In the August 7th issue of Cell Stem Cell, T. Hoey et al. from Oncomed Pharmaceuticsls, Inc. (Redwood City, CA) reported their findings on the use of neutralizing antibodies to the Delta-like ligand 4 (DLL4) as an anti-cancer therapeutic agent. It was noted that DLL4 blockade resulted in broad spectrum antitumor activity in cancer cell-lined based xenograft models. This anti-tumor effect was demonstrated to be the result of dysregulated angiogenesis. Since the Notch signaling pathway contributes to stem cell self-renewal as well as vascular development, the investigators developed both human and murine monoclonal antibodies to DLL4 to study its effect on human colon tumors both in vitro and in vivo. The experimental results showed that anti-hDLL4-treated xenografts in NOD- SCID mice reduced tumor growth, a delay in tumor recurrence after chemotherapeutic treatment (paciltaxel in breast tumor and irinotecan for colon cancer), and a decrease in the number of tumorigenic cells (CD44+/CD166+ tumor-initiating stem cells). The researchers speculated that anti-hDLL4 may have sensitized the cancer stem cells (CSCs) to respond to the cytotoxic effect of the chemotherapeutic agents. The authors concluded that their experimental results suggest that "blocking DLL4 function may be an attractive strategy for novel (anti-cancer) therapeutics, since this approach attacks the tumor through multiple mechanisms including inhibiting productive angiogenesis, inhibiting proliferation of bulk tumor cells, and reducing CSC frequency."

H. Wang et al. from Duke University Medical Centrer reported in the August 5th online edition of Stem Cells the results of their study on glioma stem cells (GSCs) which preferentially express interleukin 6 receptor alpha (IL6Rα) and glycoprotein 130 (gp130). With short hairpin RNAs, the investigators were able to inhibit the expression of IL6R or its ligand in GSCs. There was a signficant decrease in both tumor growth and neurosphere formation when the IL6 signaling pathway was disrupted in GSCs. The researchers also found that perturbing IL6 signaling also attenuated STAT3 activation and induces GSC apoptosis. The investigators surmised from their experimental results that STAT3 is a "downstream mediator of pro-survival IL6 signals in GSCs." Xenografts of human glioma treated with inhibitors of IL6 signaling increased survival of mice bearing the tumor. It was also noted that glioma patients with elevated levels of IL6 ligand and its receptor had lower survival rates. The authors concluded that their data suggests that "IL6 signaling contributes to glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for glioma patients."

P. B. Gupta et al. from Massachusetts Inst. of Technology reported in the August 13th online edition of Cell their study results in identifying agents that are cytotoxic for epithelial cancer stem cells (CSCs). With cell-based high-throughput screens, the investigator identified a compound, salinomycin, which appears to have greater than a 100-fold increase in potency compared to pacilitaxel in reducing the number of CSCs in breast tumors. In vivo experiments with mice demonstrated the drug's ability to inhibit mammary tumor growth concomitant with induction of epithelial differentiation of tumor cells. Gene expression analyses revealed loss in expression of breast CSC genes following treatment with salinomycin. The authors concluded that their study "demonstrates the ability to identify agents with specific toxicity for epithelial CSCs."

In today's (Aug. 7th) issue of Cell, Y. Shimono et al. from Stanford University reported their findings linking differential expression of a cluster of microRNAs in breast cancer stem cells (BCSCs) to non-tumorigenic human cancer cells. The investigators found that miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. In vitro studies revealed that miR-200c modulates the expression of BMI-1 (a regulator of stem cell self-renewal). It appears that miR-200c inhibits the clonal expansion of breast cancer cells by suppressing BMI-1 expression. Additionally, the researchers found that miR-200c blocks normal mammary stem cells to form mammary ducts and form tumors in vivo. The authors concluded from their study results that "the coordinated downregulation of the three (above) microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular-link that connects BCSCs with normal stem cells."

Australian scientists from the Walter Eliza Hall Medical Institute, E. Lim et al., reported in the August 2nd online publication of Nature Medicine, their study on human breast cancers in women carrying mutations for the tumor suppressor gene, BRACA. In studying the epithelial subpopulations of basal stem/progenitor, luminal progenitor and mature luminal cells of breast tissue from women who are heterozygous for a BRACA mutation, the investigators found a subpopulation of luminal progenitor cells that in vitro were highly proliferative. The study results also revealed that these expanded luminal progenitor subpopulation did not require growth factors in the culture media. Gene expression profiling analysis confirmed that cells from BRACA mutations and basal breast tumors were more similar to normal luminal progenitor cells than the stem cell-enriched population in normal breast tissues. The researchers also found that c-KIT tyrosine kinase receptor was a key marker of tumorigenic luminal progenitor cells. The authors concluded from their study results that an aberrant luminal progenitor population leads to transformation in BRACA1-associated basal tumors.