Molecular switch allows mobile cancer cells
themselves from the host of other cancer cells and move away to a
different parts of the body has been discovered Researchers believe
this molecular step is a viable target of which drugs designed to
block the process can be designed to great effect.
The process of migration, also known as metastasis, directly accounts for 90 per cent of cancer deaths. The characteristic local invasion and distant metastasis of tumour cells, is poorly understood and an insight into how this process works in cancer has been urgently needed.
The switch, in the form of an enzyme known as GSK-3ß, is known to alter the function of proteins and may offer an anticancer strategy to pursue. A drug therapy, for example, that bolsters GSK-3ß may repress the ability of cancer to spread.
GSK-3ß, which is important in the regulation of glycogen synthesis and is also critical to neuronal development, plasticity, and survival; it is known, for example, to regulate levels of proteins (eg, phosphorylated tau) involved in neurodegeneration.
Mien-Chie Hung, the study's lead author said: "It always has been a mystery as to what allows a cancer cell to become mobile and move away from a tumour, but now we have found a very interesting mechanism that explains it."
Most cancers are "solid tumours" and are composed of epithelial cell, those that make up the membranous tissue covering organs and other internal surfaces of the body. Although epithelial cells are firmly fixed to each other in a network that makes up tissue, researchers know that embryonic epithelial cells have the ability to move.
To achieve this, epithelial cells take on characteristics of mesenchymal cells, those that develop into connective tissue and blood vessel cells. They form collagen fibres allowing them to form at locations where they are needed during development.
This process, known as epithelial-mesenchymal transition (EMT), has been observed in cancer progression, Hung said: "Increased motility and invasiveness of cancer cells resembles the EMT that occurs during embryonic development."
Epithelial cells contain protein known as E-cadherin, which fix the cells onto the tissue membrane while gluing cells to each other. Mesenchymal cells, in contrast, do not express E-cadherin, which allows them to move freely.
A transcription factor known as "snail" was found to control the gene that produces the E-cadherin protein. Snail turns off E-cadherin expression, thus freeing epithelial cells.
"Cells without E-cadherin are not stuck to each other any more and can move, so we looked for the regulator of snail," Hung commented.
The researchers discovered that the GSK-3ß enzyme controls snail. It achieves this by telling the snail transcription factor to go to the wrong place, where it is then destroyed. The cancer cells continue to produce E-cadherin and retains all the properties of a fixed epithelial cell.
Hung also said that known cancer pathways, such as those that involve the epidermal growth factor receptor (EGFR) have been shown to inhibit the GSK-3ß enzyme.
"We have mechanistically shown how a signalling pathway known to promote cancer development can also promote metastasis," he says. "Now we have to work on ways to inhibit that process."
The research, from The University of Texas M. D. Anderson Cancer Center, appears in the advance online edition of the journal Nature Cell Biology
