New Clues from Fruit Flies about the Critical Role of Sex Hormones in Stem Cell Control
In one of the first studies addressing the role of sex hormones' impact on stem cells in the gut, scientists outline new insights showing how a steroidal sex hormone, that is structurally and functionally similar to human steroid hormones, drastically alters the way intestinal stem cells behave, ultimately affecting the overarching structure and function of this critical organ. The authors found that ecdysone, a steroid hormone produced by fruit flies, stimulates intestinal stem cell growth and causes the gut of the female fruit fly to grow in size, and induces other critical changes. The study also provides a mechanism to account for sex-specific roles for intestinal stem cells in normal gut function. Moreover, the research presents evidence that gut hormones may accelerate tumor development. The findings, reported jointly by the German Cancer Research Center (DKFZ) and the Huntsman Cancer Institute (HCI) at the University of Utah (U of U), are published in the journal Nature.
Sex hormones increase the risk of oncogenic mutations triggering tumours: Middle: Intestinal stem cells with a carcinogenic mutation (green), right: the same cells under the influence of the sex hormone
© Teleman/DKFZ
Bruce Edgar, a stem cell biologist at HCI and professor of oncological sciences at the U of U, together with Aurelio Teleman, division head at DKFZ and professor at Heidelberg University jointly led the work. They asked whether sex hormones affect intestinal stem cells' ability to multiply and contribute to gut growth. "My lab and many others around the world have studied the Drosophila gut for some time to better understand how stem cells are regulated," says Edgar. "We knew that male and female fruit flies exhibited differences in their intestine – for example, the female's intestine is larger than the male's, and females develop intestinal tumors much more readily than males – but we didn't know why." This study adds significant insights into these differences, and how they arise.
The Edgar and Teleman teams found that ecdysone, a sex-specific hormone, can drastically alter the growth properties of stem cells in an organ that, remarkably, is not directly involved in reproduction. They found that these changes affect the structure and function of the entire organ. They discovered that subjecting male flies to ecdysone caused their otherwise slow dividing stem cells to divide as fast as in females, leading to intestinal growth in males as well. This suggests that the limiting difference between the division of stem cells in male and female flies is the circulating levels of the hormone.
This process confers both advantages and disadvantages to the female fruit fly during the course of its life. Initially, more ecdysone in females helps with the evolutionarily critical processes of reproduction. It promotes gut enlargement, facilitating nutrient absorption, which helps the fly lay more eggs. But later in life, the ecdysone hormone, produced by the ovaries, eventually causes gut disfunction that can shorten the lifespan in female fruit flies by creating an environment that favors tumor growth. While humans don't produce ecdysone, they do have related steroid hormones such as estrogen, progesterone and testosterone, which have similar mechanisms of action.
The experimental work on this study was performed primarily by Sara Ahmed, a joint PhD student between the Edgar and Teleman labs at the Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) and the DKFZ. Ahmed designed experiments utilizing various genetic tools to switch genes on and off in different cell types in the fly's intestine and in its ovaries, which produce ecdysone. "Our study provides conclusive evidence that sex hormones alter the behavior of non-sex organs like the intestine," says Ahmed. "This opens up possible future study directions, of using sex hormone-targeted therapeutics in treating human cancers of non-sex organs."
According to the researchers, understanding whether a similar stem cell-hormone relationship operates in human organs will require further studies. They plan to explore this in the future. In addition to the critical role played by sex hormones in intestinal stem cell behavior, the authors believe this study in Drosophila potentially unveils a new mechanism that may play out in human physiology and pathology. Insights from this study add to a broad body of work showing that the incidence of many cancers of non-reproductive organs, including colon and gastric cancer, is strongly affected by sex.
This study was supported by the National Institutes of Health including the National Cancer Institute P30 CA01420114, the National Institute of General Medical Sciences R01 124434, the European Research Council AdG268515, DKFZ, and Huntsman Cancer Foundation.
Sara Mahmoud H. Ahmed, Julieta A. Maldera, Damir Krunic, Gabriela O. Paiva-Silva, Clothilde Pénalva, Aurelio A. Teleman & Bruce A. Edgar: Fitness trade-offs incurred by ovary-to-gut steroid signalling in Drosophila.
Nature 2020, https://doi.org/10.1038/s41586-020-2462-y
About Huntsman Cancer Institute: Huntsman Cancer Institute (HCI) at the University of Utah is the official cancer center of Utah. The cancer campus includes a state-of-the-art cancer specialty hospital as well as two buildings dedicated to cancer research. HCI treats patients with all forms of cancer and is recognized among the best cancer hospitals in the country by U.S. News and World Report. As the only National Cancer Institute (NCI)-Designated Comprehensive Cancer Center in the Mountain West, HCI serves the largest geographic region in the country, drawing patients from Utah, Nevada, Idaho, Wyoming, and Montana. More genes for inherited cancers have been discovered at HCI than at any other cancer center in the world, including genes responsible for hereditary breast, ovarian, colon, head, and neck cancers, along with melanoma. HCI manages the Utah Population Database, the largest genetic database in the world, with information on more than 11 million people linked to genealogies, health records, and vital statistics. HCI was founded by Jon M. and Karen Huntsman.
About DKFZ: The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.
Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.
