Cancer stem cells and the guardian of the genome

Are there cancer stem cells?
LifeSciencesToday based on the materials of the Salk Institute:
The stemness of cancer cells

Scientists at the Salk Institute for Biological Studies and the Institute for Advanced Study have found that the p53 tumor suppressor, which has long been considered the "guardian of the genome," has greater capabilities than just preventing cancer-causing mutations. It can prevent the transition of already formed cancer cells into a more aggressive state, close to the state of stem cells, acting as a "defender against reprogramming of the genome."

A new work (Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures), authored by Geoffrey M. Wahl and Benjamin Spike from the Salk Institute and Arnold J. Levine and Hideaki Mizuno from the Institute for Advanced Studies, has been published online-publication of the journal Proceedings of the National Academy of Sciences. It presents striking parallels between the increased efficiency of reprogramming normal adult cells devoid of p53, the inherent plasticity and tumorigenicity of stem cells and the high level of p53 mutations in cancer cells.

"Cellular and genetic heterogeneity and low differentiation are well–known signs of many aggressive and incurable forms of cancer," explains Val, professor at the Salk Institute's Gene Expression Laboratory, "and it has recently been suggested that these properties are explained by the presence of stem–like cancer cells in tumors. Our data show that p53 mutations can allow tumor cells to turn back time by mastering a "program" similar to the "program" of stem cells."

Cancer cells need to acquire some of the properties of stem cells in order to survive and adapt to constantly changing conditions. Such properties include immortality, the ability to self-renew and the production of precursors that differentiate into other types of cells. "Each tumor is a set of cancer cells with a great variety," explains Val, "and the question is how to explain the occurrence of such heterogeneity."

In the past, the cellular diversity of a cancerous tumor was mainly associated with the genetic instability that occurs when p53 is disabled, which Val and his group demonstrated many years ago. As the population of tumor cells increases, as considered in the dominant theory, random mutations occur in individual cells, and their molecular identity is violated. By the time cancer is detected, the millions of cells that make up the tumor become as different from each other as the relatives who are referred to as "the seventh water on jelly" are different.

For a long time there was also the idea that fully committed and specialized cells could dedifferentiate at the stage of initiation and progression of the tumor, although it was unclear how this happens. In the end, the theory was rejected in favor of the currently fashionable theory of cancer stem cells, according to which cancer stem cells – cells that can potentially arise from normal stem cells or early precursors – differ from the bulk of cancer cells in that they can self-renew and produce non-stem cells in the same way as normal stem cells do.

The tumor suppressor p53 prevents the transition of cancer cells into a more aggressive state, similar to the state of stem cells. Tumor cells with inactivated p53 demonstrate a high degree of similarity of the genetic profile with embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). (Red shows the highest degree of similarity). (Illustration: Courtesy of Dr. Benjamin Spike)

"Our data show that cancer cells resembling stem cells do not necessarily have to be part of the original tumor, but rather can occur at later stages of its development as a result of the loss of p53," says Benjamin Spike. "The observed tumor heterogeneity is probably a combination of increasing genetic instability and epigenetic instability associated with the acquisition of a phenotype similar to that of stem cells."

When Val and his colleagues were already considering the possibility that p53 is not only the "guardian of the genome", a joint study with Juan-Carlos Izpisúa Belmonte, also a professor at the gene expression laboratory, showed that this tumor suppressor is also a barrier to the reprogramming of somatic cells.

To find out whether inactivation of p53 leads to the appearance of tumor cells resembling stem cells, Spike and Mizuno studied hundreds of archived gene expression profiles of breast and lung tumors in search of signs characteristic of stem cells, while correlating them with the status of p53.

"We found a close correlation between tumors with confirmed mutations of p53 or its inactivation and gene expression patterns typical of stem cells," explains Spike. "This will affect our understanding of p53, since now its loss seems to reflect not only the impossibility of immediate cell death and the elimination of proliferative barriers to tumorigenicity."

Val hopes that a new understanding of the process leading to the return of tumor cells to a state closer to that of stem cells will reveal new targets for therapeutic intervention. "The more tumor cells resemble stem cells, the more aggressive the tumor appears to be, but the cells may still have a residual ability to differentiate into less aggressive types," he says. "If we manage to use this potential, we can make them differentiate and become less dangerous. This is an old idea that we have to seriously rethink today."

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14.01.2011