Research progress in the mechanism and treatment of osteosarcoma

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.

Figure 1

Wnt/β-catenin signaling pathway and OS. Wnt ligands bind to the Frizzled and low density LRP5/6. Thereafter, this signal activates the protein dishevelled (Dsh) in the cytoplasm. Dsh can reduce the degradation of β-catenin by inhibiting the activity of GSK-3β kinase. Accumulation of higher amounts of β-catenin induces its translocation from the cell membrane to the nucleus, where it acts as a transcriptional co-activator of transcription factors to participate in the TCF/LEF family. C-myc: Cellular-myelocytomatosis viral oncogene; CCND1:CyclinD1; Dsh: Dishevelled; GSK-3β: Glycogen synthase kinase-3 beta; LRP5/6: Lipoprotein receptor-related protein5 and 6; MMP-2: Matrix Metallo-peptidase 2; OS: Osteosarcoma; TCF: T-cell factor; LEF: Lymphoid enhancer-binding factor; Wnt: Wingless/Integrated.

Figure 2

PI3K/AKT signaling pathway and OS. After the ligand binds to the receptor, PI3K binds to PIP2 on the inner membrane inducing phosphorylation of PIP2 to PIP3. Thereafter, PIP3 activates AKT through PDK1. AKT can activate the proteins mTOR and NK-κB or inhibit GSK-3β and FOXO1, and then activate the expression of downstream target genes. AKT: Protein Kinase B; Bcl-2:B-cell lymphoma-2; C-myc:Cellular-myelocytomatosis viral oncogene; CCND1: CyclinD1; FOXO1: Forkhead box O1; GSK-3β: Glycogen synthase kinase-3β; NK-κB: Nuclear factor-κB; MMP-2: Marix Metallo-peptidase 2; mTOR: Mammalian target of rapamycin; OS: Osteosarcoma; PDK1: Pyruvate dehydrogenase kinase, isozyme1; PI3K/AKT: Phosphatidylinositol 3 kinase/protein kinase B; PIP2: Phosphatidylinosital biphosphate; PIP3: Phosphatidylinositol triphosphate; RTK: Receptor tyrosine kinase.

Figure 3

Hedgehog signaling pathway and OS. The HH ligand binds to the Ptch1 receptor. SMO attenuates and inhibits the proteolysis of GLI proteins. Thereafter, the active GLI protein translocates to the nucleus and activates the downstream transcription factors. GLI: Glioma-associated oncogene homolog; GSK-3β: Glycogen synthase kinase-3β; HH: Hedgehog; OS: Osteosarcoma; PTCH1: Patched homolog 1; PKA: Protein Kinase A; SUFU: Suppressor of fused homolog; SMO: Smoothened.

Figure 4

Notch signaling pathway and OS. After ligand binding to the receptor, the complex is cleaved by ADAM and γ-secretase yielding the NICD, and NICD is translocated into the nucleus. It binds to the transcription factor cbf-1, CSL and transcriptional coactivator of the MAML. This complex activates transcription of the target gene. ADAM: A cellular disintegrin and metalloproteinase; CCND1: CyclinD1; C-myc: Cellular-myelocytomatosis viral oncogene; CSL: Suppressor of hairless and lag; Hey-1: Hes Related Family BHLH Transcription Factor With YRPW Motif 1; Hes-1:Hes family bHLH transcription factor 1; MAML: Mastermind-like family members; NICD: Notch intracellular domain; Notch1: Notch homolog 1; OS: Osteosarcoma.

Figure 5

MAPK/ERK signaling pathway and OS. After acting on and RAS, A-RAF, B-RAF, and C-RAF are activated and phosphorylate its dual-specific protein kinase substrates MEK1 and MEK2. Thereafter, MEK1/2 phosphorylates its substrate ERK1/2. The MAPK/ERK signaling pathway interacts with PI3K/AKT, and its targets include PI3K, GSK-3β, and RAS. AKT: Protein Kinase B; A-RAF: A-cellular rapidly accelerated fibrosarcoma; C-RAF: C-rapidly accelerated fibrosarcoma; ERK1/2: Extracellular regulated protein kinases1/2; GSK-3β: Glycogen synthase kinase-3β; MEK1: Mitogen activated kinase kinase 1; MAPK/ERK: Mitogen-activated protein kinase/extracellular regulated protein kinase; MAPKK: Mitogen-activated protein kinase kinase; MAPKKK: Mitogen-activated protein kinase kinase kinase; mTOR: Mammalian target of rapamycin; OS: Osteosarcoma; PI3K: Phosphoinositide 3-Kinase; RSK: Ribosomal S6 Kinase; RAS: Rapidly accelerated sarcoma.

Figure 6

Major OS-related signaling pathway. Mediation of genes, inhibitor of target genes, natural compounds, IncRNA and microRNA can participate in the regulation of OS-related signaling pathways including Wnt/β-catenin, PI3K/AKT, HH, Notch and MAPK/ERK signaling pathways, thereby inhibiting the malignant behavior of OS. HH: Hedgehog; LncRNA: Long non-coding RNA; MAPK/ERK: Mitogen-activated protein kinase/extracellular regulated protein kinase; OS:Osteosarcoma; PI3K/AKT: Phosphatidylinositol 3 kinase/protein kinase B.