title: Autophagy Inhibition in Childhood Nephroblastoma and the Therapeutic Significance.
abstract: Autophagy is a physiological pathway characterized by lysosomedependent self-digestion to recycle damaged or superfluous cellular content. Deregulation of autophagy hampers the maintenance of cellular homeostasis and contributes to tumorigenesis. However, during anticancer therapy, autophagy activation contributes to development of resistance. Thus autophagy has been recognized as an important pathway and a therapeutic target in cancer. Nephroblastoma (Wilm's tumor) is a common childhood malignancy. The role of autophagy in nephroblastoma is largely uninvestigated.
  
  
  
  This study is to investigate the change of autophagy level in nephroblastoma, and whether autophagy could be a therapeutic target in anaplastic nephroblastoma.
  
  
  
  In clinical samples of childhood nephroblastoma, autophagy activity was evaluated by the expressions of selected autophagy markers as well as the presence of autophagosome ultrastructure. Use of autophagy inhibitors alone and in combination with conventional chemotherapeutics, was studied both in vivo and in vitro.
  
  
  
  In nephroblastoma, there was decrease in the Beclin 1 level and the number of autophagosomes, suggesting autophagy inhibition. Furthermore, in two anaplastic nephroblastoma cell lines, G401 and SK-NEP1, autophagy inhibitors further enhanced the efficacy of conventional chemotherapeutics including vincristine and cisplatin. In G401 tumor model established in nude mice, combinational use of chloroquine, an inhibitor of autophagy degradation, further decreased the tumor mass compared with single use of the chemotherapeutics vindesine, although no statistical significance was achieved.
  
  
  
  Our results suggest that autophagy deregulation is involved in nephroblastoma, and targeting autophagy can serve as a potential adjuvant strategy for the highly malignant cases.
authors.affiliation: Departments of Central Laboratory, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Lin-Jie
authors.initials: LJ
authors.lastname: Li
authors.affiliation: Departments of Central Laboratory, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Departments of Central Laboratory, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Lin-Qing
authors.initials: LQ
authors.lastname: Yuan
authors.affiliation: Pathology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Gu
authors.affiliation: Pathology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Pathology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Child Health Care, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Departments of Central Laboratory, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Min-Ju
authors.initials: MJ
authors.lastname: Li
authors.affiliation: Child Health Care, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Key Laboratory of Diagnosis and Treatment of Neonatal Diseases of Zhejiang Province, Zhejiang, China.
authors.forename: Zheng-Yan
authors.initials: ZY
authors.lastname: Zhao
authors.affiliation: Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Jin-Hu
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Departments of Central Laboratory, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.|Key Laboratory of Diagnosis and Treatment of Neonatal Diseases of Zhejiang Province, Zhejiang, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*; D009396:Wilms Tumor / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine; D002738:Chloroquine; D002945:Cisplatin
keywords: Beclin 1; Nephroblastoma; Wilm's tumor; autophagy; chemotherapy; combinational therapy.