Generic placeholder image

Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Molecular Signaling Pathways as Potential Therapeutic Targets in Osteosarcoma

Author(s): Parisa Maleki Dana, Fatemeh Sadoughi, Zatollah Asemi* and Bahman Yousefi

Volume 29, Issue 25, 2022

Published on: 30 March, 2022

Page: [4436 - 4444] Pages: 9

DOI: 10.2174/0929867329666220209110009

Price: $65


Among primary bone malignancies, osteosarcoma (OS) is the most common form causing morbidity and mortality in both adults and children. The interesting point about this malignancy is that nearly 10-20% of its newly diagnosed cases have developed metastasis. This adds up to the fact that the survival rate of both metastatic and non-metastatic patients of osteosarcoma has not changed in the past 30 years; therefore, it has been suggested that we need to revise our therapeutic options for OS. In recent years, diverse signaling pathways have drawn the attention of the scientific community since they can be great candidates for treating complicated diseases, such as cancer. In this review, we have tried to explain the pathophysiology of osteosarcoma with the help of different signaling pathways taking part in its initiation/progression and explore how this pathway can be targeted for providing more efficient methods.

Keywords: Osteosarcoma, signaling pathway, STATs, Wnt, MAPK, Akt, PI3K/ERK, Notch.

Unni, K.K.; Dahlin, D.C. Grading of bone tumors. Semin. Diagn. Pathol., 1984, 1(3), 165-172.
[PMID: 6400634]
Evola, F.R.; Costarella, L.; Pavone, V.; Caff, G.; Cannavò, L.; Sessa, A.; Avondo, S.; Sessa, G. Biomarkers of osteosarcoma, chondrosarcoma, and ewing sarcoma. Front. Pharmacol., 2017, 8, 150.
[] [PMID: 28439237]
Harrison, D.J.; Geller, D.S.; Gill, J.D.; Lewis, V.O.; Gorlick, R. Current and future therapeutic approaches for osteosarcoma. Expert Rev. Anticancer Ther., 2018, 18(1), 39-50.
[] [PMID: 29210294]
Mirabello, L.; Troisi, R.J.; Savage, S.A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer, 2009, 115(7), 1531-1543.
[] [PMID: 19197972]
Luetke, A.; Meyers, P.A.; Lewis, I.; Juergens, H. Osteosarcoma treatment - where do we stand? A state of the art review. Cancer Treat. Rev., 2014, 40(4), 523-532.
[] [PMID: 24345772]
Moore, D.D.; Luu, H.H. Osteosarcoma. Cancer Treat. Res., 2014, 162, 65-92.
[] [PMID: 25070231]
Ottaviani, G.; Jaffe, N. The etiology of osteosarcoma. Cancer Treat. Res., 2009, 152, 15-32.
[] [PMID: 20213384]
Hameed, M.; Mandelker, D. Tumor Syndromes Predisposing to Osteosarcoma. Adv. Anat. Pathol., 2018, 25(4), 217-222.
[] [PMID: 29668499]
Ferguson, J.L.; Turner, S.P. Bone Cancer: Diagnosis and treatment principles. Am. Fam. Physician, 2018, 98(4), 205-213.
[PMID: 30215968]
Bernthal, N.M.; Federman, N.; Eilber, F.R.; Nelson, S.D.; Eckardt, J.J.; Eilber, F.C.; Tap, W.D. Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer, 2012, 118(23), 5888-5893.
[] [PMID: 22648705]
Kaste, S.C.; Pratt, C.B.; Cain, A.M.; Jones-Wallace, D.J.; Rao, B.N. Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis: imaging features. Cancer, 1999, 86(8), 1602-1608.
[<1602::AID-CNCR31>3.0.CO;2-R] [PMID: 10526292]
Meyers, P.A.; Gorlick, R. Osteosarcoma. Pediatr. Clin. North Am., 1997, 44(4), 973-989.
[] [PMID: 9286295]
Chou, A.J.; Geller, D.S.; Gorlick, R. Therapy for osteosarcoma: where do we go from here? Paediatr. Drugs, 2008, 10(5), 315-327.
[] [PMID: 18754698]
