In the May 22nd issue of Nature, scientist from the Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, W. Guo et al., reported their findings on the role of the tumor suppressor gene, Pten, and the formation of leukemic stem cells. The investigators found that deletion of Pten in mouse hematopoietic stem cells (HSCs) led to acute T-ymphoblastic leukemia (T-ALL). The cells in the bone compartment following gene deletion were enriched for c-Kit^midCD3+Lin- cells in which the cells had an increase in unphosphorylated β-catenins. Experimental results also demonstrated that deletion of one of the β-catenins alleles decreases the incidence and delays the onset of T-ALL. It appears as if loss of Pten results in activation of the β-catenin pathway can give rise to leukemic stem cells (LSCs). The researchers also noted that the oncogene, c-myc, is overexpressed in c-Kit^midCD3+Lin- in the LSCs as well as in the CD3+ leukemia blasts. The experimental data also revealed that aberrant Notch1 signaling is not involved in T-ALL. The authors concluded that loss of Pten activity as well other genetic events can give rise to the formation of leukemic stem cells.

The question as to whether CD133 was a bona fide marker for cancer stem cells (CSCs) was raised in a commentary by M. A. LaBarge and M. J. Bissell from Lawrence Berkeley National Laboratory in the May 1st issue of the J. Clinical Investigation. The authors cited the work of S. V. Shemelkov et al. from the Weill Medical College of Cornell University who published in this same issue of JCI the results of their study demonstrating that CD133 expression is not restricted to stem cells. With a mouse model, Shmelkov et al. generated a knock-in lacZ reporter mouse for the CD133 promoter to track the expression of CD133 in both normal tissues and during tumorigenesis. The authors noted that the mouse knock-in model developed by Shmelkov et al. for the lacZ reporter gene controlled by all endogenous CD133 promoter was "a far more accurate representation of CD133 tissue-specific gene expression in contrast to only AC133 monoclonal antibody staining (a accepted standard by stem cell researchers). With confirmational AC133 immunostaining experiments, Shmelkov et al. found that luminal epithelial cells in the colon express CD133 in mice and humans. Thus, the question was raised whether the position of the CD133 epitope on the cell surface and the type of monoclonal antibody used could complicate the observations and the interpretation of others with respect to CD133 being expressed only on CSCs and not universally expressed on most epithelial tissues. The authors also noted that Shmelkov et al. demonstrated that in tumors from human colon cancer patients both CD133+ and the CD133- malignant epithelial cells (EpCAM+) were present. Both of these subpopulations (CD133+EpCAM+ and CD133-EpCAM+) cells were found in the primary metstatic tumors and each subpopulation of cells had tumor-initiating activity when implanted into mice. Interestingly, the subpopulation of CD133+EpCAM+ could generate tumors containing a subpopulation of CD133-, which behaved more aggressively with a faster growth rate than the engrafted CD133+ cells. Shmelkov et al. hypothesized that the CD133- cells were derived from the CD133+ cells during tumor progression concomitant with a downregulation of CD133 expression. The authors noted that the hypothesis is consistent with the observation that epithelial-mesenchymal transition reflects the initial phases of metastasis in solid tumors.

Stanford University scientists, D. J. Wong et al., published the results of their study on systematically studying a group of genes involved in transcriptional programs in embryonic stem cells (ESCs), adult stem cells, and human cancers. In the April 10th issue of Cell Stem Cell, the investigators reported that their mapping studies revealed two predominant gene modules that distinguish ESCs from adult stem cells. In human epithelial cancers, it was found that the ESC-like genes involved in transcriptional program were activated and highly prognostic for metatstasis and death. The experimental results demonstrated that the oncogene, c-Myc, could reactivate the ESC-like program in both normal and cancer cells. Primary human keratinocytes which were transformed by Ras, IκBα, and c-Myc resulted in a subpopulation of cancer stem cells with a 150-fold increase in their tumor-initiating potential when propagated in immunodeficient animals. The authors concluded that "ESC-like transcriptional program in differentiated adult cells may induce pathologic sel-renewal characteristic of cancer stem cells."