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Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin-1

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Summary

The availability of effective medication for the treatment of refractory or recurrent neuroblastoma remains limited. This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab-paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained positive for DCN, SPARC and stabilin-1 respectively and correlated to age, stage and N-MYC status in 96 children and adolescents with neuroblastoma. Transfected neuroblastoma cells stably expressed DCN, with in vivo and in vitro studies demonstrating rAAV-DCN sensitized the anticancer effect of nab-paclitaxel. Systemic rAAV-DCN in neuroblastoma-grafted nude mice inhibited stabilin-1, up-regulated SPARC, and increased the intratumoral uptake of paclitaxel. Macrophage depletion or anti-stabilin-1 monoclonal antibody increased the intratumoral uptake of nab-paclitaxel and its anticancer effects to a degree comparable to that achieved by systemic rAAV-DCN. The systemic administration of rAAV-DCN up-regulates DCN in neuroblastoma and accelerates the intratumoral uptake of nab-paclitaxel by inhibiting stabilin-1 mediated SPARC degradation.

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References

  1. Cheung NK, Cheung IY, Kushner BH, Ostrovnaya I, Chamberlain E, Kramer K, Modak S (2012) Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol 30(26):3264–3270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, Haas-Kogan DA, Laquaglia MP, Yu AL, Diller L, Buxton A, Park JR, Cohn SL, Maris JM, Reynolds CP, Villablanca JG (2013) Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14(10):999–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yoo SY, Kim JS, Sung KW, Jeon TY, Choi JY, Moon SH, Son MH, Lee SH, Yoo KH, Koo HH (2013) The degree of tumor volume reduction during the early phase of induction chemotherapy is an independent prognostic factor in patients with high-risk neuroblastoma. Cancer 119(3):656–664

    Article  PubMed  Google Scholar 

  4. Saulnier Sholler GL, Bond JP, Bergendahl G, Dutta A, Dragon J, Neville K, Ferguson W, Roberts W, Eslin D, Kraveka J, Kaplan J, Mitchell D, Parikh N, Merchant M, Ashikaga T, Hanna G, Lescault PJ, Siniard A, Corneveaux J, Huentelman M, Trent J (2015) Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma. Cancer Med 4(6):871–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kretschmar CS, Kletzel M, Murray K, Thorner P, Joshi V, Marcus R, Smith EI, London WB, Castleberry R (2004) Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: a pediatric oncology group study. J Clin Oncol 22(20):4119–4126

    Article  CAS  PubMed  Google Scholar 

  6. Zhen Z, Sun X, He Y, Cai Y, Wang J, Guan Z (2011) The sequence of drug administration influences the antitumor effects of bevacizumab and cyclophosphamide in a neuroblastoma model. Med Oncol 28(Suppl 1):S619–S625

    Article  PubMed  Google Scholar 

  7. Desai NP, Trieu V, Hwang LY, Wu R, Soon-Shiong P, Gradishar WJ (2008) Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status. Anti-Cancer Drugs 19(9):899–909

    Article  CAS  PubMed  Google Scholar 

  8. Zhang L, Marrano P, Kumar S, Leadley M, Elias E, Thorner P, Baruchel S (2013) Nab-paclitaxel is an active drug in preclinical model of pediatric solid tumors. Clin Cancer Res 19(21):5972–5983

    Article  CAS  PubMed  Google Scholar 

  9. Houghton PJ, Kurmasheva RT, Kolb EA, Gorlick R, Maris JM, Wu J, Tong Z, Arnold MA, Chatterjee M, Williams TM, Smith MA (2015) Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(®)) by the pediatric preclinical testing program (PPTP). Pediatr Blood Cancer 62(7):1214–1221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim H, Samuel S, Lopez-Casas P, Grizzle W, Hidalgo M, Kovar J, Oelschlager D, Zinn K, Warram J, Buchsbaum D (2016) SPARC-independent delivery of nab-paclitaxel without depleting tumor stroma in patient-derived pancreatic cancer xenografts. Mol Cancer Ther 15(4):680–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chlenski A, Cohn SL (2010) Modulation of matrix remodeling by SPARC in neoplastic progression. Semin Cell Dev Biol 21(1):55–65

