ESCs and Cancer Stem Cells Share Genetic Expression Pattern

ESCs and Cancer Stem Cells Share Genetic Expression Pattern Wednesday, 09 April 2008 A new study suggests that a genetic fingerprint associated with normal embryonic stem cells may be important for the development and function of cancer stem cells. 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. Cancer Stem Cells Created With a bit of genetic trickery, the researchers turned normal skin cells into cancer stem cells, a step that will make these naturally rare cells easier to study. Dr. Chang said being able to generate cancer stem cells from normal cells will help move that research forward. "The upshot is that there may be a way to directly create cancer stem cells in the lab so you don't always have to purify these rare cells from patients in order to study them directly," he said. Cancer stem cells are thought to be the ones that drive a cancer, and are therefore the targets of any cancer therapy that must kill them in order to be effective. Understanding these cells has been a challenge, however, because they are rare, difficult to isolate and don't grow well in the lab. 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 tumour-inducing genes Ras and I(kappa)B(alfa), c-Myc increased the number of tumour-initiating cells that exhibited key properties associated with cancer stem cells and dramatically increased the frequency of tumour formation in mice. The study also demonstrated that cancer stem cells are much more similar to the stem cells found in embryos, which can develop to form all tissue types, than they are to the more-restricted adult stem cells. This finding has important implications for understanding how cells go awry when they become cancerous. Cancer stem cells were first discovered in 1994 by researchers at the University of Toronto. In 2003, Michael Clarke, PhD, who was then at the University of Michigan, discovered cancer stem cells in the first solid tumour, breast cancer in this case, showing that the concept of cancer stem cells wasn't restricted to blood cancers. Clarke has since moved to Stanford, where he is the Karel H. and Avice N. Beekhuis Professor in Cancer Biology. One question among cancer stem cell researchers has been how those cells originate. "By the time a patient comes to a hospital, they already have a cancer, so that process has already happened," Chang said. Generating cancer stem cells in the lab gives scientists insight into how the transformation happens and could lead to new ways of either stopping the transformation early on or detecting and destroying those cells once they form. Chang and first author David Wong, MD, PhD, postdoctoral scholar, began to answer the question of how cancer stem cells originate by comparing genetic activity in embryonic stem cells with the activity in normal adult stem cells. They found a large group of genes that were active only in embryonic cells. They then looked at which genes were active in cancer stem cells and found that the pattern resembled that of embryonic stem cells. The finding was a surprise, given that once embryonic stem cells become committed to forming adult cells, such as skin, brain or blood, they were thought to forever deactivate those embryonic genes. Instead, Chang said this work suggests that when those adult cells become cancerous, they turn those embryonic genes back on. The group also noticed that the genes active in both embryonic and cancer stem cells are controlled by a few biological master regulators. One of those genes, called Myc, has also been shown recently to help convert normal skin cells into embryonic-like cells. By activating two genes in addition to Myc in normal skin cells, those cells were transformed into what appeared to be cancer stem cells. When transplanted into laboratory mice, the cells formed tumours, one hallmark of a true cancer stem cell. From here, Chang and Wong hope to learn more about how these genes activate a cancerous state. "Our particular interest is in using this approach to find the mechanism that turns a normal cell into a cancer stem cell," said Chang. In conclusion, 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. References: Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells David J. Wong, Helen Liu, Todd W. Ridky, David Cassarino, Eran Segal, and Howard Y. Chang Cell Stem Cell, Vol 2, 333-344, 10 April 2008 Inappropriate Expression of Stem Cell Programs? Yingzi Wang, and Scott A. Armstrong Cell Stem Cell, Vol 2, 297-299, 10 April 2008 ......... ZenMaster

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