Developmental biology : Integrin, the protein which gives cells a licence to roam

If the cells destined to form the future enteric nervous system lack ß1 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 ß1 integrin cannot survive, so Marie Breau studied the consequences of “switching off” this gene in the neural crest cells of mouse embryos. Without ß1 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.