    Article  CAS  PubMed  Google Scholar 

  12. Cheetham S, Tang MJ, Mesak F, Kennecke H, Owen D, Tai IT (2008) SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-2'deoxycytidine to increase SPARC expression and improve therapy response. Br J Cancer 98(11):1810–1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang E, Kang HJ, Koh KH, Rhee H, Kim NK, Kim H (2007) Frequent inactivation of SPARC by promoter hypermethylation in colon cancers. Int J Cancer 121(3):567–575

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki M, Hao C, Takahashi T, Shigematsu H, Shivapurkar N, Sathyanarayana UG, Iizasa T, Fujisawa T, Hiroshima K, Gazdar AF (2005) Aberrant methylation of SPARC in human lung cancers. Br J Cancer 92(5):942–948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tai IT, Tang MJ (2008) SPARC in cancer biology: its role in cancer progression and potential for therapy. Drug Resist Updat 11(6):231–246

    Article  CAS  PubMed  Google Scholar 

  16. Chlenski A, Liu S, Crawford SE, Volpert OV, DeVries GH, Evangelista A, Yang Q, Salwen HR, Farrer R, Bray J, Cohn SL (2002) SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. Cancer Res 62(24):7357–7363

    CAS  PubMed  Google Scholar 

  17. Zafiropoulos A, Tzanakakis GN (2008) Decorin-mediated effects in cancer cell biology. Connect Tissue Res 49(3):244–248

    Article  CAS  PubMed  Google Scholar 

  18. Shi YF, Zhang Q, Cheung PY, Shi L, Fong CC, Zhang Y, Tzang CH, Chan BP, Fong WF, Chun J, Kung HF, Yang M (2006) Effects of rhDecorin on TGF-beta1 induced human hepatic stellate cells LX-2 activation. Biochim Biophys Acta 1760(11):1587–1595

    Article  CAS  PubMed  Google Scholar 

  19. Bozoky B, Savchenko A, Guven H, Ponten F, Klein G, Szekely L (2014) Decreased decorin expression in the tumor microenvironment. Cancer Med 3(3):485–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Reed CC, Waterhouse A, Kirby S, Kay P, Owens RT, McQuillan DJ, Iozzo RV (2005) Decorin prevents metastatic spreading of breast cancer. Oncogene 24(6):1104–1110

    Article  CAS  PubMed  Google Scholar 

  21. Henke A, Grace OC, Ashley GR, Stewart GD, Riddick AC, Yeun H, O'Donnell M, Anderson RA, Thomson AA (2012) Stromal expression of decorin, Semaphorin6D, SPARC, Sprouty1 and Tsukushi in developing prostate and decreased levels of decorin in prostate cancer. PLoS One 7(8):e42516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Arnold SA, Rivera LB, Miller AF, Carbon JG, Dineen SP, Xie Y, Castrillon DH, Sage EH, Puolakkainen P, Bradshaw AD, Brekken RA (2010) Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech 3(1–2):57–72

    Article  CAS  PubMed  Google Scholar 

  23. Kzhyshkowska J, Workman G, Cardó-Vila M, Arap W, Pasqualini R, Gratchev A, Krusell L, Goerdt S, Sage EH (2006) Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J Immunol 176(10):5825–5832

    Article  CAS  PubMed  Google Scholar 

  24. David C, Nance JP, Hubbard J, Hsu M, Binder D, Wilson EH (2012) Stabilin-1 expression in tumor associated macrophages. Brain Res 1481C:71–78

    Article  PubMed Central  Google Scholar 

  25. Williams KJ, Qiu G, Usui HK, Dunn SR, McCue P, Bottinger E, Iozzo RV, Sharma K (2007) Decorin deficiency enhances progressive nephropathy in diabetic mice. Am J Pathol 171(5):1441–1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. World Medical Association (2013) World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310(20):2191–2194

    Article  Google Scholar 

  27. Zhen Z, Guo X, Liao R, Yang K, Ye L, You Z (2016) Involvement of IL-10 and TGF-β in HLA-E-mediated neuroblastoma migration and invasion. Oncotarget 7(28):44340–44349

