title: Polymeric nanoparticle-encapsulated hedgehog pathway inhibitor HPI-1 (NanoHHI) inhibits systemic metastases in an orthotopic model of human hepatocellular carcinoma.
abstract: OBJECTIVE
  To illustrate the prognostic significance of hedgehog (Hh) signaling in patients with hepatocellular carcinoma (HCC) and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor, Gli1 (NanoHHI) using in vitro and in vivo models of human HCCs.
  
  
  METHODS
  Patched1 (Ptch1) expression was detected in tumor tissue microarrays of 396 patients with HCC who underwent curative surgical resection during February 2000 to December 2002. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. The effects of NanoHHI alone and in combination with sorafenib were investigated on HCC cell lines. Primary HCC tumor growth and metastasis were examined in vivo using subcutaneous and orthotopic HCC xenografts in nude mice.
  
  
  RESULTS
  Elevated expression of Ptch1 in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in patients with HCC. In vitro, NanoHHI significantly inhibited the proliferation and invasion of HCC cell lines. NanoHHI potently suppressed in vivo tumor growth of HCC xenografts in both subcutaneous and orthotopic milieus, and in contrast to sorafenib, resulted in significant attenuation of systemic metastases in the orthotopic setting. Furthermore, NanoHHI significantly decreased the population of CD133-expressing HCC cells, which have been implicated in tumor initiation and metastases.
  
  
  CONCLUSIONS
  Downstream Hh signaling has prognostic significance in patients with HCC as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and antimetastatic effects in HCC models, which may provide a new strategy in the treatment of patients with HCC and prevention post-operative recurrence.
authors.affiliation: Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Key Laboratory for Carcinogenesis & Cancer Invasion, Shanghai, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Venugopal
authors.initials: V
authors.lastname: Chenna
authors.forename: Chaoxin
authors.initials: C
authors.lastname: Hu
authors.forename: Hai-Xiang
authors.initials: HX
authors.lastname: Sun
authors.forename: Mehtab
authors.initials: M
authors.lastname: Khan
authors.forename: Haibo
authors.initials: H
authors.lastname: Bai
authors.forename: Xin-Rong
authors.initials: XR
authors.lastname: Yang
authors.forename: Qin-Feng
authors.initials: QF
authors.lastname: Zhu
authors.forename: Yun-Fan
authors.initials: YF
authors.lastname: Sun
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D016130:Immunophenotyping; D008113:Liver Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D053769:Nanocapsules / Q000737:chemistry / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010671:Phenylurea Compounds; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D053769:Nanocapsules; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C000606240:Ptch1 protein, mouse; D011725:Pyridines; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D009536:Niacinamide; D000077157:Sorafenib