The majority of cancer deaths occur due to metastases – Where cancer cells from a tumor break away and cause cancers in other parts of the body. Some cancers are more likely than others to metastasise, and consequently, these cancers have a higher mortality rate.
While many studies have been conducted to identify genetic mutations that allow cancer cells to break away, the process by which cancers metastasize is still largely unknown. Relatively few genetic mutations have been identified that are believed to drive metastasis.
However, a recent study conducted by researchers at the MRC Cancer Unit at the University of Cambridge provides new clues into how metastasis occurs.
While previous research has concentrated on mutations, the MRC Cancer Unit researchers looked for other methods that could potentially be involved, including the switching on and off of certain genes. DNA sequences called enhancers are sections of DNA that proteins (transcription factors) can bind to, which activates particular genes.
The researchers studied samples of human renal cancer in a mouse model and saw that genes in cancer cells that were capable of spreading to other tissues had certain genes switched on that were not switched on in other cancer cells.
Genes that were normally switched off in kidney cells had been switched on and were being expressed. The researchers concluded that cancer cells hijacked those expressed genes, enabling them to spread around the body to other locations.
“Oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states,” wrote the researchers.
The researchers studied the enhancers and enhancer clusters in metastatic cancer cell populations and compared those to samples taken from patients with clear cell renal cell carcinoma, the most common type of kidney cancer. The patterns of gene activation in their mouse model were similar to those in the clinical samples. Further, experimental models of breast cancer suggest a similar mechanism is involved in metastasis.
“We show for the first time how cancers can steal the activity of specific enhancers – genetic regions which turn genes on and off – to activate genes from different tissue types. Activating these genes allows the cancer cells to steal features from normal cells, which facilitates their spread in the body,” said senior author of the paper, Dr Sakari Vanharanta.
While the research has helped to identify the mechanism by which cancers can metastasize, other than through genetic mutation, what is not yet understood is how changes in enhancer activation occurs.
Further research in this area is required. If that process is better understood, it could lead to the development of new cancer drugs that could be used to stop cancers from metastasizing and thus improve survival rates.
The study – NF-κB–Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis – was recently published in the journal Cancer Discovery: DOI: 10.1158/2159-8290.CD-17-1211