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ratajczak-Wielgomas K, Gosk J, Rabczyński J, Augoff K, Podhorska-Okołów M, Gamian A, Rutowski R (2012) Expression of MMP-2, TIMP-2, TGF-β1, and decorin in Dupuytren's contracture. Connect Tissue Res 53(6):469–477

    Article  CAS  PubMed  Google Scholar 

  29. Chaudhary K, Moore H, Tandon A, Gupta S, Khanna R, Mohan RR (2014) Nanotechnology and adeno-associated virus-based decorin gene therapy ameliorates peritoneal fibrosis. Am J Physiol Ren Physiol 307(7):F777–F782

    Article  CAS  Google Scholar 

  30. Sun JY, Sun Y, Wu HJ, Zhang HX, Zhao ZH, Chen Q, Zhang ZG (2012) Transgene therapy for rat anti-Thy1.1 glomerulonephritis via mesangial cell vector with a polyethylenimine/decorin nanocomplex. Nanoscale res Lett 7 (1): 451.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shi X, Liang W, Yang W, Xia R, Song Y (2015) Decorin is responsible for progression of non-small-cell lung cancer by promoting cell proliferation and metastasis. Tumour Biol 36(5):3345–3354

    Article  CAS  PubMed  Google Scholar 

  32. Gao M, Xu Y, Qiu L (2015) Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes. Int J Nanomedicine 10:6615–6632

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Stolzenburg N, Breinl J, Bienek S, Jaguszewski M, Löchel M, Taupitz M, Speck U, Wagner S, Schnorr J (2016) Paclitaxel-coated balloons: investigation of drug transfer in healthy and atherosclerotic arteries - first experimental results in rabbits at low inflation pressure. Cardiovasc Drugs Ther 30(3):263–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Martín-Fernández B, Rubio-Navarro A, Cortegano I, Ballesteros S, Alía M, Cannata-Ortiz P, Olivares-Álvaro E, Egido J, de Andrés B, Gaspar ML, de Las HN, Lahera V, Moreno JA (2016) Aldosterone induces renal fibrosis and inflammatory M1-macrophage subtype via mineralocorticoid receptor in rats. PLoS One 11(1):e0145946

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ma HI, Hueng DY, Shui HA, Han JM, Wang CH, Lai YH, Cheng SY, Xiao X, Chen MT, Yang YP (2014) Intratumoral decorin gene delivery by AAV vector inhibits brain glioblastomas and prolongs survival of animals by inducing cell differentiation. Int J Mol Sci 15(3):4393–4414

    Article  PubMed  PubMed Central  Google Scholar 

  36. Xu W, Neill T, Yang Y, Hu Z, Cleveland E, Wu Y, Hutten R, Xiao X, Stock SR, Shevrin D, Kaul K, Brendler C, Iozzo RV, Seth P (2015) The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. Gene Ther 22(3):31–40

    Article  Google Scholar 

  37. Biaoxue R, Xiguang C, Hua L, Hui M, Shuanying Y, Wei Z, Wenli S, Jie D (2011) Decreased expression of decorin and p57(KIP2) correlates with poor survival and lymphatic metastasis in lung cancer patients. Int J Biol Markers 26(1):9–21

    Article  PubMed  Google Scholar 

  38. Clément N, Grieger JC (2016) Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Mol Ther Methods Clin Dev 3:16002

    Article  PubMed  PubMed Central  Google Scholar 

  39. Rey-Rico A, Cucchiarini M (2016) Controlled release strategies for rAAV-mediated gene delivery. Acta Biomater 29:1–10

    Article  CAS  PubMed  Google Scholar 

  40. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G, German Breast Group (GBG), Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators (2016) Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol 17(3):345–356

    Article  CAS  PubMed  Google Scholar 

  41. Lindner JL, Loibl S, Denkert C, Ataseven B, Fasching PA, Pfitzner BM, Gerber B, Gade S, Darb-Esfahani S, Sinn BV, Huober J, Engels K, Tesch H, Karn T, Pommerenke F, Liedtke C, Untch M, Müller V, Rack B, Schem C, von Minckwitz G (2015) Expression of secreted protein acidic and rich in cysteine (SPARC) in breast cancer and response to neoadjuvant chemotherapy. Ann Oncol 26(1):95–100

