Decoding the Impact of Tumor Microenvironment in Osteosarcoma Progression and Metastasis

SIMPLE SUMMARY: Osteosarcoma (OS) is the most common bone tumor in the pediatric population. Currently, no effective molecularly targeted therapies are available for OS. The five-year survival rate of OS has increased to about 70% since the 1970s but is only 20–30% for patients with metastasis. The management of OS is challenging and requires a multidisciplinary approach. Surgical excision and systematic multiagent therapy are standard clinical practices for OS treatment. However, there is a pressing need to identify novel therapeutic approaches and biomarkers to manage the disease better. Understanding osteosarcoma’s tumor microenvironment (TME) has recently gained much interest towards providing valuable insights into tumor heterogeneity, progression, metastasis, and the identification of novel therapeutic avenues. In this review, we discuss the current understanding of the OS TME, including different cellular and noncellular components, their crosstalk with OS tumor cells, and their involvement in tumor progression and metastasis. Discovering more specific therapeutic targets, determining interactions among cellular and noncellular components of the OS TME, and using rational combination therapies targeting tumor intrinsic and TME features will inevitably improve OS patient outcomes. ABSTRACT: Osteosarcoma (OS) is a heterogeneous, highly metastatic bone malignancy in children and adolescents. Despite advancements in multimodal treatment strategies, the prognosis for patients with metastatic or recurrent disease has not improved significantly in the last four decades. OS is a highly heterogeneous tumor; its genetic background and the mechanism of oncogenesis are not well defined. Unfortunately, no effective molecular targeted therapy is currently available for this disease. Understanding osteosarcoma’s tumor microenvironment (TME) has recently gained much interest among scientists hoping to provide valuable insights into tumor heterogeneity, progression, metastasis, and the identification of novel therapeutic avenues. Here, we review the current understanding of the TME of OS, including different cellular and noncellular components, their crosstalk with OS tumor cells, and their involvement in tumor progression and metastasis. We also highlight past/current clinical trials targeting the TME of OS for effective therapies and potential future therapeutic strategies with negligible adverse effects.