Investigators from the Fred Hutchinson Cancer Research Center (Seattle, WA), S. J. Diede et al. reported in today's (Dec. 18th) online edition of PNAS the results of their study on DNA methylation of primary medulloblastomas. With denaturation analysis of methylation differences (melthing temperatures of methylated DNA) between DNAs of cancerous and normal tissue samples, the investigators found changes in methylation regions from primary medulloblastomas were regions of the DNA critically involved in regulating developmental pathways such as Sonic hedgehog (Shh), Wingless (Wnt), retinoic acid receptor (RAR), and bone morphogenetic proteins (BMPs). Of particular note, the researchers found methylation at the PTCH-1C locus in the Shh regulatory pathway of both primary patient samples and medulloblastoma cell lines. In vitro experiments demonstrated that treating the malignant cells with methyltranferase inhibitor increased the expression of PTCH1. The authors concluded that either genetic mutations in PTCH1 or epigenetic silencing of the genes involved differentiation of stem cells can result in a "fundamental process of pediatric medulloblastoma formation."

Notch signaling is known to regulate adult stem cell homeostasis and a stem cell's fate (lineage specification) in adult mammals. Cancer biologists have also demonstrated that dysregulation of the Notch signaling pathway can lead to many cancers. Italian scientists from the Fondazion Institute of Molecular Oncology (IFOM, Milan), B. Westhoff et al., reported their study results on the alteration of Notch signaling in cancer patients diagnosed with non-small-cell lung carcinomas (NSCLCs). In the December 10th online edition of PNAS, the investigators reported that approximately 33% of the patients with NSCLCs have altered Notch signaling in their tissue samples. The experimental results also revealed that in 30% of the NSCLCs, a loss of Numb expression, which is a cell fate determinant that counteracts Notch, leads to increase Notch activity. The researchers found that Notch activity in NSCLCs correlates with a poor clinical outcome. In vitro experiments showed that primary epithelial cells derived from NSCLCs which appears to harbor cancer stem cells with upregulated Notch expression are selectively killed by γ-secretase, an inhibitor of Notch. The authors concluded from their observation that "deregulation of Notch pathway is a relatively fequent event in NSCLCs and suggest that it might represent a possible target for molecular therapies in these tumors."

In the November 22nd online edition of Nature Cell Biology, U. Wellner et al. from the University of Freiburg (Freiburg, Germany) reported their study results on the role of a zinc finger E-box binding homeobox1 (ZEB1) promoting metastasis and tumor-inititating capacity of pancreatic and colorectal cancer cells. The investigators reported that ZEB1 not only activates the embryonic program of eptihelial to mesenchymal transition (EMT/leading to invasion and metastasis of carcinomas), but also inhibits expression of microRNA-200 (miR-200), which are strong inducers of epithelial differentiation. Specifically, the experimental data demonstrated ZEB1 repressing expression of miR-203 which along with other miR-200 family members targets stem cell factors and inhibits stemness in stem cells. Additionally, the study revealed that expression of miR-200c, miR-203 and miR-183 appear to suppress expression of stem cell factors in cancer cells and mouse embryonic stem cells (similar to the polycomb repressor, Bmi). The authors proposed that "ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs and thereby is a promoter of mobile, migrating cancer stem cells."