In the September 18th online edition of Stem Cells, G. Rappa et al. from the University of South Alabama reported their experimental results in reducing the metastatic potential in melanoma by downregulating the expression of CD133 (Prominin-1). CD133 is a surface marker associated with neural stem cells as well as being being expressed by cancer stem cells (CSCs). The investigators conducted in vivo and in vitro experiments in which CD133 is downregulated in human metastatic melanoma and in a human melanoma cell line (FEMX-I). With two different siRNAs, CD133 expression was decreased by 8.7 and 1.8 fold in FEMX-I cells. Down-regulation of CD133 resulted in slower cell growth concomitant with a decreased ability to form spheroids. Monoclonal antibodies directed against the two epitopes of the CD133 protein exhibited a dose-dependent cytotoxic effect. In vivo studies revealed that down-regulation of CD133 reduced metastasis of the melanoma cells, particularly, the inability to colonize the spinal cord. Microarry analysis showed that down-regulation of CD133 upregulated genes encoding for Wnt inhibitors; suggesting interaction between CD133 expression and the Wnt pathway. The authors concluded from both their in vivo and in vitro studies that CD133 may become an important therapeutic target for metastatic cancers expressing the CD133 epitope.

In the September 19th online edition of PNAS, N. Dumont et al. from UCSF reported the results of their study on de novo DNA methylation of CpG islands following induction of the epithelial to mesenchymal transition leads to tumorigenesis. The investigators used an in vitro cell culture system in which epigenetically plastic cells were induced into epithelial to mesenchymal transition (EMT). The study results also revealed repression of E-cadherin transcription prior to methylation of the CpG target sites. Induction of EMT also resulted in methylation of gene promoters for the estrogen receptor and Twist. The authors concluded that their experimental data "demonstrate that signals from the microenvironment can induce phenotypic and gene expression changes associated with targeted de novo epigenetic alterations important in tumor progression, and that these alterations occur through deterministic, rather than stochastic mechanism."

In studying vasculogenesis and metastasis in solid tumors, scientist from Harvard Medical School, A. C. Dudley et al., conducted experiments to dissect the biology of tumor-specific endolthelial cells (ECs) during tumor development in mice. The results published in the September 9th issue of Cancer Cell revealed that clonal populations of tumor-derived endothelial cells co-expressed hematopoietic and mesechymal stem cell markers. These ECs were found to be able to differentiate into chrondrocytes via upregulation of cartilage-specific genes, Col2a1 and Sox9 as well as the ability to differentiate into osteocytes in which the cells expressed osteocalcin and osteopontin. The investigators also found that in both human and mouse prostate tumors, ectopic vascular calcification was primarily localized in the luminal region of the blood vessels in which the cells were found to express the CD31 surface marker. The authors concluded that "prostate tumor endothelial cells are atypically multipotent and can undergo a mesenchymal-like transition."

In the September 3, 2007 post, we summarized the controversy revolving around hematopoietic stem cells protecting their genome from mutation by retaining the older strand of DNA during self-renewal as a mechanism to prevent accumulation of mutations which may lead to cancer. Belgium scientists reported in the September 4th online of edition of Stem Cells, conducted in vivo chromosome segregation studies using double-label pulse-chase assays during morphogenesis of multipotent hair follicle stem cells (HFSCs). The experimental results demonstrated that HFSCs incorporated two different nucleotide analogs, which contradicted the immortal strad hypothesis of John Cairns. The investigators also noted that chromosomal co-segregation and label retention in HFSCs are a "mark of relative quiescence." Additionally, the authors concluded from their experimental results that chromosome segregation occurs randomly during morphogenesis, development, and tissue homeostasis following activation of the HFSCs.

In the September 3rd online edition of PNAS, scientists from the National Cancer Institute, Y. J. Chung et al., reported their ability to transfer myelodysplastic syndromes (MDS) into wild-type recipients engrafted with hematopoietic stem cells (HSCs) from donors with MDS. The HSC were bone marrow-derived long-term repopulating HSCs carrying the NUP98-HOXD13 (NHD13) transgene which give rise to MDS and acute myeloid leukemia (AML). The recipients receiving the MDS bone marrow displayed the clinical symptoms of MDS such as blood cytopenia, dysplasia, and transformation to AML. The experimental results revealed that approx. 1/6,000 to 1/16,000 of the MDS bone marrow-derived cells could transmit the disease with overt disease usually occurring 46-49 weeks after transplant. The authors concluded that their findings "demonstrate that MDS originates in a transplantable, premalignant, long-term repopulating, MDS-initiating cell."