Bozorgi, A.; Sabouri, L. Osteosarcoma, personalized medicine, and tissue engineering; an overview of overlapping fields of research. Cancer Treat. Res. Commun., 2021, 27, 100324.
[] [PMID: 33517237]
Mediouni, M.; R Schlatterer, D.; Madry, H.; Cucchiarini, M.; Rai, B. A review of translational medicine. The future paradigm: how can we connect the orthopedic dots better? Curr. Med. Res. Opin., 2018, 34(7), 1217-1229.
[] [PMID: 28952378]
Aoki, M.; Fujishita, T. Oncogenic Roles of the PI3K/AKT/mTOR Axis. Curr. Top. Microbiol. Immunol., 2017, 407, 153-189.
[] [PMID: 28550454]
Alzahrani, A.S. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol., 2019, 59, 125-132.
[] [PMID: 31323288]
Zhang, Y.; Cheng, H.; Li, W.; Wu, H.; Yang, Y. Highly-expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β-catenin and mTOR/HIF1α/VEGF signaling. Int. J. Cancer, 2019, 145(4), 1068-1082.
[] [PMID: 30761524]
Li, X.; Huang, Q.; Wang, S.; Huang, Z.; Yu, F.; Lin, J. HER4 promotes the growth and metastasis of osteosarcoma via the PI3K/AKT pathway. Acta Biochim. Biophys. Sin. (Shanghai), 2020, 52(4), 345-362.
[] [PMID: 32181480]
Wang, B.; Li, J. Piceatannol suppresses the proliferation and induced apoptosis of osteosarcoma cells through PI3K/AKT/mTOR pathway. Cancer Manag. Res., 2020, 12, 2631-2640.
[] [PMID: 32368141]
Li, Z.; Dong, H.; Li, M.; Wu, Y.; Liu, Y.; Zhao, Y.; Chen, X.; Ma, M. Honokiol induces autophagy and apoptosis of osteosarcoma through PI3K/Akt/mTOR signaling pathway. Mol. Med. Rep., 2018, 17(2), 2719-2723.
[PMID: 29207060]
Liu, J.; Chen, M.; Ma, L.; Dang, X.; Du, G. LncRNA GAS5 suppresses the proliferation and invasion of osteosarcoma cells via the miR-23a-3p/PTEN/PI3K/AKT pathway. Cell Transplant., 2020, 29, 963689720953093.
[] [PMID: 33121268]
Huang, Y.; Xu, Y.Q.; Feng, S.Y.; Zhang, X.; Ni, J.D. LncRNA TDRG1 promotes proliferation, invasion and epithelial-mesenchymal transformation of osteosarcoma through PI3K/AKT signal pathway. Cancer Manag. Res., 2020, 12, 4531-4540.
[] [PMID: 32606946]
Sun, Y.; Liu, W.Z.; Liu, T.; Feng, X.; Yang, N.; Zhou, H.F. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J. Recept. Signal Transduct. Res., 2015, 35(6), 600-604.
[] [PMID: 26096166]
Gui, Z.L.; Wu, T.L.; Zhao, G.C.; Lin, Z.X.; Xu, H.G. MicroRNA-497 suppress osteosarcoma by targeting MAPK/Erk pathway. Bratisl. Lek Listy, 2017, 118(8), 449-452.
[] [PMID: 29050481]
Miao, J.H.; Wang, S.Q.; Zhang, M.H.; Yu, F.B.; Zhang, L.; Yu, Z.X.; Kuang, Y. Knockdown of galectin-1 suppresses the growth and invasion of osteosarcoma cells through inhibition of the MAPK/ERK pathway. Oncol. Rep., 2014, 32(4), 1497-1504.
[] [PMID: 25069486]
Duchartre, Y.; Kim, Y.M.; Kahn, M. The Wnt signaling pathway in cancer. Crit. Rev. Oncol. Hematol., 2016, 99, 141-149.
[] [PMID: 26775730]
Niehrs, C. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol., 2012, 13(12), 767-779.
[] [PMID: 23151663]
Teo, J.L.; Kahn, M. The Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivators. Adv. Drug Deliv. Rev., 2010, 62(12), 1149-1155.
[] [PMID: 20920541]
Nusse, R.; Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169(6), 985-999.
[] [PMID: 28575679]
Zhang, Y.; Wang, X. Targeting the Wnt/β-catenin signaling pathway in cancer. J. Hematol. Oncol., 2020, 13(1), 165.
[] [PMID: 33276800]
Nomura, M.; Rainusso, N.; Lee, Y.C.; Dawson, B.; Coarfa, C.; Han, R.; Larson, J.L.; Shuck, R.; Kurenbekova, L.; Yustein, J.T. Tegavivint and the β-Catenin/ALDH axis in chemotherapy-resistant and metastatic osteosarcoma. J. Natl. Cancer Inst., 2019, 111(11), 1216-1227.
