The research, published by Cell Press in the April 10th issue of Cell Stem Cell, demonstrates that embryonic stem cells and multiple types of human cancer cells share a genetic expression pattern that is repressed in normal differentiated cells, a finding that may have significant clinical implications for cancer therapeutics.
Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial, explains study co-author, Dr. Howard Y. Chang from Stanford University. Dr. Chang, Dr. Eran Segal from the Weizmann Institute in Israel and their colleagues constructed a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells and human cancers.
The researchers identified two predominant gene modules that distinguish ESCs and adult tissue stem cells. Importantly, the ESC-like transcriptional program was activated in diverse human epithelial cancers and strongly predicted metastasis and death, says Dr. Segal. Conversely, the adult tissue stem gene module had an opposite pattern, activated in normal tissues relative to cancer and repressed in various human cancers when compared to normal tissues.
The researchers went on to demonstrate that c-Myc, but not other oncogenes, was sufficient to reactivate the ESC-like program in normal and cancer cells. In primary cells transformed by tumor-inducing genes Ras and I"B", c-Myc increased the number of tumor-initiating cells that exhibited key properties associated with cancer stem cells and dramatically increased the frequency of tumor formation in mice."
These findings suggest that activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristics of cancer stem cells. Further, the map of gene modules may prove to be a valuable tool for establishing improved standards for classifying and defining stem cells by using the expression signature modules as fingerprints rather than reliance on just a few molecular markers.
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After ten days, approximately 90 percent of the embryoid bodies mixed with retinoic acid-loaded microspheres began to display the hollow structure signifying differentiation, compared to 6 percent of the untreated bodies, 10 percent of the bodies coated with soluble retinoic acid, and 30 percent of the bodies mixed with empty microspheres. In addition, thirty percent of the embryoid bodies mixed with retinoic acid-loaded microspheres were completely hollow in the center, compared to nearly zero percent for the other groups.
These results suggest that if you can control the signaling by presenting molecules locally on the inside of the embryoid body from biodegradable microspheres, you can effectively change the course and synchrony of differentiation, said McDevitt.
To examine the cells in more detail, McDevitt teamed with Georgia Tech School of Biology chair John McDonald and research scientist Nathan Bowen to conduct microarray gene expression studies to determine cell phenotype.
The results revealed enhanced expression of fibroblast growth factor 5 (FGF-5) “ a marker for primitive ectoderm “ in the embryoid bodies mixed with retinoic acid-loaded microspheres compared to the other treatment groups after 10 days. The researchers also confirmed increased or inhibited expression of many additional markers.
The importance of these findings is that we've shown that biomaterial-based approaches to regulate stem cell microenvironments can significantly improve differentiation methods, said McDevitt. Our ultimate goal is to improve the efficiency of this differentiation process into specific cell types for cell replacement therapies.
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