Michael Fowler III

Background: Although it is a rare cancer, osteosarcoma (OS) is the most common primary malignancy of bone. These tumors are of mesenchymal origin and most often arise out of the metaphyseal growth plates of long bones and their highest incidence occurs during the pubertal growth spurt in adolescents. Advancing therapeutics is a major issue as the standard treatment protocol of surgical resection and destructive systemic chemotherapy has seen minimal changes since its establishment in the 1980’s.² The etiology and pathogenesis of osteosarcoma are not well understood.³ Canonical Wnt signaling pathways have been implicated in tumorigenicity.⁴ Recent studies have suggested downregulation of Wnt signaling molecules may mitigate aggressive proliferation of OS.^{5, 6, 7} And conversely, it has been upheld that the upregulation of canonical Wnt signaling molecules may inhibit proliferation of OS tumors.^{8, 9, 10}

 Objective: In this narrative review, we explored multiple mechanisms of modulating the canonical Wnt signaling pathway to affect tumorigenesis of OS.

Search Methods: An online search in the PubMed database was conducted from 2017-2023 using the following keywords: “Canonical Wnt signaling,” “Osteosarcoma,” “Mesenchymal stem cells,” and “cancer stem cells.”

Results:  Studies indicate that inactivating the Wntless gene, a driver of Wnt ligand expression, in mouse models decreased OS tumor size and proliferative ability. Micro-CT imaging and immunostain showed marked reduction in tumor burden of Wntless knockout groups.⁶ Mir-342-5p is shown to bind the Wnt7b gene, an important Wnt ligand, and inactivate its expression.⁷  Mir-342-5p treated models in vitro showed increased levels of apoptosis in OS cells, less migratory ability, and decreased B-catenin (the molecule by which Wnt signaling modifies gene transcription.⁷ Ptch1 is a potent Wnt inhibitor.⁸ Ptch1 deletion in murine models led to significant increase in tumor burden and average tumor volume.⁸ STEAP1 is a gene that is a known activator of Wnt signaling.⁹ Activation of STEAP1 in OS inducible mice showed large increase in tumor volume and malignant characteristics on immunostaining.⁹ DACT1 is an inhibitor of the canonical Wnt signaling pathway.¹⁰ DACT1 downregulation showed an oncogenic effect in OS cell lines in-vitro, increasing malignant phenotypes and cell viability.¹⁰

Conclusions: The canonical Wnt signaling pathway has been shown to play a powerful role in modulating OS in both in-vitro and murine models. Stimulating Wnt signaling has been shown to drive oncogenesis when targeted at multiple steps in the pathway. Conversely, inhibiting Wnt signaling has been shown to mitigate aggressive invasion and proliferative capability of OS cells. Consideration of Wnt signaling modulation could be a fruitful area for future therapeutic targets.

Works Cited:

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9. Zhang D, Han S, Pan X, et al. EFEMP1 binds to STEAP1 to promote osteosarcoma proliferation and invasion via the Wnt/β-catenin and TGF-β/Smad2/3 signal pathways. J Bone Oncol. 2022;37:100458. Published 2022 Oct 28. doi:10.1016/j.jbo.2022.100458
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