[] [PMID: 30793158]
Zhu, S.; Liu, Y.; Wang, X.; Wang, J.; Xi, G. lncRNA SNHG10 promotes the proliferation and invasion of osteosarcoma via wnt/β-catenin signaling. Mol. Ther. Nucleic Acids, 2020, 22, 957-970.
[] [PMID: 33251045]
Xu, Y.; Yu, P.; Wang, S.; Jiang, L.; Chen, F.; Chen, W. Crosstalk between Hh and Wnt signaling promotes osteosarcoma progression. Int. J. Clin. Exp. Pathol., 2019, 12(3), 768-773.
[PMID: 31933884]
Chen, X.; Zhao, W.; Fan, W. Long non‑coding RNA GHET1 promotes osteosarcoma development and progression via Wnt/β‑catenin signaling pathway. Oncol. Rep., 2020, 44(1), 349-359.
[] [PMID: 32319657]
Yu, L.; Xia, K.; Gao, T.; Chen, J.; Zhang, Z.; Sun, X.; Simões, B.M.; Eyre, R.; Fan, Z.; Guo, W.; Clarke, R.B. The notch pathway promotes osteosarcoma progression through activation of ephrin reverse signaling. Mol. Cancer Res., 2019, 17(12), 2383-2394.
[] [PMID: 31570655]
Cao, Y.; Yu, L.; Dai, G.; Zhang, S.; Zhang, Z.; Gao, T.; Guo, W. Cinobufagin induces apoptosis of osteosarcoma cells through inactivation of Notch signaling. Eur. J. Pharmacol., 2017, 794, 77-84.
[] [PMID: 27845066]
Tanaka, M.; Setoguchi, T.; Hirotsu, M.; Gao, H.; Sasaki, H.; Matsunoshita, Y.; Komiya, S. Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br. J. Cancer, 2009, 100(12), 1957-1965.
[] [PMID: 19455146]
Engin, F.; Bertin, T.; Ma, O.; Jiang, M.M.; Wang, L.; Sutton, R.E.; Donehower, L.A.; Lee, B. Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum. Mol. Genet., 2009, 18(8), 1464-1470.
[] [PMID: 19228774]
Ferrara, N.; Adamis, A.P. Ten years of anti-vascular endothelial growth factor therapy. Nat. Rev. Drug Discov., 2016, 15(6), 385-403.
[] [PMID: 26775688]
Assi, T.; Watson, S.; Samra, B.; Rassy, E.; Le Cesne, A.; Italiano, A.; Mir, O. Targeting the VEGF Pathway in Osteosarcoma. Cells, 2021, 10(5), 1240.
[] [PMID: 34069999]
Wang, G.; Sun, M.; Jiang, Y.; Zhang, T.; Sun, W.; Wang, H.; Yin, F.; Wang, Z.; Sang, W.; Xu, J.; Mao, M.; Zuo, D.; Zhou, Z.; Wang, C.; Fu, Z.; Wang, Z.; Duan, Z.; Hua, Y.; Cai, Z. Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma. Int. J. Cancer, 2019, 145(4), 979-993.
[] [PMID: 30719715]
Liao, Y.Y.; Tsai, H.C.; Chou, P.Y.; Wang, S.W.; Chen, H.T.; Lin, Y.M.; Chiang, I.P.; Chang, T.M.; Hsu, S.K.; Chou, M.C.; Tang, C.H.; Fong, Y.C. CCL3 promotes angiogenesis by dysregulation of miR-374b/ VEGF-A axis in human osteosarcoma cells. Oncotarget, 2016, 7(4), 4310-4325.
[] [PMID: 26713602]
Liu, Y.; Liao, S.; Bennett, S.; Tang, H.; Song, D.; Wood, D.; Zhan, X.; Xu, J. STAT3 and its targeting inhibitors in osteosarcoma. Cell Prolif., 2021, 54(2), e12974.
[] [PMID: 33382511]
Oi, T.; Asanuma, K.; Matsumine, A.; Matsubara, T.; Nakamura, T.; Iino, T.; Asanuma, Y.; Goto, M.; Okuno, K.; Kakimoto, T.; Yada, Y.; Sudo, A. STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma. Int. J. Oncol., 2016, 49(6), 2275-2284.
[] [PMID: 27840900]
Zuo, D.; Shogren, K.L.; Zang, J.; Jewison, D.E.; Waletzki, B.E.; Miller, A.L., II; Okuno, S.H.; Cai, Z.; Yaszemski, M.J.; Maran, A. Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells. J. Exp. Clin. Cancer Res., 2018, 37(1), 244.
[] [PMID: 30286779]
Ryu, K.; Choy, E.; Yang, C.; Susa, M.; Hornicek, F.J.; Mankin, H.; Duan, Z. Activation of signal transducer and activator of transcription 3 (Stat3) pathway in osteosarcoma cells and overexpression of phosphorylated-Stat3 correlates with poor prognosis. J. Orthop. Res., 2010, 28(7), 971-978.
