CNRS researchers at the Institut Curie have shown in embryos that a cell-surface protein called Я1 integrin is essential for the formation of the enteric nervous system, which controls the passage of food through the gut. If the cells destined to form the future enteric nervous system lack Я1 integrin, their capacity to migrate is impaired and they fail to colonize the whole intestine. This anomaly resembles Hirschsprung's disease, a rare human congenital malformation. These findings also shed new light on how cancer becomes invasive when tumor cells acquire the ability to move around the body, giving rise to metastases. This discovery, which is reported in the May 2006 edition of Development, should enhance understanding of the development of Hirschsprung's disease and tissue invasion in cancer.
Life's great adventure starts when an ovum fuses with a spermatozoa to form an egg, which divides into two cells, then four, eight, and so forth, before the embryo attaches to the womb lining and develops. The embryo's cells don't just divide, they also specialize: some become nerve cells, others muscle or blood cells. They move around and join forces to form organs within the embryo, which progressively becomes a fetus. A "neural" tube subsequently forms throughout the length of the embryo and supplies all the cells needed to make the central nervous system, that is the brain and spinal cord, as well as the peripheral nervous system, the body's other nerve cells.
The peripheral nervous system arises from a particular population of cells in the dorsal region of the neural tube. These so-called neural crest cells migrate through the embryo and invade the different tissues. For example, the cells that give rise to the enteric nervous system migrate towards the intestine that is being formed and colonize it by advancing to its distal end, the future rectum. It is only after they have invaded the whole intestine that the cells acquire all the special features of the enteric nervous system. In newborn babies and adults alike, these cells control the passage of food through the gut and its absorption during digestion.
Cell migration in formation of the enteric nervous system
Marie Breau in Sylvie Dufour's group(1) is studying the formation of the enteric nervous system in mouse embryos, and particularly the role of integrins(2), the cell-surface proteins that anchor cells to their environment. Mice that do not express the gene of Я1 integrin cannot survive, so Marie Breau studied the consequences of "switching off" this gene in the neural crest cells of mouse embryos. Without Я1 integrin on their surface, the precursor cells of the future enteric nervous system fail to fully colonize the intestine and stop halfway down the colon because their ability to migrate is greatly impaired. The resulting "mutant" mice therefore lack a nervous system in the descending colon. This anomaly resembles Hirschsprung's disease in humans, a rare congenital disorder which affects one in 5000 newborns (see Further information).
When tumor cells escape…
Colonization of the embryonic gut by cells from the neural crest has a number of points in common with the development of metastases in cancer patients. Certain cancer cells do not stop their progression after invasion of the original tissue but instead spread throughout the body. As long as the cancer cells remain where they are the tumor is localized and can be controlled by local treatment (surgery, radiotherapy), thereby curing the patient. However, if the cancer cells acquire the capacity to disseminate through the body, the tumor is considered to be metastatic and is more difficult to eradicate. The mouse model developed by the Institut Curie researchers should help us understand how metastases form, information essential to the improvement of cancer management.
Integrins, which are already known to be involved in the transformation of local tumors into invasive ones, appear to be possible targets for cancer treatments. It therefore seems doubly important to decode the mechanisms linking integrins to the process of tissue invasion.
(1) Cellular morphogenesis and tumor progression" group headed by Jean Paul Thiery - UMR 144 CNRS/Institut Curie "Subcellular structure and cellular dynamics"
(2) Integrins, which constitute a large family of proteins involved in signal transmission, control the proliferation, survival, migration and differentiation of cells.
Embryonic development, a "mirror image" of oncogenesis
The transformation of one cell into many underlies both embryo formation and cancer growth. The cells of the fertilized egg divide rapidly, before migrating to form future organs. Similarly, cancer cells that escape from the original tumor may engender metastases. Embryonic development is therefore a sort of "mirror image" of tumor transformation, and oncologists and developmental biologists have already shown that the same genes are often involved in the two processes.
Between now and 2008, the Institut Curie will open a new international research center dedicated to developmental genetics and biology. This milestone should spur rapid advances in the understanding of cancer formation as well as the development of new therapeutic strategies.
Further information on Hirschsprung's disease
Hirschsprung's disease is one of the most frequent congenital malformations of the digestive tract and occurs in approximately one out of every 5 000 live births. More common in boys than girls, it is usually apparent in the first three to five months of life, and is due to the partial or total absence of nerve ganglia essential to the correct functioning of the intestinal muscles. The degree of aganglionosis determines the severity of the resulting diffuse or localized intestinal paralysis affecting the colon (large intestine), the distal colon, or the rectum (which links the colon and anus). Movement of food through the digestive tract and the absorption of its nutrients are impaired, the gut becomes blocked and swells.
About the INSTITUT CURIE
The Curie Institute : Fighting cancer. Hospital and Research center, side by side. Not-for-profit foundation accredited as a French public service body since 1921. 26 rue d'Ulm 75248 Paris cedex 05 - France. The Curie Institute has expanded upon the pioneering work of Marie Curie, who was awarded the Nobel Prize in physics (1903) and in chemistry (1911). Since its origins, the institute has favoured an interdisciplinary co-operation between physicists, chemists, biologists and clinicians, in order to put research progress at the disposal of patients as fast as possible. The Curie Institute is gathering 1500 staff members within two sections : The Research center is composed of 12 units associated with the CNRS (National Centre of Scientific Research) or INSERM (National Institute of Health and Medical Research) and dedicated to fundamental cancer research. The Hospital is committed to the diagnosis and treatment of cancer, where 7500 new patients are treated each year. L'Institut Curie : Face au cancer, l'union d'un Hфpital et d'un Centre de Recherche Fondation reconnue d'utilitй publique depuis 1921. 26 rue d'Ulm 75248 Paris cedex 05 - France. L'Institut Curie est nй des travaux pionniers de Marie Curie, rйcompensйe par le Prix Nobel de physique (1903) et de chimie (1911). Depuis ses origines, l'institut a su favoriser les collaborations interdisciplinaires entre physiciens, chimistes, biologistes et cliniciens, afin de mettre le plus rapidement possible les derniers progrиs de la recherche а la disposition des malades. L'Institut Curie rassemble 1500 collaborateurs au sein de deux pфles d'activitйs : Le Centre de Recherche est composй de 12 unitйs associйes au CNRS ou а l'INSERM et dйdiйe а la recherche fondamentale en cancйrologie . L'Hфpital se consacre au diagnostic et au traitement des cancers, et accueille chaque annйe 7500 nouveaux patients.
INSTITUT CURIE
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75005 Paris Cedex 05
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