Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms.

Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway. (Cancer Res 2005; 65(9): 3555-61)

The mitotic checkpoint is thought to be essential for ensuring accurate chromosome segregation by implementing mitotic delay in response to a spindle defect. To date, however, very little data has become available on the defects of the mitotic checkpoint in human cancer cells. In the present study, impaired mitotic checkpoint was found in four (44%) of nine human lung cancer cell lines. To our knowledge, this is the ®rst demonstration of frequent impairment of the mitotic checkpoint in this leading cause of cancer deaths. As an initial step towards elucidation of the underlying mechanism, we further undertook a search for mutations in a key component of the mitotic checkpoint, known as hsMAD2, and its immediate downstream molecule, p55CDC. No such mutations were found, however, in either 21 lung cancer cell lines or 25 primary lung cancer cases, although we could identify silent polymorphisms and the transcribed and processed hsMAD2 pseudogene that was subsequently mapped at 14q21-q23. The present observations appear to warrant further investigations, such as search for alterations in other components, to better understand the molecular pathogenesis of this fatal disease, and warn against potential misinterpretation when performing mutational analyses for other cancer types based on cDNA templates.

Cell cycle progression is monitored by checkpoint mechanisms to ensure the integrity of the genome and the fidelity of sister chromatid separation. Failure of such checkpoint functions results in genomic instability, a condition that predisposes cells to neoplastic transformation and tumor progression. Recently, Scolnick and Halazonetis defined a new mitotic checkpoint that acts at prophase and delays chromosome condensation in response to mitotic stress, and identified a gene, named checkpoint with FHA and ring finger (Chfr), that seems to be required for delaying prophase in human cells. In the present study, we examined human Chfr mRNA expression in 15 human esophageal cancer cell lines and 43 primary esophageal cancers to investigate the potential involvement of Chfr in the pathogenesis of esophageal cancers. We report here that a significant proportion of human esophageal cancer has loss of expression of Chfr gene. Furthermore, we found aberrant hypermethylation of the promoter region of this checkpoint gene in four of 15 (26.7%) esophageal cancer cell lines and in seven of 43 (16.3%) primary cancers.