Nerve cell mechanism in cancer metastasis
Highly aggressive cancer cells spread throughout the body using an array of sophisticated mechanisms. Researchers have now discovered a new promoter of metastasis which lies in a core neural signalling pathway.
Metastasis – the process of cancer cells moving from one location in the body to another – is largely the reason why cancers become terminal. Researchers are aware of the different ways tumour cells hijack cellular mechanisms to aid in their dissemination; the most important being the recruitment of blood vessels to the tumour site. ‘Angiogenesis’ is the process of blood vessel attraction to an organ or tissue. This is important in order for tissues to receive oxygen and nutrients for cellular grown and division. Cancer cells have evolved to adopt this mechanism, mimicking the release of cytokines which attract endothelial cells lining blood vessel walls. These endothelial cells, in turn, release ‘angiocrine’ growth factors and a second wave of cytokines which attract blood-producing stem cells and epithelial cells to form blood vessels around the tumour. Not only does this new vasculature promote tumour growth and survival, it also allows cancer cells to enter the bloodstream and seed new tumours at different locations in the body.
Researchers from Rockerfeller University looked further into the role of endothelial cells in metastasis and found that a specific gene, Slit2, was highly expressed in the endothelial cells found in blood vessels embedded in malignant tumours which were particularly aggressive such as lung and breast cancers. In fact, there was a correlation between the level of Slit2 expression and known ability of a particular cancer to metastasise. Slit2 is naturally involved in neural signalling, axon guidance and establishment of neural connections. The scientists confirmed these findings by introducing fluorescent antibodies designed specifically against the protein into samples of breast and lung tumours and noted its presence in the surrounding blood vessels.
Looking further, the researchers experimented with mouse models of lung and breast cancers which were genetically designed to lack Slit2 expression in endothelial cells or the tumour cells themselves. By doing so, they were able to confirm that the upregulation of Slit2 in the walls of blood vessels promotes the migration of cancer cells into the blood stream, whilst the expression of Slit2 in tumour cells had no effect on cancer metastasis.
This upregulation of gene expression was found to be induced by the cancer cells themselves, which encourage endothelial cells to produce Slit2 and trigger the first step of cancer metastasis. Now that the researchers have identified this important stage in cancer progression, inhibiting this pathway in tumours specifically could give way to a novel drug to stop metastasis before it occurs.
Bernardo Tavora, Tobias Mederer, Kai J. Wessel, Simon Ruffing, Mahan Sadjadi, Marc Missmahl, Benjamin N. Ostendorf, Xuhang Liu, Ji-Young Kim, Olav Olsen, Alana L. Welm, Hani Goodarzi, Sohail F. Tavazoie. Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis. Nature, 2020; DOI: 10.1038/s41586-020-2774-y