Molecular markers for reinforcement of histological subclassification of neuroendocrine lung tumors.

The degree of malignancy of neuroendocrine lung tumors (NEs) increases in this order: from typical carcinoids (TCs) through atypical carcinoids (ACs) to large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs). However, histological classification has sometimes proved difficult. We here investigated loss of heterozygosity (LOH) using eight microsatellite markers and expression of p53, Bcl-2 and Bax proteins using immunohistochemical methods in 57 NEs (19 TCs, 5 ACs, 14 LCNECs and 19 SCLCs), looking for objective genetic markers to distinguish between subtypes. The frequencies of LOHs on D3S1300, RBi2 and TP53, the combinations of LOH status for RBi2 and TP53, and the immunohistochemically demonstrated Bcl-2/Bax ratios and p53-positive rates significantly differed among histopathologically diagnosed NEs. Differentiation between TC and AC was possible with reference to LOH on D3S1300, RBi2 and TP53, and the combined LOH status on RBi2 and TP53 (i.e., both LOH(-) versus one LOH(+)). For comparison between AC and LCNEC + SCLC, LOH on TP53 or the combination of two markers--one LOH(+) versus both LOH(+)--was applied. Furthermore, in three discordant cases of diagnoses based on histology and LOH markers, diagnoses using the latter were considered to be more probable by survival analysis. The present study indicated that assessment of LOHs using microsatellite markers could provide objective markers that can distinguish subtypes of NEs, for which histological assessment may commonly result in disagreement.

A role for the pituitary tumor-transforming gene in the genesis and progression of non-small cell lung carcinomas.

BACKGROUND: The product of the pituitary tumor-transforming gene (PTTG) inhibits chromatid separation, which is considered to promote chromosome instability, especially in the absence of the p53 gene product, and also induces basic fibroblast growth factor (bFGF) production. Its expression and these variables in primary non-small cell carcinomas (NSCLCs) of known p53 status were examined. MATERIALS AND METHODS: Comparative genomic hybridization analysis of 78 lesions revealed a wide range of total (gain + loss) chromosomal imbalance numbers (tCINs). Seven each with the highest and lowest tCINs were examined for PTTG mRNA by semi-quantitative RT-PCR and bFGF production immunohistochemically. RESULTS: Mean relative values for PTTG mRNA for the tumors and corresponding normal lung tissues were 1.46 and 0.88, respectively, the difference being statistically significant. Overexpression of bFGF was observed in 12 out of 14 with intense immunostaining of carcinoma cells, in contrast to the weak or lack of staining in normal lung tissues. However, relative PTTG values did not correlate with tCINs or immunoreactivity for bFGF among the tumors regardless of the p53 status. CONCLUSION: The results indicate that overexpression of PTTG plays a role in the genesis and progression of NSCLCs, although its effects on CINs and bFGF production may be obscured by other complicating factors.

Differentiation of Various Cell Types during Fruiting Body Formation of Dictyostelium Discoideum.

The processes of differentiation of the presumptive cells (prespore and prestalk cens) into mature spores, stalk and basal-disc cells in Dictyotelium discoideum was investigated. The number of stalk and disc cells in pre-labeled culminating cell masses was estimated by determining the radioactivity of the undissociable fraction separated by filtration from the dissociable fraction containing presumptive cells and spores. Changes in the proportion of amoeboid cells stainable with fluorescein-conjugated antispore serum and encapsulated spores were also followed in the dissociable fraction. Formation of stalk and disc cells began at 17 hr of development and was completed at 26 hr, while formation of morphologically identifiable spores began at 18 hr and was completed at 20 hr, long before completion of stalk formation. At the onset of culmination, unstained cells abruptly increased with an accompanying decrease of stained cells, when unstained rear-guard cells appeared in the hind region. Although some of the rear-guard cells soon differentiated into basal-disc cells, the rest remained amoeboid in the upper part of the spore mass (sorus) after complete formation of a fruiting body. Despite the presence of the amoeboid cells in mature sori, the proportion of the sorus to the stalk and disc of a fruiting body was approximately equal to that of stained (prespore) to unstained (prestalk) cells in a migrating slug.