The Role of Tumor Microenvironment in Regulating the Plasticity of Osteosarcoma Cells.

Osteosarcoma (OS) is a malignancy that is becoming increasingly common in adolescents. OS stem cells (OSCs) form a dynamic subset of OS cells that are responsible for malignant progression and chemoradiotherapy resistance. The unique properties of OSCs, including self-renewal, multilineage differentiation and metastatic potential, 149 depend closely on their tumor microenvironment. In recent years, the likelihood of its dynamic plasticity has been extensively studied. Importantly, the tumor microenvironment appears to act as the main regulatory component of OS cell plasticity. For these reasons aforementioned, novel strategies for OS treatment focusing on modulating OS cell plasticity and the possibility of modulating the composition of the tumor microenvironment are currently being explored. In this paper, we review recent studies describing the phenomenon of OSCs and factors known to influence phenotypic plasticity. The microenvironment, which can regulate OSC plasticity, has great potential for clinical exploitation and provides different perspectives for drug and treatment design for OS.

A Soft Matrix Enhances the Cancer Stem Cell Phenotype of HCC Cells.

Cancer stem cells (CSCs) comprise a small portion of cancer cells, have greater self-renewal ability and metastatic potential than non-CSCs and are resistant to drugs and radiotherapy. CSCs and non-CSCs, which can reversibly change their stemness states, typically play roles in plasticity and cancer cell heterogeneity. Furthermore, the component that plays a key role in affecting CSC plasticity remains unknown. In this study, we utilized mechanically tunable polyacrylamide (PA) hydrogels to simulate different stiffnesses of the liver tissue matrix in various stages. Our results showed that hepatocellular carcinoma (HCC) cells were small and round in a soft matrix. The soft matrix increased the expression levels of liver cancer cells with stemness properties (LCSC) surface markers in HCC cells and the number of side population (SP) cells. Moreover, the soft matrix elicited early cell cycle arrest in the G1 phase and increased the cell sphere-forming ability. In addition, cells grown on the soft matrix showed enhanced chemoresistance and tumorigenicity potential. In summary, our study demonstrated that a soft matrix increases the stemness of HCC cells.

MT1-MMP downregulation via the PI3K/Akt signaling pathway is required for the mechanical stretching-inhibited invasion of bone-marrow-derived mesenchymal stem cells.

Mobilization from the bone marrow and the migration of bone-marrow-derived mesenchymal stem cells (BMSCs) through the peripheral circulation to injured tissue sites are regulated by multiple mechanical and chemical factors. We previously demonstrated that mechanical stretching promotes the migration but inhibits the invasion of BMSCs. However, the involved mechanisms, especially the mechanism of stretching-inhibited BMSC invasion, have not been thoroughly elucidated to date. In this study, we found that mechanical stretching with a 10% amplitude at a 1-Hz frequency for 8 hr significantly reduces BMSC invasion and downregulates the expression of membrane type-1 matrix metalloproteinases (MT1-MMP) at both the messenger RNA and protein levels. The overexpression of MT1-MMP restores mechanical stretching-reduced BMSC invasion. Moreover, phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation in BMSCs was found to be inactivated by mechanical stretching. Pharmacological inhibitors of PI3K/Akt signaling (LY294002 or A443654) reduced the expression of MT1-MMP and impaired BMSC invasion. In addition, the upregulation of Akt phosphorylation by a pharmacological activator (SC79) increased MT1-MMP expression and suppressed mechanical stretching-reduced BMSC invasion. Taken together, our results suggest that mechanical stretching inhibits BMSC invasion by downregulating MT1-MMP expression by suppressing the PI3K/Akt signaling pathway.