Research models and mesenchymal/epithelial plasticity of osteosarcoma

Abstract

Most osteosarcomas (OSs) develop from mesenchymal cells at the bone with abnormal growth in young patients. OS has an annual incidence of 3.4 per million people and a 60-70% 5-year surviving rate. About 20% of OS patients have metastasis at diagnosis, and only 27% of patients with metastatic OS survive longer than 5 years. Mutation of tumor suppressors RB1, TP53, REQL4 and INK4a and/or deregulation of PI3K/mTOR, TGFβ, RANKL/NF-κB and IGF pathways have been linked to OS development. However, the agents targeting these pathways have yielded disappointing clinical outcomes. Surgery and chemotherapy remain the main treatments of OS. Recurrent and metastatic OSs are commonly resistant to these therapies. Spontaneous canine models, carcinogen-induced rodent models, transgenic mouse models, human patient-derived xenograft models, and cell lines from animal and human OSs have been developed for studying the initiation, growth and progression of OS and testing candidate drugs of OS. The cell plasticity regulated by epithelial-to-mesenchymal transition transcription factors (EMT-TFs) such as TWIST1, SNAIL, SLUG, ZEB1 and ZEB2 plays an important role in maintenance of the mesenchymal status and promotion of cell invasion and metastasis of OS cells. Multiple microRNAs including miR-30/9/23b/29c/194/200, proteins including SYT-SSX1/2 fusion proteins and OVOL2, and other factors that inhibit AMF/PGI and LRP5 can suppress either the expression or activity of EMT-TFs to increase epithelial features and inhibit OS metastasis. Further understanding of the molecular mechanisms that regulate OS cell plasticity should provide potential targets and therapeutic strategies for improving OS treatment.

Keywords: EMT-TFs; EMT/MET-related process; Experimental model; Metastasis; Osteosarcoma.

Fig. 1

The types and subtypes (a) as well as the skeletal distribution (b) of osteosarcomas

Fig. 2

The different cellular features associated with the different plasticity states of osteosarcoma (OS) cells. In this model, OS cells can maintain different states of hybrid epithelial/mesenchymal phenotypes characteristic of different expression levels of epithelial and mesenchymal markers. These OS cells can undergo either more epithelial or more mesenchymal transition states, which are correlated with different cellular features associated with the aggressiveness of OS. EMT, epithelial-to-mesenchymal transition; MET, mesenchymal-to-epithelial transition; V, vimentin; E, E-cadherin; N, nucleus. +++, strong or high; ++, moderate; +, weak; −, negative

Fig. 3

The molecular regulatory mechanisms for MET in OS cells. The EMT-inducing transcription factors including SNAIL, SLUG, TWIST1 and ZEB1 are expressed in OS cells, which directly or indirectly repress the expression of epithelial genes such as E-cadherin to maintain mesenchymal cell features. MET is initiated by inhibiting EMT-TFs through activating upstream signaling pathways such as SYT-SSX1/2, OVOL2 and miRNAs or suppressing AMF/PGI or LRP5 in OS cells. Please refer to the text for related references. VDR vitamin D receptor, TIMP1 TIMP metallopeptidase inhibitor 1