Perspectives on cancer stem cells in osteosarcoma

Abstract

Osteosarcoma is an aggressive pediatric tumor of growing bones that, despite surgery and chemotherapy, is prone to relapse. These mesenchymal tumors are derived from progenitor cells in the osteoblast lineage that have accumulated mutations to escape cell cycle checkpoints leading to excessive proliferation and defects in their ability to differentiate appropriately into mature bone-forming osteoblasts. Like other malignant tumors, osteosarcoma is often heterogeneous, consisting of phenotypically distinct cells with features of different stages of differentiation. The cancer stem cell hypothesis posits that tumors are maintained by stem cells and it is the incomplete eradication of a refractory population of tumor-initiating stem cells that accounts for drug resistance and tumor relapse. In this review we present our current knowledge about the biology of osteosarcoma stem cells from mouse and human tumors, highlighting new insights and unresolved issues in the identification of this elusive population. We focus on factors and pathways that are implicated in maintaining such cells, and differences from paradigms of epithelial cancers. Targeting of the cancer stem cells in osteosarcoma is a promising avenue to explore to develop new therapies for this devastating childhood cancer.

Keywords: Bone cancer; Cancer stem cell; FGF; Mesenchymal tumors; Osteosarcoma; Sox2; Tumor initiating cell; Wnt signaling.

Figure 1. Schematic of the commitment of MSCs and progression of the osteoblast lineage

Markers of osteoblast commitment and differentiation are in green = Runx2, osterix (osx), collagen1, alkaline phosphatase (ALP). Self-renewal of MSCs and osteoprogenitors (curved arrows). Sox2 decreases and Wnt signaling increases as differentiation progresses. Sox2 is expressed in MSC and immature osteoprogenitors. Osteosarcomas are thought to originate from multipotent MSCs, or progenitors in the osteoblast lineage that still retain bipotency. Osteosarcoma induction is promoted by Rb and p53 inactivation (*).

Figure 2. Opposite Wnt activity in epithelial and mesenchymal CSCs (sphere forming cells)

A. Spheres of osteosarcoma (OS-NYU1) [32] and colon cancer (HCT116) [105] cells expressing a Wnt-eGFP reporter that is also marked with RFP [106]. Wnt activity in the sphere is evident by expression of eGFP (green). dsRFP expression (red) measures transduction efficiency of the reporter. B. Composite data showing relative sphere formation in osteosarcoma and epithelial tumors (colon and prostrate) before (control) and following canonical Wnt activation (“ON”) or inhibition (“OFF”). Data for epithelial tumors have been adapted from references [98; 99; 100; 101]. Data for the osteosarcoma cell line was generated by treating the OS-NYU1 cell line with the Wnt activator (CHIR99201) and assaying sphere formation.