Stem cell propagation fuels cancer risk in different organs

August 25, 2016

(MEMPHIS, Tenn. - August 25, 2016) The idea that stem cells - special cells that divide to repair and generate tissues - might be the major determinant of cancer risk has provoked great debate in the scientific community. Some researchers maintain that environmental carcinogens are more important in determining cancer risk. Now a team of researchers at St. Jude Children's Research Hospital and the University of Cambridge, England, has performed a large systematic, organism-wide study that confirms the crucial contribution of stem cells to the origins of cancer in different organs of mice. The results appear online today in the journal Cell.

"The chance accrual of random mistakes in cell DNA likely plays an important role in generating cancer; but whether this has to happen in specific cell types, such as stem cells, and precisely how other factors such as environmental carcinogens contribute to cancer is unclear," said the study's senior author Richard Gilbertson, M.D., Ph.D., director of the Cancer Research UK Cancer Center at Cambridge University, England, and former St. Jude scientific and Comprehensive Cancer Center director. "Indeed, an argument has raged across the scientific community for some years now - some say cancer is 'bad luck' because mutations arise by chance in stem cells, while others argue environmental carcinogens are more important. This disagreement has arisen largely from the use of different mathematical models to look at existing human cancer and stem cell data, from which it is extremely difficult to tease out the impact of individual factors. Therefore, we tested these different opinions in actual experimental models that looked at the individual components that might drive cancer."

The researchers used a specific "marker molecule" called Prom1 to map the activity of cells in different organs throughout the life of mice. In some organs, Prom1+ cells were mature, non-dividing cells that did not repair or regenerate the organ, but in a handful of organs these cells were highly active stem cells. "By following these Prom1+ cells in all the major organs in mice through their lifetime journey we were able to identify in which organs these cells were actively dividing stem cells," said Liqin Zhu, Ph.D., a research associate at St. Jude and the first author of the study.

Once they had an organism-wide map of the function of these cells, the researchers introduced DNA mutations into these cells similar to the changes that occur in human cancers. "This approach does away with the need for carcinogens, removing them from the cancer equation and allowing us to test if the generative capacity of stem cells influenced cancer risk," said Zhu. After a rigorous study lasting more than seven years and comprehensive statistical modeling of the results by Dr. Arzu Onar-Thomas at St. Jude, the clear answer was that only cells with stem cell activity make cancer.

"But that's not the whole story," said Gilbertson. "While we have shown that stem cell function is required to generate cancer, our study also revealed that damage to tissues such as the liver, the kind that can occur in humans, can 'wake up' sleeping stem cells, make them divide and massively increase cancer risk. Therefore, we propose that the origin of cancer lies in a 'perfect storm' that includes DNA mutations, stem cell function and tissue damage," concluded Gilbertson

The scientists also showed that stem cells in newborn animals are far less likely to undergo malignant transformation compared to adult stem cells, which suggests that stem cells in the newborn are intrinsically resistant to the formation of tumors. "If this biology were to hold true in humans, then it may explain why cancer rates are many-fold lower in children than adults, despite the fact that childhood cancers accrue significant numbers of mutations that alter proteins, and the growth rates of organs peak in childhood," said Zhu.

Many of the new cancer models described in the study bear striking similarities to human diseases and should provide a valuable resource for further biological and therapeutic studies.
-end-
The study's authors are Liqin Zhu, David Finkelstein, Culian Gao, Lei Shi, Yongdong Wang, Stanley Pounds, Geoffrey Neale, David Ellison, Arzu Onar-Thomas of St. Jude. The study's other authors are Dolores López-Terrada of Baylor College of Medicine, Kasper Wang and Sarah Utley of Children's Hospital Los Angeles, and Richard James Gilbertson of CRUK Cambridge Institute (formerly at St. Jude).

This research was supported by funding from the National Institutes of Health (P01CA96832, R01 and P30CA021765), Cancer Research UK and ALSAC.

Further reading:
1. Tomasetti, C., and Vogelstein, B. (2015) Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78-81.
2. Wu, S., Powers, S., Zhu, W., and Hannun, Y.A. (2016) Substantial contribution of extrinsic risk factors to cancer development. Nature 529(7584): 43-47.

St. Jude Children's Research Hospital

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.