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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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Urokinase plasminogen activating system (PA system) and vascular endothelial growth factor (VEGF) were recently suggested to contribute synergistically to tumor progression. To evaluate the roles of the PA system and VEGF in gastric cancer, the effects of the PA system and VEGF on tumor angiogenesis and the survival of patients with gastric cancer were investigated. Cancer tissues from 101 gastric cancer patients were assayed immunohistochemically for expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), PA inhibitor-1 (PAI-1) and VEGF protein. The positive rates of uPA, uPAR, PAI-1, VEGF expression were 22.8%, 32.7%, 36.6% and 26.7%, respectively. Positive staining was observed in tumor cells (uPA, uPAR, VEGF), or in both tumor cells and stromal cells (PAI-1). The expressions of uPA, uPAR, PAI-1 and VEGF were significantly correlated with the clinicopathological factors: uPA, depth of tumor invasion, differentiation, lymphatic and vascular invasion; uPAR, tumor size, depth, lymph node involvement, differentiation, vascular invasion; PAI-1, tumor size, depth, lymph node involvement, differentiation, vascular invasion; VEGF, differentiation, vascular invasion. The microvessel density (MVD) assessed immunohistochemically was significantly higher in the patients with expression of uPA, uPAR or VEGF, and stepwise analysis identified uPA as an independent correlated factor with MVD. Furthermore, multivariate analysis demonstrated that depth of tumor invasion, lymph node involvement and uPA expression were independent prognostic factors. uPA is a key factor in the PA system, being associated with a poor outcome of gastric cancer, and contributing not only to invasive activity, but also to angiogenesis.

To identify a set of genes related to radiosensitivity of cervical squamous cell carcinomas and to establish a predictive method, we compared expression profiles of 9 radiosensitive and 10 radioresistant tumors obtained by biopsy before treatment, on a cDNA microarray consisting of 23,040 human genes. We identified 121 genes whose expression was significantly greater in radiosensitive cells than in radioresistant cells, and 50 genes that showed higher levels of expression in radioresistant cells than in radiosensitive cells. Some of these genes had already known to be associated with the radiation response, such as aldehyde dehydrogenase 1 (ALDH1) and X-ray repair cross-complementing 5 (XRCC5) (P<.05, Mann-Whitney test). The validity of the total of 171 genes as radiosensitivity related genes were certified by permutation test (P<.05). Furthermore, we selected 62 genes on the basis of a clustering analysis, and confirmed the validity of these genes with cross-validation test. The cross-validation test also indicates the possibility of making prediction of radiosensitivity for discriminating radiation-sensitive from radiation resistant biopsy samples by predicting score (PS) values calculated from expression values of 62 genes in 19 samples, because the prediction successfully and unequivocally discriminated the radiosensitive phenotype from the radioresistant phenotype in our test panel of 19 cervical carcinomas. The extensive list of genes identified in these experiments provides a large body of potentially valuable information for studying the mechanism(s) of radiosensitivity, and selected 62 genes opens the possibility of providing appropriate and effective radiotherapy to cancer patients.

Several mutations were identified in the kinase domain of the RET proto-oncogene in patients with multiple endocrine neoplasia (MEN) 2B, familial medullary thyroid carcinoma (FMTC) or sporadic medullary thyroid carcinoma. We introduced seven mutations (glutamic acid 768-->aspartic acid (E768D), valine 804-->leucine (V804L), alanine 883-->phenylalanine (A883F), serine 891-->alanine (S891A), methionine 918-->threonine (M918T), alanine 919-->proline (A919P) and E768D/A919P) into the short and long isoforms of RET cDNA and transfected the mutant cDNAs into NIH3T3 cells. The transforming activity of the long isoform of Ret with each mutation was much higher that that of its short isoform. Based on the levels of the transforming activity, these mutant RET genes were classified into two groups; a group with high transforming activity (A883F, M918T and E768D/A919P) and a group with low transforming activity (E768D, V804L, S891A and A919P) (designated high group and low group). Interestingly, the level of transforming activity correlated with clinical phenotypes; high group Ret with the A883F or M918T mutation and low group Ret with the E768D, V804L or S891A mutation were associated with the development of MEN 2B and FMTC, respectively. In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not affect the activities of high group Ret.

Background: p27 protein is one of the cdk inhibitors which regulates the progression from G1 to S phase of the cell cycle. Reduced expression of p27 protein has been reported to be correlated with poor clinical outcome in patients with various cancers., Materials and Methods: We performed immunohistochemistry of both p27 and Ki67 in 136 cases of resected human esophageal squamous cell carcinoma, and evaluated the association between p27 immunoreactivity and clinicopathological features including clinical outcome in these patients. We also examined the correlation between labeling index or the percentage of positive tumor cells for p27 and Ki67 in serial tissue sections in these cases., Results: Cases with invasion of the muscularis propria or adventitia had significantly (p < 0.05) higher p27 LI (65.0 +/- 23.7) than those with invasion limited to mucosa or submucosa and those with carcinoma in situ (58.9 +/- 18.3). There were no significant correlations between p27 and other clinicopathological factors such as sex, age, tumor size, differentiation type, nodal status and histological stage. The cases with p27 LI below 40% tended to have a worse prognosis than those with p27 LI above 40%. There was no significant correlation between Ki67 and p27 LIs., Conclusions: Reduced expression of p27 may be correlated with the biological behavior of esophageal squamous cell carcinoma and may play an important role in the early stages of cancer.