In the November 21st online edition of PNAS, J-P. De La O et al. from the University of Utah reported their study results on Kras mutations in mice which results in pancreatic intraepithelial neoplasia (PanIN). The investigators noted that activated Kras mutations in mice produce lesions similar to those in humans. However, only a small number of cells that express mutant Kras go on to form PanINs. Since cells from PanINs exhibited active Notch signaling, the researchers found through conditional expression experiments that in mouse pancreas activated Notch synergized mutant Kras in the induction of PanINs. The experimental data revealed that "Kras activation in mature acinar cells induces PanIN lesions identical to those seen upon ubiquitous Kras activation." Thus, Notch signaling appears to inhibit differentiation of tumor-initiating cells concomitant with promoting dysplastic progression of acinar-derived PanINs. The authors concluded at the cellular level, "Notch/Kras coactivation promotes rapid reprogramming of acinar cells to a duct-like phenotype, providing an explanation for how a characteristically ductal tumor can arise from nonductal acinar cells."

Scientists from the Univ. of California, San Diego, Y. Minami et al., reported in the November 11th online edition of PNAS the ability to generate leukemic stem cells (leukemia-initiating cells) by transforming mouse hematopoietic stem cells (mHSCs) with p210^BCR-ABL. These bone marrow-derived cells from E2A knock-out mice retained their pluripotency in ex vivo culture. Transplantation of the transformed cells into cogenic mice recapitulated chronic myelogenous leukemia in the recipient mice. More importantly, the leukemia-initiating cells were found in the granulocyte macrophage progenitor (GMP) compartment of the bone marrow. Additionally, the leukemogenic GMP displayed higher levels of nuclear β-catenin activity than the non-transformed GMP. Restoration of E2A function did not reverse the BCR-ABL-induced transformation. The authors concluded that their "results provide further evidence that BCR-ABL-transformed GMP with abnormal β-catenin activity can function as leukemic stem cells."

Italian scientists from the Università di Genova, R. M. R. Gangemi et al. reported in the November 6th online edition of Stem Cells, a new therapeutic approach in targeting cancer stem cells in a highly aggressive cerebral tumor, glioblastoma. With gene silencing techniques, the investigators targeted Sox2, the master gene for self-renewal in neural stem cells. The researchers silenced Sox2 expression in tumor initiating cells (TICs)/cancer stem cells isolated from primary glioblastoma tumors. After implantation into immunodeficient mice, the experimental results revealed that the TICs stopped proliferating concomitant with losing their tumorigenicity. The authors concluded that their experimental results suggest that Sox2 is important for the maintenance of self-renewal not only in neural stem cells but also in those stem cells which had been transformed. The authors also concluded that" Sox2 or its immediate downstream effectors, would...be an ideal target for glioblastoma therapy."

Scientists from Stanford University, B. Bedogni et al., reported in the the October 16th issue of J. Clinical Investigations their study results on Notch1 signaling and Akt acitvation under hypoxic conditions which can give rise to melanomas. The investigators found that Notch1 signaling is elevated in biopsies specimens and cell lines of human melanomas. In vitro experiments revealed that Notch1 serves as an effector for Akt signaling and under hypoxic conditions it can transform melanocytes. The investigators speculated that transformation and tumor growth is attributed to Notch protecting cells from stress-dependent cell death and where the cells are maintained in a highly proliferative state. It was also found that Notch1 expression is controlled by PI3K/Akt pathway through NF-kB and by tissue hypoxia through HIF-1α. The authors concluded that their study results that "Notch1 signaling mediates the interaction between Akt and hypoxia in melanoma development" and that targeting Notch signaling pathway as potential therapeutic target in melanoma treatment.