summary
Epithelial-mesenchymal transition (EMT) occurs in the tumor microenvironment and presents an important mechanism of tumor cell intravasation, stemness acquisition, and metastasis. Once translocated into blood vessels, tumor cells present in blood vessels are continually exposed to severe shear stress (SS) under normoxic conditions, and subjected to cell cycle arrest due to hypoxic-to-normoxic transition and apoptosis from the absence of cell-ECM interaction and tumor growth factors. Only those CTCs acquiring EMT potential during systemic circulation can survive and metastasize to distant sites. Much less is known about the SS effect on intravascular tumor cells of epithelial origin
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