[] [PMID: 20063378]
Jiang, C.Q.; Ma, L.L.; Lv, Z.D.; Feng, F.; Chen, Z.; Liu, Z.D. Polydatin induces apoptosis and autophagy via STAT3 signaling in human osteosarcoma MG-63 cells. J. Nat. Med., 2020, 74(3), 533-544.
[] [PMID: 32222939]
Subramaniam, D.; Angulo, P.; Ponnurangam, S.; Dandawate, P.; Ramamoorthy, P.; Srinivasan, P.; Iwakuma, T.; Weir, S.J.; Chastain, K.; Anant, S. Suppressing STAT5 signaling affects osteosarcoma growth and stemness. Cell Death Dis., 2020, 11(2), 149.
[] [PMID: 32094348]
Cai, N.; Zhou, W.; Ye, L.L.; Chen, J.; Liang, Q.N.; Chang, G.; Chen, J.J. The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression. Am. J. Transl. Res., 2017, 9(8), 3853-3866.
[PMID: 28861175]
Ji, X.L.; He, M. Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma. Aging (Albany NY), 2019, 11(15), 5848-5863.
[] [PMID: 31422383]
Wang, S.; Wei, H.; Huang, Z.; Wang, X.; Shen, R.; Wu, Z.; Lin, J. Epidermal growth factor receptor promotes tumor progression and contributes to gemcitabine resistance in osteosarcoma. Acta Biochim. Biophys. Sin. (Shanghai), 2021, 53(3), 317-324.
[] [PMID: 33432347]
Dai, G.; Deng, S.; Guo, W.; Yu, L.; Yang, J.; Zhou, S.; Gao, T. Notch pathway inhibition using DAPT, a γ-secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma. Mol. Carcinog., 2019, 58(1), 3-18.
[] [PMID: 29964327]
Wang, L.; Jin, F.; Qin, A.; Hao, Y.; Dong, Y.; Ge, S.; Dai, K. Targeting Notch1 signaling pathway positively affects the sensitivity of osteosarcoma to cisplatin by regulating the expression and/or activity of Caspase family. Mol. Cancer, 2014, 13, 139.
[] [PMID: 24894297]
Zhang, H.; Yan, J.; Lang, X.; Zhuang, Y. Expression of circ_001569 is upregulated in osteosarcoma and promotes cell proliferation and cisplatin resistance by activating the Wnt/β-catenin signaling pathway. Oncol. Lett., 2018, 16(5), 5856-5862.
[] [PMID: 30344736]
Zhao, G.; Cai, C.; Yang, T.; Qiu, X.; Liao, B.; Li, W.; Ji, Z.; Zhao, J.; Zhao, H.; Guo, M.; Ma, Q.; Xiao, C.; Fan, Q.; Ma, B. MicroRNA-221 induces cell survival and cisplatin resistance through PI3K/Akt pathway in human osteosarcoma. PLoS One, 2013, 8(1), e53906.
[] [PMID: 23372675]
Liu, Y.; Zhu, S.T.; Wang, X.; Deng, J.; Li, W.H.; Zhang, P.; Liu, B.S. MiR-100 inhibits osteosarcoma cell proliferation, migration, and invasion and enhances chemosensitivity by targeting IGFIR. Technol. Cancer Res. Treat., 2016, 15(5), NP40-NP48.
[] [PMID: 26306402]
Meng, C.Y.; Zhao, Z.Q.; Bai, R.; Zhao, W.; Wang, Y.X.; Xue, H.Q.; Sun, L.; Sun, C.; Feng, W.; Guo, S.B. MicroRNA‑22 mediates the cisplatin resistance of osteosarcoma cells by inhibiting autophagy via the PI3K/Akt/mTOR pathway. Oncol. Rep., 2020, 43(4), 1169-1186.
[] [PMID: 32323781]
Shao, X.J.; Miao, M.H.; Xue, J.; Xue, J.; Ji, X.Q.; Zhu, H. The Down-Regulation of MicroRNA-497 Contributes to Cell Growth and Cisplatin Resistance Through PI3K/Akt Pathway in Osteosarcoma. Cell. Physiol. Biochem., 2015, 36(5), 2051-2062.
[] [PMID: 26202364]
Wang, K.; Zhuang, Y.; Liu, C.; Li, Y. Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling. Arch. Biochem. Biophys., 2012, 526(1), 38-43.
[] [PMID: 22820099]
Wang, Z.; Yang, L.; Xia, Y.; Guo, C.; Kong, L. Icariin enhances cytotoxicity of doxorubicin in human multidrug-resistant osteosarcoma cells by inhibition of ABCB1 and down-regulation of the PI3K/Akt pathway. Biol. Pharm. Bull., 2015, 38(2), 277-284.
[] [PMID: 25747987]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy