Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies

Abstract

Osteosarcoma (OS) is a highly prevalent bone malignancy among adolescents, accounting for 40% of all primary malignant bone tumors. Neoadjuvant chemotherapy combined with limb-preserving surgery has effectively reduced patient disability and mortality, but pulmonary metastases and OS cells' resistance to chemotherapeutic agents are pressing challenges in the clinical management of OS. There has been an urgent need to identify new biomarkers for OS to develop specific targeted therapies. Recently, the continued advancements in genomic analysis have contributed to the identification of clinically significant molecular biomarkers for diagnosing OS, acting as therapeutic targets, and predicting prognosis. Additionally, the contemporary molecular classifications have revealed that the signaling pathways, including Wnt/β-catenin, PI3K/AKT/mTOR, JAK/STAT3, Hippo, Notch, PD-1/PD-L1, MAPK, and NF-κB, have an integral role in OS onset, progression, metastasis, and treatment response. These molecular classifications and biological markers have created new avenues for more accurate OS diagnosis and relevant treatment. We herein present a review of the recent findings for the modulatory role of signaling pathways as possible biological markers and treatment targets for OS. This review also discusses current OS therapeutic approaches, including signaling pathway-based therapies developed over the past decade. Additionally, the review covers the signaling targets involved in the curative effects of traditional Chinese medicines in the context of expression regulation of relevant genes and proteins through the signaling pathways to inhibit OS cell growth. These findings are expected to provide directions for integrating genomic, molecular, and clinical profiles to enhance OS diagnosis and treatment.

Keywords: clinic treatment; osteosarcoma; signaling pathway; traditional Chinese medicine.

FIGURE 1

Main signaling pathways and fundamental factors in osteosarcoma. The major signaling of PI3K/AKT/mTOR, Wnt/β‐linked protein, JAK/STAT3, Hippo, PD‐1/PD‐L1, Notch, MAPK, and NF‐κB pathways were elucidated, as well as their regulatory roles in cellular processes.

FIGURE 2

Mechanism of the PD‐1/PD‐L1 signaling pathway in OS. The immune checkpoint proteins PD‐1 on the surface of T cells interact with the ligands PD‐L1/PD‐L2 on OS cells, IFN‐γ produced by T lymphocytes induces PD‐L1 expression in angiosarcoma, resulting in immune tolerance.

FIGURE 3

A partial herbal medicine that acts on PI3K/AKT/mTOR, JAK/ STAT3, and NF‐κB signaling pathway in osteosarcoma. Figure are made by Chemdraw. Physakengose G molecular formula is uncertain and not shown in the figure.

FIGURE 4

A partial herbal medicine that acts on Wnt/β‐catenin, MAPK signaling pathway in osteosarcoma. Figure are made by Chemdraw. Polyphyllin I and Ganoderma lucidum molecular formula is uncertain and not shown in the figure.

FIGURE 5

Overview of clinical studies on targeted therapies and immunotherapy for osteosarcoma. The representative therapeutic targets in OS and the corresponding targeted or immunotherapeutic agents that have entered clinical investigations are depicted. (A) Describe targeted therapies in osteosarcoma, (B) describe the immune checkpoint pathways linked to immunity in osteosarcoma, and (C) describe the relay immune cell therapy and tumor vaccines.