Polymeric Nanoparticle Encapsulated Hedgehog Pathway Inhibitor HPI-1 ('NanoHHI') Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma

Autor: Xin-Rong Yang, Yang Xu, Robert A. Anders, Jia Fan, Haibo Bai, Yun Fan Sun, Chaoxin Hu, Qin Feng Zhu, Mehtab Khan, Venugopal Chenna, Hai Xiang Sun, Anirban Maitra
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Male
Cancer Research
Pathology
Pyridines
Tumor initiation
Metastasis
Mice
Recurrence
Neoplasm Metastasis
education.field_of_study
Mice
Inbred BALB C
biology
Benzenesulfonates
Liver Neoplasms
Middle Aged
Sorafenib
Prognosis
Patched-1 Receptor
Oncology
Hepatocellular carcinoma
Female
medicine.drug
Signal Transduction
Adult
Niacinamide
Patched Receptors
medicine.medical_specialty
Carcinoma
Hepatocellular
Population
Mice
Nude
Antineoplastic Agents
Receptors
Cell Surface
Zinc Finger Protein GLI1
Article
Immunophenotyping
Nanocapsules
GLI1
Cell Line
Tumor
medicine
Carcinoma
Animals
Humans
Hedgehog Proteins
Neoplasm Invasiveness
education
neoplasms
Protein Kinase Inhibitors
Aged
Cell Proliferation
business.industry
Phenylurea Compounds
Cancer
medicine.disease
digestive system diseases
Cancer research
biology.protein
business
Transcription Factors
Popis: Purpose: 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. Experimental Design: 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. Conclusion: 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. Clin Cancer Res; 18(5); 1291–302. ©2011 AACR.
Databáze: OpenAIRE
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