Abstract
BackgroundIn vivo, the transforming growth factor-beta1 (TGF-β1)-induced epithelial to mesenchymal transition (EMT) occurs in seconds during cancer cells intravasation and extravasation. Although it has been established that cellular stiffness can change as a cancer cell transformed, the precise relationship between TGF-β1-induced mesenchymal stem cell mechanics and cancer prognosis remains unclear. Accordingly, it is hard to define the effects of EMT on cell mechanical properties (CMs), tumor recurrence and metastasis risks. This study bridges physical and pathological disciplines to reconcile single-cell mechanical measurements of tumor cells.Methods and resultsWe developed a microplate measurement system (MMS) and revealed the intrinsic divergent tumor composition of retrieval cells by cell stiffness and adhesion force and flow cytometry analysis. After flow cytometry sorting, we could measure the differences in CMs of the Sca-1+-CD44+ (mesenchymal-stem-cell-type) and the other subgroups. As well as the stiffer and heterogeneous compositions among tumor tissues with higher recurrence risk were depicted by MMS and atomic force microscopy (AFM). An in vitro experiment validated that Lewis lung carcinoma (LLC) cells acquired higher CMs and motility after EMT, but abrogated by SB-505124 inhibition. Concomitantly, the CD31, MMP13 and TGF-β1 enriched micro-environment in the tumor was associated with higher recurrence and distal lung metastasis risks. Furthermore, we report a comprehensive effort to correlate CMs to tumor-prognosis indicators, in which a decreased body weight gain ratio (BWG) and increased tumor weight (TW) were correlated with increased CMs.ConclusionsTogether, we determined that TGF-β1 was significantly associated with malignant tumor progressing. In terms of clinical applications, local tumor excision followed by MMS analysis offers an opportunity to predict tumor recurrence and metastasis risks.
Highlights
In vivo, the transforming growth factor-beta1 (TGF-β1)-induced epithelial to mesenchymal transition (EMT) occurs in seconds during cancer cells intravasation and extravasation
Together, we determined that Transforming growth factor-beta1 (TGF-β1) was significantly associated with malignant tumor progressing
In this study, we defined the malignancy status and poor-prognosis indicators that are associated with increased cell stiffness and adhesion force
Summary
The transforming growth factor-beta (TGF-β1)-induced epithelial to mesenchymal transition (EMT) occurs in seconds during cancer cells intravasation and extravasation. It has been established that cellular stiffness can change as a cancer cell transformed, the precise relationship between TGF-β1-induced mesenchymal stem cell mechanics and cancer prognosis remains unclear. It is hard to define the effects of EMT on cell mechanical properties (CMs), tumor recurrence and metastasis risks. Since 1994, transforming growth factorbeta (TGF-β1) has been known to be an effective EMT inducer and plays a key role in the early process of cancer cell metastasis [3,4]. The cell mechanical properties (CMs) have been proposed as an indicator of multiple cellular processes, including cancer malignant transformation [11], metastasis [12,13,14,15] and apoptosis [16,17]. The importance of CMs to cancer is appreciated, yet the contributions of CMs to tumor recurrence and prognosis remain unclear
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