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Angiopoietin-Like 4 Promotes Osteosarcoma Cell Proliferation and Migration and Stimulates Osteoclastogenesis T

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Angiopoietin-Like 4 Promotes Osteosarcoma Cell Proliferation and Migration and Stimulates Osteoclastogenesis T Zhang et al. BMC Cancer (2018) 18:536 https://doi.org/10.1186/s12885-018-4468-5 RESEARCHARTICLE Open Access Angiopoietin-like 4 promotes osteosarcoma cell proliferation and migration and stimulates osteoclastogenesis T. Zhang1,2, A. Kastrenopoulou1, Q. Larrouture1, N. A. Athanasou1 and H. J. Knowles1* Abstract Background: Osteosarcoma is the most common primary bone cancer in children and young adults. It is highly aggressive and patients that present with metastasis have a poor prognosis. Angiopoietin-like 4 (ANGPTL4) drives the progression and metastasis of many solid tumours, but has not been described in osteosarcoma tissue. ANGPTL4 also enhances osteoclast activity, which is required for osteosarcoma growth in bone. We therefore investigated the expression and function of ANGPTL4 in human osteosarcoma tissue and cell lines. Methods: Expression of ANGPTL4 in osteosarcoma tissue microarrays was determined by immunohistochemistry. Hypoxic secretion of ANGPTL4 was tested by ELISA and Western blot. Regulation of ANGPTL4 by hypoxia-inducible factor (HIF) was investigated using isoform specific HIF siRNA (HIF-1α,HIF-2α). Effects of ANGPTL4 on cell proliferation, migration (scratch wound assay), colony formation and osteoblastogenesis were assessed using exogenous ANGPTL4 or cells stably transfected with ANGPTL4. Osteoclastogenic differentiation of CD14+ monocytes was assessed by staining for tartrate-resistant acid phosphatase (TRAP), bone resorption was assessed by lacunar resorption of dentine. Results: ANGPTL4 was immunohistochemically detectable in 76/109 cases. ANGPTL4 was induced by hypoxia in 6 osteosarcoma cell lines, under the control of the HIF-1α transcription factor. MG-63 cells transfected with an ANGPTL4 over-expression plasmid exhibited increased proliferation and migration capacity and promoted osteoclastogenesis and osteoclast-mediated bone resorption. Individually the full-length form of ANGPTL4 could increase MG-63 cell proliferation, whereas N-terminal ANGPTL4 mediated the other pro-tumourigenic phenotypes. Conclusions: This study describes a role(s) for ANGPTL4 in osteosarcoma and identifies ANGPTL4 as a treatment target that could potentially reduce tumour progression, inhibit angiogenesis, reduce bone destruction and prevent metastatic events. Keywords: Angiopoietin-like 4 (ANGPTL4), Osteosarcoma, Proliferation, Migration, Colony formation, Osteoclastogenesis, Bone resoprtion Background metastatic disease at diagnosis or with recurrent disease Osteosarcoma is the most common primary bone have a poor prognosis, with a 5 year survival rate of only tumour in children and young adults. It is a highly 30% [1]. There is therefore an urgent need for new aggressive tumour which rapidly invades and destroys targeted therapies to improve survival of patients with the surrounding bone and metastasises through the vas- metastatic or recurrent disease. culature early in the course of disease. Although survival Micro-environmental hypoxia and expression of the has improved in the past two decades for patients with HIF transcription factor are common features of osteosar- non-metastatic osteosarcoma, those with either coma which strongly correlate with disease progression, recurrence and poor survival [2–8]. Both isoforms of HIF * Correspondence: [email protected] α α 1 (HIF-1 ,HIF-2 ) promote osteosarcoma cell proliferation Botnar Research Centre, Nuffield Department of Orthopaedics – Rheumatology and Musculoskeletal Sciences, University of Oxford, and migration in vitro [9 11]. In vivo studies with micro- Headington, Oxford OX3 7LD, UK RNAs or HIF inhibiting drugs have shown that HIF Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. BMC Cancer (2018) 18:536 Page 2 of 10 inhibition reduces tumour growth [12, 13] and overcomes detected in osteosarcoma patients even after successful chemo-resistance of osteosarcoma [14]; conversely HIF- treatment [46]. 