Christopher Bui

 Background: Osteosarcoma is a common type of cancer that is most prevalent in the bones of children and adolescents.¹ The mechanism of the disease is associated with multiple cellular signaling pathways, with many mechanisms that can adapt to current treatment options.¹ Despite the great strides made in chemotherapy development, 5-year survival rates still remain around 50-60%.² Approximately 30% of patients progressing to metastasis or return of the cancer despite surgical intervention and chemotherapy.² Current research has aimed to examine cancer-associated fibroblast (CAF) related mechanisms as a possible avenue for treatment. These CAFs are normal fibroblasts that have been reprogrammed by the tumor microenvironment.³ These CAFs have been found to promote pro-tumorigenic functions that aid in the growth and metastasis of osteosarcoma via various mechanisms.³

Objective: This narrative review examined five CAF mechanisms that can be possible therapeutic targets to prevent or treat metastases of osteosarcoma.

 Search Methods: An online search in the PubMed database was conducted from 2018 to 2026 using the keywords: “bone disease”, “osterosarcoma”, “cancer-associated fibroblast.”

 Results: One study demonstrated how the activation of the CD-36-PPARG-FABQ-ANGPTL4 via CAFs leads to T-cell exhaustion, ultimately leaving the immune system vulnerable.⁴ Furthermore, this study found that combining vitamin E with anti-PD-1 therapy was able to act on this pathway and lessen tumor size.⁴ Another study examined the miR-214-3p-GPX4 pathway and found that activation of this pathway led to shielding of tumor cells from ferroptotic cell death.⁵ This ultimately led to osteosarcoma resistance to conventional cisplatin treatment, thus allowing osteosarcoma metastasis.⁵ The next study looked at the PSAT1/mTOR pathway and found that activation of this pathway enabled the epithelial-mesenchymal transition of cells.⁶ This allowed the osteosarcoma cells to easily migrate and invade various parts of the body.⁶ This study identified rapamycin as a possible therapeutic agent that could reverse this metastatic behavior of this pathway, thus decreasing mortality.⁶ The fourth study looked at a mechanism involving the exosome-mediated fibroblast education of lung cells.⁷ Exosomes released by osteosarcoma cells were found to be able to educate normal lung fibroblasts and reprogram them to a CAF phenotype.⁷ Following this reprogramming, the metastatic potential of the osteosarcoma increased greatly which in turn leads to poorer patient outcomes.⁷ The final study described how the lncRNA SNHG17 pathway leads to MMP2 overexpression.⁸ This overexpression of MMP2 allows for increased osteosarcoma cell proliferation, migration, and metastatic potential.⁸

Conclusions: The five CAF-mediated mechanisms collectively demonstrate the importance of understanding the role of CAFs in osteosarcoma metastases. By targeting the miR-214-3p-GPX4 axis, PSAT1/mTOR, exosome-mediated fibroblast education, lncRNA SNHG17, and the CD-36-PPARG-FAB4-ANGPTL4 pathways we can possibly find better treatment options that treat and prevent osteosarcoma metastasis. Future research should not only aim to understand these mechanisms but also find therapeutic agents that act on these pathways.

 Works Cited:

1. Bayraktar Ekmekcigil O, Eroglu S, Bharadwaj S, Farooqi AA, Gozuacik D, Kutlu O. Targeting the Autophagy-Apoptosis Axis in Osteosarcoma: Therapeutic Potential of Biocompounds: A Review. Chem Biol Drug Des. 2026;107(2):e70257. doi:10.1111/cbdd.70257
2. Zhang Y, Wu J, Liu J. LncSNHGs: new targets in osteosarcoma. Cancer Gene Ther. 2025;32(10):1031-1041. doi:10.1038/s41417-025-00952-2
3. Sahai E, Astsaturov I, Cukierman E, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174-186. doi:10.1038/s41568-019-0238-1
4. Zeng A, Chen H, Luo T, et al. Targeting OxLDL-mediated CD36 + CAF reprogramming potentiates PD-1 immunotherapy in osteosarcoma. Mol Cancer. 2025;25(1):14. Published 2025 Dec 18. doi:10.1186/s12943-025-02516-2
5. Tian W, Chen K, Deng L, et al. Cancer associated fibroblast exosomal miR-214-3p regulated by hnRNPA2B1 promotes cisplatin resistance by inhibiting ferroptosis. Int J Surg. Published online December 16, 2025. doi:10.1097/JS9.0000000000003946
6. Feng L, Xiao G, Chen Y, et al. Cancer-associated Fibroblast-like Cells Promote Osteosarcoma Metastasis by Upregulation of Phosphoserine Aminotransferase 1 and Activation of the mTOR/S6K Pathway. Int J Biol Sci. 2025;21(9):4153-4171. Published 2025 Jun 20. doi:10.7150/ijbs.109169
7. Palmer EP, Cronise KE, Haines LA, et al. Osteosarcoma Exosome Priming of Primary Human Lung Fibroblasts Induces an Immune Modulatory and Protumorigenic Phenotype. Cancer Res Commun. 2025;5(4):594-608. doi:10.1158/2767-9764.CRC-24-0371
8. Zhao A, Zhao Z, Liu W, et al. Carcinoma-associated fibroblasts promote the proliferation and metastasis of osteosarcoma by transferring exosomal LncRNA SNHG17. Am J Transl Res. 2021;13(9):10094-10111. Published 2021 Sep 15.