Deciphering signaling networks in osteosarcoma pathobiology

Abstract

Osteosarcoma is the most frequent type of primary bone tumors among children and adolescents. During the past years, little progress has been made regarding prognosis of osteosarcoma patients, especially for those with metastatic disease. Genomic instability and gene alterations are common, but current data do not reveal a consistent and repeatable pattern of osteosarcoma development, thus paralleling the tumor's high heterogeneity. Critical signal transduction pathways have been implicated in osteosarcoma pathobiology and are being evaluated as therapeutic targets, including receptor activator for nuclear factor-κB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction pathways. Herein, we recapitulate and discuss recent advances in the context of molecular mechanisms and signaling networks that contribute to osteosarcoma progression and metastasis, towards patient-tailored and novel-targeted treatments.

Keywords: Osteosarcoma; activator protein-1; mammalian target of rapamycin; mechanotransduction; nuclear factor-κB; signal transduction.

Figure 1

Key events during osteosarcoma development. The figure depicts normal osteogenesis from MSCs to osteocytes versus OS development accompanied by critical genomic alterations, which drive cell transformation. ATRX: transcriptional regulator ATRX; DLG2: disks large homolog 2; GRM4: glutamate receptor metabotropic 4; MSCs: mesenchymal stem cells; OS: osteosarcoma; RB1: retinoblastoma 1; RUNX2: RUNX-related transcription factor 2; SNP: single nucleotide polymorphism; TP53: tumor protein p53

Figure 2

Signal transduction pathways in osteosarcoma development. The figure illustrates the main signal transduction cascades and putative molecular crosstalk implicated in OS progression, including RANKL/RANK, MAPKs, PI3K/Akt/mTOR, cAMP/PKA, Wnt/β-catenin, Notch, mechanoresponsive pathways, which are funneled through respective transcription factor activation. AP-1: activator protein-1; CREB: cAMP response element-binding protein; CSL: CBF1/ suppressor of hairless/Lag-1; ERK1/2: extracellular signal-regulated kinase 1/2; Fzs: frizzleds; Gαs: Gs alpha subunit; HES-1: hairy/enhancer of split 1; HEY-2: hairy/enhancer-of-split related with YRPW motif protein 2; ICD: intracellular domain of Notch; IκBα: nuclear factor of κB inhibitor: alpha; IKK: IκB kinase; ILK: integrin-linked kinase; JNK: c-Jun N-terminal kinase; LRP5/6: low-density lipoprotein receptor-related protein 5/6; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor-κB; NKD2: naked cuticle homolog 2; OPG: osteoprotegerin; OS: osteosarcoma; PI3K: phosphatidylinositol 3-kinase; PKA: protein kinase A; PTEN: tumor-suppressor phosphatase and tensin homolog; PTH: parathyroid hormone; PTHR: parathyroid hormone receptor; RANK: receptor activator for nuclear factor-κB; RANKL: receptor activator of nuclear factor-κB ligand; RTKs: receptor tyrosine kinases; TRAF6: TNF receptor associated factor 6; TCF/LEF: T cell factor/lymphoid enhancer factor; WIF1: Wnt inhibitory factor 1