Yao et al. Cell Death and Disease (2018) 9:701 DOI 10.1038/s41419-018-0647-1 Cell Death & Disease REVIEW ARTICLE Open Access Hedgehog signalling in the tumourigenesis and metastasis of osteosarcoma, and its potential value in the clinical therapy of osteosarcoma Zhihong Yao1,LeiHan1, Yongbin Chen2,FeiHe3,BinSun3, Santosh kamar1, Ya Zhang1,YihaoYang1, Cao Wang1 and Zuozhang Yang1 Abstract The Hedgehog (Hh) signalling pathway is involved in cell differentiation, growth and tissue polarity. This pathway is also involved in the progression and invasion of various human cancers. Osteosarcoma, a subtype of bone cancer, is commonly seen in children and adolescents. Typically, pulmonary osteosarcoma metastases are especially difficult to control. In the present paper, we summarise recent studies on the regulation of osteosarcoma progression and metastasis by downregulating Hh signalling. We also summarise the crosstalk between the Hh pathway and other cancer-related pathways in the tumourigenesis of various cancers. We further summarise and highlight the therapeutic value of potential inhibitors of Hh signalling in the clinical therapy of human cancers. 1234567890():,; 1234567890():,; Facts Open questions ● The Hh pathway regulates the progression of ● How does the Hh pathway regulate the tumourigenic osteosarcoma. progression and invasion of human osteosarcoma? ● The Hh pathway is involved in the metastasis of ● How does the Hh pathway interact with other osteosarcoma into other organs, such as the lungs. cancer-related pathways in the progression and ● The Hh pathway crosstalks with other cancer-related metastasis of cancers? pathways in the tumourigenesis of cancers. ● Could the Hh pathway be used as a target or ● The therapeutic value of the Hh pathway in the biomarker in clinical therapy for human clinical therapy of osteosarcoma is summarised. osteosarcoma? Introduction Correspondence: Zuozhang Yang ([email protected]) Osteosarcoma, which is a malignant bone tumour with 1Department of Orthopaedics, Bone and Soft Tissue Tumors Research Center of Yunnan Province, The Third Affiliated Hospital of Kunming Medical locally aggressive growth and high metastatic potential, is University (Tumor Hospital of Yunnan Province), Kunming, Yunnan 650118, one of the most commonly observed diseases1. Distant China 2 metastases of osteosarcoma, such as lung metastases, are Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming 2 Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, hard to control and usually have a poor prognosis . The China survival rate of osteosarcoma patients has gradually Full list of author information is available at the end of the article. These authors contributed equally: Zhihong Yao, Lei Han, Yongbin Chen, Fei He. Edited by A. Oberst © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Yao et al. Cell Death and Disease (2018) 9:701 Page 2 of 12 improved3. However, ~20% of osteosarcoma patients organisms. Briefly, the core constituents of the Hh/Gli continue to present with lung metastases at diagnosis, and pathway in Drosophila are the Hh ligand; Ptc; cubitus the 5-year survival rate has not significantly increased4. interruptus (Ci); Smo; and signal transducers, such as Cos2, – An exact description of the molecular basis of the pro- Fused (Fu), or SuFu(Fig. 1)19 23. In higher organisms, the liferation and metastasis of osteosarcoma will help in the core constituents of Hh signalling are more complex, clinical treatment of osteosarcoma and improvement of comprising three Hh ligands, Sonic hedgehog (Shh), Desert patient survival. hedgehog (Dhh) and Indian hedgehog (Ihh); two twelve- Hedgehog (Hh)/Gli signalling is a conserved signal pass transmembrane receptors, Patched1 (PTCH1) and transduction pathway that possesses a key regulatory Patched2 (PTCH2); Smo; and three transcription factors, – function in physiological processes, including embryonic including GLI1, GLI2 and GLI3(Fig. 2)24 27. The three Gli development, tissue differentiation and cell growth5,6. nuclear transcription factors are highly similar in amino Recently, the Hh pathway was found to possess a key acid sequence. Usually, Gli1 is involved in transcriptional function in the progression and metastasis of various activation, while Gli2 and Gli3 can both activate and inhibit – – cancers7 10. The