Role of autophagy in osteosarcoma

Abstract

Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. It is a highly aggressive tumor with a tendency to spread to the lungs, which are the most common site of metastasis. Advanced osteosarcoma patients with metastasis share a poor prognosis. Despite the use of chemotherapy to treat OS, the 5-year overall survival rate for patients has remained unchanged at 65-70% for the past 20 years. In addition, the 5-year survival of patients with a metastatic disease is around 20%, highlighting the need for novel therapeutic targets. Autophagy is an intracellular degradation process which eliminates and recycles damaged proteins and organelles to improve cell lifespan. In the context of cancer, numerous studies have demonstrated that autophagy is used by tumor cells to repress initial steps of carcinogenesis and/or support the survival and growth of established tumors. In osteosarcoma, autophagy appears to be deregulated and could also act both as a pro or anti-tumoral process. In this manuscript, we aim to review these major findings regarding the role of autophagy in osteosarcoma.

Keywords: Autophagy; Cell death; Osteosarcoma; Survival.

Fig. 1

Autophagy mechanism. The autophagy mechanism and the different molecular complexes involved in the process are presented. In response to different stimuli such as mTORC1 inactivation, autophagy is initiated through the action of the ULK1 complex and the class III PI3K complex. A phagophore is generated in the cytosol to isolate damaged organelles, aggregates and proteins. The ATG12 conjugation system and the LC3 conjugation system are then involved in the elongation and closure of the phagophore, leading to autophagosome formation. Finally, the autophagosome fuses with lysosomes to degrade the material which will then be recycled.

Fig. 2

Autophagy role in cancer. In early stages of tumor development, autophagy can exert tumor suppressive functions by DNA damage limitation through reactive oxygen species (ROS) elimination, inflammation limitation and cell death induction. In established tumors, autophagy can support tumor growth through various mechanisms such as nutrient generation, microenvironment modification, drug resistance, CSC maintenance promotion and immune response inhibition.

Fig. 3

Potential autophagy deregulation in osteosarcoma. Effect on autophagy of tumor suppressors frequently inactivated and oncogenes frequently activated in osteosarcoma. Green arrow: autophagy stimulation; Orange arrow: dual effect on autophagy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)