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

Abstract

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.

Keywords: cancer stem cell; cell plastic; osteosarcoma; tumor microenvironment.

Figure 1

Role of microenvironment signaling in regulating OSC and non-OSC reversion. Complex pathways are necessary for the maintenance of the homeostasis of the OSC population. All microenvironment components, including cells (mesenchymal cells and immune cells) and non-cellular factors (hypoxia, cytokines and mechanical EVs), can influence the dynamic transition between OSCs and non-OSCs. OSCs, osteosarcoma stem cells; miR, microRNA; HIF, hypoxia-inducible factor; EVs, extracellular vesicles; EMT, epithelial-mesenchymal transition; BMP, bone morphogenetic protein; TNF, tumor necrosis factor; TGF, transforming growth factor; TRA2B, transformer 2β homolog.

Figure 2

Key non-coding RNAs in non-OSC and OSC interconversion signaling. A series of studies have reported that a number of non-coding RNAs, including microRNAs, lncRNAs and circRNAs, can participate in the OSC interconversion mechanism. OSC, osteosarcoma stem cell; lncRNA, long non-coding RNA; circRNA, circular RNA; AS1, antisense 1; B4GALT1, β-1,4-galactosyltransferase 1; DANCR, differentiation antagonizing non-protein coding RNA; LINK-A, long intergenic non-coding RNA for kinase activation; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; Sex-determining region Y-box 2 overlapping transcript; THOR, testis-associated oncogenic lncRNA; NIRP1, Nuclear receptor interacting protein 1; PIP5K1A, Phosphatidylinositol-4-Phosphate 5-Kinase Type 1^α; let, lethal; FER1L4, fer-1 family member 4; HIF2PUT, hypoxia-inducible factor-2α promoter upstream transcript.