    Article  CAS  PubMed  Google Scholar 

  42. Chlenski A, Guerrero LJ, Peddinti R, Spitz JA, Leonhardt PT, Yang Q, Tian Y, Salwen HR, Cohn SL (2010) Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors. Mol Cancer 9:138–147

    Article  PubMed  PubMed Central  Google Scholar 

  43. Hashimoto O, Yoshida M, Koma YI, Yanai T, Hasegawa D, Kosaka Y, Nishimura N, Yokozaki H.J (2016) Collaboration of cancer-associated fibroblasts and tumour-associated macrophages for neuroblastoma development. J Pathol 240 (2): 211–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Workman G, Sage EH (2011) Identification of a sequence in the matricellular protein SPARC that interacts with the scavenger receptor stabilin-1. J Cell Biochem 112(4):1003–1008

    Article  CAS  PubMed  Google Scholar 

  45. Liu S, Tian Y, Chlenski A, Yang Q, Salwen HR, Cohn SL (2005) 'Cross-talk' between Schwannian stroma and neuroblasts promotes neuroblastoma tumor differentiation and inhibits angiogenesis. Cancer Lett 228(1–2):125–1231

    Article  CAS  PubMed  Google Scholar 

  46. Streck CJ, Zhang Y, Zhou J, Ng C, Nathwani AC, Davidoff AM (2005) Adeno-associated virus vector-mediated delivery of pigment epithelium-derived factor restricts neuroblastoma angiogenesis and growth. J Pediatr Surg 40(1):236–243

    Article  PubMed  Google Scholar 

  47. Xu T, Xiao X, Zheng S, Zheng J, Zhu H, Ji Y, Yang S (2013) Antiangiogenic effect of propranolol on the growth of the neuroblastoma xenografts in nude mice. J Pediatr Surg 48(12):2460–2465

    Article  PubMed  Google Scholar 

  48. Köninger J, Giese NA, Bartel M, di Mola FF, Berberat PO, di Sebastiano P, Giese T, Büchler MW, Friess H (2006) The ECM proteoglycan decorin links desmoplasia and inflammation in chronic pancreatitis. J Clin Pathol 59(1):21–27

    Article  PubMed  PubMed Central  Google Scholar 

  49. Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhão JG, Lemarchand P, Pfeilschifter J, Schaefer RM, Iozzo RV, Schaefer L (2011) Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21. Sci signal 4 (199): ra75.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Han MW, Lee JC, Park SY, Kim YM, Cho KJ, Kim SW, Lee M, Nam SY, Kim IS, Kim SY (2016) Homotypic interaction of Stabilin-2 plays a critical role in lymph node metastasis of tongue cancer. Anticancer Res 36(12):6611–6618

    Article  CAS  PubMed  Google Scholar 

  51. Géraud C, Mogler C, Runge A, Evdokimov K, Lu S, Schledzewski K, Arnold B, Hämmerling G, Koch PS, Breuhahn K, Longerich T, Marx A, Weiss C, Damm F, Schmieder A, Schirmacher P, Augustin HG, Goerdt S (2013) Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival. Liver Int 33(9):1428–1440

    Article  PubMed  Google Scholar 

  52. Boström MM, Irjala H, Mirtti T, Taimen P, Kauko T, Ålgars A, Jalkanen S, Boström PJ (2015) Tumor-associated macrophages provide significant prognostic information in urothelial bladder cancer. PLoS One 10(7):e0133552

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank all the patients who participated in this study and their families, as well as staff at all investigational sites. The authors would also like to thank Dr. Youjian He participated in study design, data analysis and data interpretation of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangzhou, China

    Zijun Zhen

  2. Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China

    Zijun Zhen, Kaibin Yang, Litong Ye, Zhiyao You, Rirong Chen & Ying Liu

  3. Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

    Zijun Zhen

  4. Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, China

    Kaibin Yang, Litong Ye, Zhiyao You, Rirong Chen & Ying Liu

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  1. Zijun Zhen
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Correspondence to Zijun Zhen.

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This study was supported by a grant from the Science and Technology Planning Project of Guangdong Province, China (2012B031800460 and 2013B021800069). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Zhen, Z., Yang, K., Ye, L. et al. Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin-1. Invest New Drugs 35, 566–575 (2017). https://doi.org/10.1007/s10637-017-0477-5

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