1α over-expression enhances tumourigenicity [15]. Investigating the expression and function of However current HIF inhibitors are not specific to the ANGPTL4 in osteosarcoma will provide fundamental HIF pathway. information as to its suitability as a target for the treat- ANGPTL4 is a secreted adipokine, expression of ment of osteosarcoma. This is particularly relevant as which is regulated by hypoxia and HIF-1α [16–18]. It such a treatment would potentially target the primary was originally described as a central regulator of lipid tumour, inhibit angiogenesis, reduce metastatic events metabolism and the primary physiological regulator of and prevent bone destruction. lipoprotein lipase activity [19, 20], under the control of the PPAR family of transcription factors [21–23]. It is a blood-borne hormone directly involved in regulating Methods glucose homeostasis, lipid metabolism and insulin Materials sensitivity [24, 25]. Tissue culture reagents were from Lonza (Cheltenham, There are three isoforms of ANGPTL4. Full-length UK) except FBS (Invitrogen, Paisley, UK). MCSF, full- ANGPTL4 (flANGPTL4) is the largest isoform, which length ANGPTL4, c-terminal and n-terminal ANGPTL4 can be proteolytically cleaved at an internal linker region were from R&D Systems (Abingdon, UK); RANKL was by proprotein convertases to generate N-terminal produced in-house. Unless stated, other reagents were coiled-coil domain (nANGPTL4) and C-terminal from Sigma-Aldrich (Poole, UK). fibrinogen-like domain (cANGPTL4) fragments [26]. This cleavage process is tissue dependent; the human Immunohistochemistry liver secretes cleaved ANGPTL4, whereas adipocytes Osteosarcoma tissue microarrays were prepared in-house. secrete the full-length form [21, 27]. The three forms of All samples were collected with donor-informed consent. ANGPTL4 exert distinct physiological functions, regula- This project was approved by the Oxford Clinical tion of lipid metabolism being the primary function of Research Ethics Committee (C01.070). Antigen retrieval nANGPTL4 (20, 22). of de-waxed and rehydrated paraffin-embedded samples ANGPTL4 expression is elevated in many epithelial was performed in boiling 1 mM EDTA (pH 8). Slides were – tumours [28 30] where it is associated with metastasis incubated in anti-ANGPTL4 (H200; Santa Cruz Biotech- – and reduced survival [31 35]. Most experimental litera- nology, Heidelberg, Germany) or a PBS control for 1 h. ture also describes ANGPTL4 as pro-tumourigenic. Immunostaining was performed using the VECTASTAIN ANGPTL4 stimulates tumour cell proliferation [36], Elite Universal ABC Kit and DAB (Vector Laboratories). supports anchorage-independent growth and confers Digital images of slides were obtained using an Olympus anoikis resistance [29, 37], so promoting in vivo tumour- BX40 microscope. Database searching of the R2: Genom- igenesis [29, 36]. ANGPTL4 is also pro-angiogenic and ics Analysis and Visualization Platform (http://r2.amc.nl) is thought to facilitate metastasis by enhancing endothe- was performed using the programme available on the lial permeability [18, 28, 30, 38, 39]. ANGPTL4 expres- website. sion has not been described in osteosarcoma tissue, although as a HIF target gene it is likely that ANGPTL4 is over-expressed in osteosarcoma and may correlate Osteosarcoma cell culture with features of tumourigenesis or metastasis. Osteosarcoma cell lines MG63, MHM, HOS-143B, IOR- ANGPTL4 also stimulates osteoclast activity to in- OS18, HOS, ZK-58 and OSA were obtained from the crease the rate of bone resorption [16, 40]. Osteoclasts EuroBoNeT cell line biobank (http://eurobonet.pathobi- are multi-nucleated cells specialised to perform lacunar ology.eu/cd/index.php), comprising fully characterised resorption of bone, over-activation of which results in bone tumour cell lines [47], and maintained in RPMI osteolytic disease. Osteoclasts are often observed within 1640 medium supplemented with 10% FBS, L-glutamine the primary tumour in osteosarcoma [41, 42], within (2 mM), penicillin (50 IU/ml) and streptomycin sulphate which increased expression of osteoclast activity genes (50 μg/ml). No ethical approval was required for their positively associates with tumour aggressiveness and use. For establishment of ANGPTL4 stable transfectants, metastatic disease [42, 43]. Tumour-induced osteolysis, osteosarcoma cell lines were transfected with an mediated by osteoclasts, is a characteristic feature of ANGPTL4 ORF expression clone (W0165-M02; osteosarcoma and use of osteoclast-targeted agents is a GeneCopoeia) or the corresponding empty vector therapeutic strategy for treatment of the disease [44, 45]. control (EV). Following clonal selection, transfected cell Increased osteoclast activity might also mediate the lines were maintained in RPMI 1640 additionally supple- reduced bone mineral density and osteoporosis often mented with G418 (0.1 mg/ml). Zhang et al. BMC Cancer (2018) 18:536 Page 3 of 10 HIF small interfering RNA (siRNA) changing the medium
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