A Polymeric Nanoparticle Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma
Menée in vitro et in vivo, cette étude évalue l'efficacité d'un nouvel inhibiteur de la voie Hedhehog, encapsulé dans une nanoparticule, pour prévenir l'apparition de métastases d'un carcinome hépatocellulaire
Purpose:To illustrate the prognostic significance of hedgehog (Hh) signaling in hepatocellular carcinoma (HCC) patients, and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor, Gli-1 ("NanoHHI") using in vitro and in vivo models of human HCC. Experimental Design:Patched1 (Ptch) expression was detected in tumor tissue microarrays of 396 HCC patients who underwent curative surgical resection during 2/2000 to 12/2002. 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 Ptch in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in HCC patients. 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. Further, 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 HCC patients as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and anti-metastatic effects in HCC models, which may provide a new strategy in the treatment of HCC patients and prevention post-operative recurrence.