Elsevier

Journal of Pediatric Surgery

Volume 45, Issue 12, December 2010, Pages 2299-2304
Journal of Pediatric Surgery

PAPS papers
Hedgehog signaling pathway in neuroblastoma differentiation

https://doi.org/10.1016/j.jpedsurg.2010.08.020Get rights and content

Abstract

Purpose

The hedgehog (Hh) signaling pathway is activated in some adult cancers. On the other hand, the Hh signaling pathway plays an important role in the development of the neural crest in embryos. The aim of this study is to show the activation of Hh signaling pathway in neuroblastoma (NB), a pediatric malignancy arising from neural crest cells, and to reveal the meaning of the Hh signaling pathway in NB development.

Methods

This study analyzed the expression of Sonic hedgehog (Shh), GLI1, and Patched 1 (Ptch1), transactivators of Hh signaling pathway, by immunohistochemistry in 82 NB and 10 ganglioneuroblastoma cases. All 92 cases were evaluated for the status of MYCN amplification.

Results

Of the 92 cases, 67 (73%) were positive for Shh, 62 cases (67%) were positive for GLI1, and 73 cases (79%) were positive for Ptch1. Only 2 (10%) of the 20 cases with MYCN amplification were positive for Shh and GLI1, and 4 cases (20%) were positive for Ptch1 (MYCN amplification vs no MYCN amplification, P ≦ .01). The percentage of GLI1-positive cells in the cases with INSS stage 1 without MYCN amplification was significantly higher than that with INSS stage 4. Of 72 cases without MYCN amplification, 60 were GLI1-positive. Twelve cases were GLI1-negative, and the prognosis of the GLI1-positive cases was significantly better than that of the GLI1-negative cases (P = .015).

Conclusions

Most of NBs without MYCN amplification were positive for Shh, GLI1, and Ptch1. In the cases without MYCN amplification, the high expression of GLI1 was significantly associated with early clinical stage and a good prognosis of the patients. In contrast to adult cancers, the activation of the Hh signaling pathway in NB may be associated with the differentiation of the NB.

Section snippets

Clinical data of patients and biological data of NB samples

Patients were diagnosed with NB between April 1988 and March 2008. Eighty-two NB samples and 10 ganglioneuroblastoma samples were obtained. The tumor was staged according to the International Neuroblastoma Staging System (INSS). All of the parents of the patients provided informed consent for tumor preservation and the biological analysis before surgery. This study was performed according to ethical guidelines for the clinical studies by Ministry of Health, Labour, and Welfare of Japan in July

Association of expression of Shh, GLI1, and Ptch1 proteins and the status of MYCN gene

The Shh and Ptch1 staining was observed in the cell membrane strongly, and GLI1 was localized in the cytoplasm in neuroblasts with ganglionic differentiation in GNB samples (Fig. 1A). The Shh, GLI1, and Ptch1 staining intensity of GNBs was higher than that of NBs, and most Schwann cells were negative for Shh, GLI1, and Ptch1 (Fig. 1A, B).

The result of immunohistochemistry of 92 samples is shown in Table 1. Sixty-seven of 92 samples (73%) were positive for Shh, 62 (67%) for GLI1, and 73 (79%)

Discussion

The current study showed that Hh signaling pathway–associated proteins such as Shh, GLI1, and Ptch1 were expressed in most NB cases, especially cases without MYCN amplification. Moreover, a number of positive cases show “++”, whereas “+” cases are rare. As a result, most of the positive cases tended to be easy to distinguish as positive cases. The percentage of GLI1-positive cells in early-stage samples was higher than that with advanced stage. The 5-year OS rate of GLI1-positive cases without

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