Dedifferentiation Turning Back the Cellular Clock

"But a civilized man is better off than the savage in this respect. He can go up against gravitation in a balloon, and why should he not hope that ultimately he may be able to stop or accelerate his drift along the Time-Dimension, or even turn about and travel the other way?" in "The Time Machine" by Herbert George Wells, 1895.Thanks to Albert Einstein's work on special relativity in the early 1900s, physicists have accepted time as the fourth dimension along with the three dimensions of space. However, even before Einstein, H.G. Wells in "The Time Machine" had alluded to the concept of time as a separate dimension. This classic along with numerous examples in history point to the centuries-old human fascination and yearning for time travel. Theoretical physicists have pored over tons of data and complicated equations, talked about wormholes and black holes hoping to get clues on this elusive concept. And in a way, we are all time travelers, hurtling down this fourth dimension super-highway.However, we are forced to travel in a unidirectional manner and only at a speed dictated by time. Hence, it is safe to say that our dream of "true" time travel is still unfulfilled and we are as far removed from achieving it as we were at the beginning of time!On the other hand, biologists have been trying and have finally succeeded in making cells go back in time, in terms of their developmental stage. They have successfully turned back the clock on cells to convert the so-called terminally differentiated cells into a more primitive stage. Development of these inducible pluripotent stem cells has been one of the most significant developments in biology, particularly in the field of stem cell research.The year 2012 would have to be regarded as an important year for stem cell research owing to the many seminal advances in this field. But perhaps the biggest nod to the importance of stem cells to basic research and clinical translation came from the Nobel Committee for Physiology or Medicine. Recognizing the importance of this area of research, the Committee awarded the Nobel Prize in Physiology or Medicine for 2012 to Sir John B. Gurdon and Dr. Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent".As early as 1962, Gurdon showed that after the nucleus from a frog egg was replaced by a nucleus from a mature, specialized cell, the egg still developed into a fully functional tadpole. This experiment suggested that even mature cells possess genetic information required to produce every cell in an organism (pluripotency). Over 4 decades later, Yamanaka showed that differentiated cells could be driven back developmentally to a more primitive stage. Cells could be reprogrammed to an embryonic-like state just by introducing four genes for proteins called transcription factors.These reprogrammed cells are designated inducible pluripotent stem cells and can be generated from any tissue or organ of an individual. The two biggest problems with embryonic stem cells are the ethical issues surrounding the source of these cells (human embryos) and the potential risk of rejection following transplantation. Human inducible pluripotent stem cells overcome both these limitations and hence hold unlimited potential for medical therapies.Another group of stem cells that have been getting some attention in recent years are the cancer-initiating cells or cancer stem cells. Researchers have been trying to identify the cell(s) of origin for cancer as this may help develop strategies to prevent cancer or treat it more effectively. Cancer stem cells were first identified in 1997 in acute myeloid leukemia and have subsequently been detected in many cancers. It is still not entirely clear how they originate or how they are regulated. However, it is understood that cancer stem cells: Can give rise to cancers Can drive uncontrolled growth of tumors Are highly resistant to chemotherapy and radiation May be the most important reason for failure of treatment to "cure" cancer completely Cancer stem cells have properties similar to normal stem cells and hence, have the potential for infinite growth and multipotency; they can differentiate to form the multitude of cells that constitute a tumor. This model in which cancer stem cells are the cells of origin and they in turn produce more differentiated tumor cells is described as a hierarchical model. This model has largely replaced the stochastic model that describes cancers to be composed of cells that have equal tumorigenic potential.Glioblastoma is a highly aggressive tumor of the central nervous system. Very few people with this deadly disease survive past two years. In an attempt to develop more effective treatment alternatives, scientists have been trying to identify the cell(s) of origin for glioblastoma. A 2002 study first described cancer stem cells for glioblastoma (1). Like other cancer stem cells, they can propagate indefinitely, express markers for neural stem cells and generate tumors in animal models. Important from the therapeutic standpoint is the fact that these cells are highly resistant to standard of care therapies for glioblastoma and are also the main reason behind tumor recurrence following surgery, radiation and chemotherapy.In spite of intense research, what exactly triggers the formation of a glioblastoma cancer stem cell remains elusive. Further, most researchers believe that these cancer stem cells originate from either normal neural stem cells or early progenitor cells. However, in a recent study, researchers at The Salk Institute for Biological Studies (La Jolla CA) challenge this dogma and show that cortical neurons in the brain can "go back in time", revert to a stem cell-like state and in turn produce tumors (2). This study represents a paradigm shift in our understanding of glioblastoma because of two main reasons: Mature neurons were thought to be terminally differentiated and incapable of any further transformation Glioblastomas were never before shown to arise from neuronal cells The approach taken by these researchers in their study was to genetically turn off the expression of two tumor suppressor proteins, p53 and neurofibromatosis type I (NF1) in the mouse central nervous system. The knockdown of these two proteins caused cortical neurons in the mouse brain to reprogram back to an immature or stem cell-like state. These cells now had a high expression of stem cell markers and a decreased expression of differentiation markers. This indicates that the cortical neurons underwent transformation to a more primitive phenotype.More importantly, they were able to produce tumors in mouse brains. Thus, following knockdown of p53 and NF1, cortical neurons regressed developmentally and formed glioblastoma cancer stem cells capable of tumorigenesis. Apart from neurons, glial cells and neural stem cells were also able to produce tumors following p53 and NF1 knockdown.The prevalent view on glioblastoma formation is that normal neural stem cells in the brain undergo malignant transformation and produce tumors. Hence, this is a landmark study that demonstrates how existing populations of mature brain cells, including neurons and glial cells can "enter a time machine and travel back to their developmental past" to a more primitive, stem-like state (a process called dedifferentiation) and eventually lead to tumor formation. Of course, the findings from this study need to be validated in human cells. But this study offers a possible explanation of the recurrence of glioblastomas following conventional therapy.In the same study, when mouse tumors generated were analyzed, their molecular profiles resembled a highly aggressive variant of glioblastomas observed clinically, designated as the mesenchymal subtype. Apart from this subtype, a previous study (3) has described three other variants, each with its distinct molecular signature. It is very likely that each of the
se subtypes originates from a distinct cancer stem cell type, which in turn may be produced by dedifferentiation of different cell populations in the central nervous system.The implication of this complexity is that an effective treatment strategy against this disease would need to include detailed molecular analyses of tumor signatures in order to personalize therapy. Findings from this study are important to understand the pathogenesis of glioblastoma and to design more effective treatment options. If a therapeutic agent can block dedifferentiation of cells, it may effectively get rid of cancer stem cell populations and prove to be a highly valuable adjunct to current therapies against glioblastoma.References:1. T. N. Ignatova et al., Glia 39, 193 (Sep 2002). DOI: 10.1002/glia.100942. D. Friedmann-Morvinski et al., Science 338, 1080 (Nov 2012). DOI: 10.1126/science.12269293. R. G. Verhaak et al., Cancer Cell 17, 98 (Jan 2010). DOI: 10.1016/j.ccr.2009.12.020Image: Human Stem Cells in Culture, Stemagen via Bloomberg News Follow Scientific American on Twitter @SciAm and @SciamBlogs.Visit ScientificAmerican.com for the latest in science, health and technology news. 2013 ScientificAmerican.com. All rights reserved.

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Dedifferentiation Turning Back the Cellular Clock