Hh/Gli signalling pathway mainly transcription28 30. Three homologous Hh ligands and Ptch includes the Hh ligand, its twelve-pass transmembrane can be combined and can perform different biological protein receptor Patched (Ptc), the seven-pass trans- functions during different stages of cancer progression. membrane protein Smoothened (Smo), and cytoplasmic The target genes of the Hh pathway involve different proteins involved in the Hh signalling protein complex, physiological processes, including stem cell formation and including Fused kinase, Costal-2 (Cos2), GSK3 beta, PKA, tumour cell invasion31,32 (Fig. 1). Fu suppressor protein (SuFu) and nuclear factor glioma- Briefly, in the Hh pathway, in the absence of the Hh associated oncogene transcription factors, which are key ligand, the cell surface receptor Ptc binds to Smo and downstream regulators in this signalling pathway and effectively suppresses Smo activity, inhibiting the activa- – have a pivotal role in signal transduction11 13. Target tion of Hh signalling33,34. At this point, Gli3 is phos- genes in the Hh pathway are related to cell proliferation, phorylated and hydrolysed by proteolytic enzymes, survival, cell cycle, stem cell formation, cell invasion and releasing the transcriptional repressor protein Gli3 into many other processes12 the nuclear area and ultimately inhibiting the levels of the In the present paper, we summarise the mechanism via Hh target genes35. When the Hh ligand is present, it which Hh/Gli signalling is regulated in the tumourigen- interacts with the receptor Ptch, initiating the classical Hh esis and metastasis of cancers, focusing on the impact of pathway. Hh induces the phosphorylation of multiple Ser/ these regulatory activities on the progression, invasion Thr residues at the carboxy terminus of Smo, resulting in – and metastasis of osteosarcoma. We also discuss the the release of Smo inhibition by Ptch28,36 38. Smo is interaction between the Hh/Gli pathway and other recruited and activated on the cell surface, which finally cancer-related signalling pathways during the progression activates the cytoplasmic protein complex to activate the of human cancers. At the end of this review, we highlight Hh signalling pathway39. The signal is transduced to Gli the therapeutic value of Hh pathway inhibitors in the factor, which transports the signal to the cell nucleus and clinical therapy of human cancers, describe future chal- regulates the transcription of related genes involved in key lenges and propose possible directions for the Hh/Gli cellular processes40. signalling-associated clinical treatment of osteosarcoma patients based on our current understanding. Regulation of the Hh pathway (miRNA, lncRNA, protein) Aberrant activation of the Hh pathway leads to the Introduction of Hedgehog signalling pathway tumourigenesis and metastasis of human cancers, such as Overview medulloblastoma, osteosarcoma, and gastric, lung, breast, Hh is a segmented polar gene that encodes a highly colorectal and prostate cancers (Fig. 2). The Hh pathway conserved secreted glycoprotein named for the bristly controls tumourigenesis and tumour invasiveness in var- phenotype of the mutation of the gene in Drosophila.Itwas ious cancers. An increasing number of agents effectively first identified in systematic searches for embryonic lethal regulate signal transduction in the Hh signalling pathway; mutants of Drosophila melanogaster by Nusslein-Volhard, these agents include proteins, compounds, and noncoding C. in 198014. The Hh/Gli pathway has a key regulatory RNA such as miRNA and lncRNA. Elucidation of the function in physiological processes15. The Hh pathway is molecular basis of Hh signalling is beneficial and will help an important signalling pathway in the carcinogenesis and guide the clinical treatment of human cancers and – metastasis of several types of cancer16 18.Thispathwayis screening of effective inhibitors to inhibit the inap- highly conserved and comprises some components that are propriate activation of the Hh pathway. Some of the regulated by post-translational events; however, there are important regulators in the Hh signalling pathway are some differences between Drosophila and higher summarised here and are shown in Fig. 3. Official journal of the Cell Death Differentiation Association Yao