Scientists find link between cell migration and cancer metastasis
A two-man research team at the Fred Hutchinson Cancer Research Center in the United States has discovered how cells migrate in the developing brain and how other types of cells may travel inside the body. Part of this study was backed with a Marie Curie Fellowship grant via the EU. Presented in the journal Nature Neuroscience, the results could provide major insight into neurological development and help elucidate cancer metastasis.
Cells divide and position themselves in appropriate patterns during the body's normal development, and specialise to create discrete tissues and organs. Normal development of a human body is contingent on how cells manage their migratory patterns. Another critical element is the process by which they differentiate or evolve from less specialised cells into more specialised cell types, according to researchers. Bad coordination could trigger abnormal development, and in turn lead to cancer.
Dr Jonathan Cooper from the Sciences Division of the Fred Hutchinson Cancer Research Center and Dr Yves Jossin, a research fellow in Dr Cooper's laboratory, probed the migration of cells in the cerebral cortex of the developing brain. The cerebral cortex, which is the grey matter of the cerebrum, plays a significant role in the human body, specifically controlling memory, attention, perceptual awareness, language, consciousness and thought.
Highly developed in humans, the cerebral cortex is composed of horizontal layers of specialised neurons and connected vertically into circuits. When nerve cells are located in wrong layers, it could result in defective wiring and cause neurological disorders such as autism, schizophrenia and epilepsy.
If we take a look at a human foetus, the cortex grows 'from the inside out' through the addition of new nerve cells. These neurons move from the inside and pass between neurons already located in intermediate layers. They then create new layers on the outside, the researchers say. The long—standing question is: how are the migrations regulated?
Drs Cooper and Jossin found a number of signals that control a specific stage in a cortical neuron's trip. According to them, new nerve cells start moving from the inside to the outside in a straight line until they reach a layer known as the 'intermediate zone', which is a niche for some neurons but a major spot for many axons (connecting fibres).
Once the new neurons reach this layer, they get lost and move erratically. When they finally leave the intermediate zone, the neurons realign with the original direction of movement and race ahead through layers of differentiated neurons towards the cortex's exterior surface, according to the team.
So how do neurons find their way after exiting the mess in the intermediate zone? Drs Cooper and Jossin identified a signalling protein called Reelin, which is created by cells found in the cortex's most outer layer. It's no secret that mutations in the Reelin gene trigger significant abnormalities in cortical layers. But no one has been able to figure out when cell migration goes awry in the absence of Reelin. The findings indicate that new nerve cells respond to Reelin as they emerge from the intermediate zone.
'This is remarkable because the top layer of the cortex, where Reelin is made, is widely separated from the top of the intermediate zone, where it acts, so the Reelin protein must be diffuse (sic),' Dr Cooper said. 'It is also remarkable that Reelin seems not to be a direction signal itself. Rather, Reelin triggers changes in the membranes of the migrating neurons that allow the cells to respond to direction signals.'
The membrane protein N—cadherin swells on the surface of the cells when Reelin enters the picture. This boost enables the neuron to select the appropriate direction for its next migration stage.
'This represents a new and surprising function for N—cadherin because normally this protein acts as a cellular stabiliser and not as an orchestrator of migration,' Dr Jossin pointed out. 'The new role for N—cadherin in orienting migrating cells is quite unexpected and suggests that cadherins on the surface of other types of normal or cancer cells may also be involved in helping them move rather than stay in place. This finding could provide new clues to how normal and cancerous cells migrate within the body.'