| Author: | Xin, Ying |
| Title: | Fluid shear stress in blood circulation selects metastasis-initiating cells from circulating tumor cells |
| Advisors: | Tan, Youhua (BME) Yang, Mo (BME) |
| Degree: | Ph.D. |
| Year: | 2022 |
| Subject: | Metastasis Cancer cells -- Identification Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Biomedical Engineering |
| Pages: | 116 pages : color illustrations |
| Language: | English |
| Abstract: | Metastasis accounts for the majority of cancer-related deaths and has been believed to be driven by metastasis-initiating cells (MICs). It is thus crucial to isolate these rare cells and characterize their unique properties. The mainstream method for MIC isolation is based on specific surface biomarkers, which highly depend on cancer type and stage and thus may be not reliable for functional characterization and targeting. Tumor cells metastasize to distal organs mainly through hematogenous dissemination, where they experience considerable levels of shear stress that can induce substantial apoptosis. Nevertheless, MICs must survive the entire metastatic process, including blood shear flow, to establish distant metastases, and thus may be enriched in the tumor cells surviving blood circulation. However, it remains elusive whether and how fluid shear stress selects MICs with metastatic advantages. This study aims to exploit fluid shear stress in vasculature to efficiently select MICs for property characterization. A microfluidics-based in vitro system was developed to mimic the shear flow in the vascular system. With the elevated magnitude of blood shear stress and circulation time, the majority of tumor cells underwent apoptosis, which depended on EMT-related signaling. However, a minor subpopulation of tumor cells was resistant to the fluid shear stress and might have the potential to eventually generate distant metastases. Based on two important properties of MICs, metastatic potential and self-renewal ability, the experimental conditions, including the magnitude of shear stress and circulation duration, were optimized to be 20 dyne/cm2 and 12 h for MICs selection. The metastasis-initiating abilities of these selected tumor cells were characterized, including high migratory and invasive potential, adhesion to the endothelium, trans-endothelial migration, self-renewal ability, chemoresistance, and cellular plasticity. The genes related to stemness and metastasis were considerably up-regulated in these shear-selected MICs, which may explain the acquisition of metastasis-initiating ability by these MICs. In addition, the selected MICs exhibited distinct biophysical properties, including reduced cell stiffness and elevated cellular contractility, which may be favourable to the completion of the subsequent metastatic steps toward metastatic colonization. The in vivo results showed that these selected tumor cells generated much larger primary tumor or in distant organs than non-selected tumor cells, suggesting shear-selected tumor cells may be highly tumorigenic and metastatic. At last, the mechanism underlying the selection of MICs by fluid shear stress was explored. As there existed heterogenicity inside the tumor, single cell clones were isolated from the whole population of tumor cells. The majority of the single cell clones were induced to a more malignant phenotype under 20 dyne/cm2 shear stress though there were minor variations between different clones. It indicated that blood shear stress converted a subpopulation of tumor cells with higher metastasis-initiating ability. In addition, the mechanosensitive CXCR4-PI3K-AKT signaling was activated in the MICs selected by fluid shear stress. Inhibiting this signaling significantly suppressed the metastatic potential of the selected MICs. In summary, hemodynamic shear stress could efficiently select a small subpopulation of circulating tumor cells with metastasis-initiating ability. The selected cells hold the essential traits for the efficient generation of distal macroscopic metastases and possess unique biophysical properties. These findings suggest that fluid shear stress in blood circulation has dual effects on circulating tumor cells, including eliminating the majority of tumor cells and enhancing the metastasis-initiating ability of the surviving cells. This may provide a novel strategy for MICs selection and characterization and cast new insight into the roles of mechanics in tumor metastasis. |
| Rights: | All rights reserved |
| Access: | open access |
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