Prostate cancer signal reawakens 'sleeper agent' cells in bones

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Prostate cancer signal reawakens 'sleeper agent' cells in bones Dormant prostate cancer cells in bone tissue can be reawakened to cause secondary tumours, according to new research published in Endocrine-Related Cancer. Targeting the wake-up call could prevent metastasis and improve prostate cancer survival rates.

Metastasis is the spread of cancer from one organ to another and is a highly complex process, involving cancer cells breaking away from a primary tumour, travelling to a distant organ and colonising it. Cancer cells that fail to form a tumour in the newly-encountered tissue can fall into a dormant state. Researchers from the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute in California found that dormant prostate cancer cells within bone tissue can be reawakened to a cancerous state when exposed to RANKL, a molecule commonly produced in inflammatory cells. This reawakening can lead to metastatic prostate cancer in bone tissue.

Produced by prostate cancer cells, RANKL is a signalling molecule that has been previously linked with human prostate cancer survival. In this study, researchers engineered a clinically relevant prostate cancer cell line to overproduce RANKL. They found that these cells could significantly alter the gene expression of surrounding cells in vitro, causing them to transform into aggressive cancer cells.

Researchers then injected engineered RANKL cells directly into the blood circulation of mice, which caused dormant cells within the skeleton to re-awaken, ultimately creating tumours within the bone. When the RANKL receptor was blocked, these tumours did not form.

After examination, these tumours were found to contain both the RANKL-overproducing prostate cancer cells, as well as the dormant cells, which had been transformed to become cancerous. Remarkably, the transformed cells displayed aggressive traits that would make them resistant to the normal hormone therapies used to treat prostate cancer.

The findings are preliminary as the study used prostate cancer cells that had been engineered to overproduce RANKL. The next step is to see if other cells known to produce RANKL may also be able to recruit dormant cells to colonise bone tissue.

"We are currently embarking into clinical research with human patients," said lead researcher and postdoctoral fellow Chia-Yi (Gina) Chu, PhD. "Though more work must be done to understand how RANKL reprograms dormant cells to become cancerous, we look forward to examining its influence on promoting metastasis and secondary tumours."

Each year, a quarter of a million men die from prostate cancer worldwide (1). Bones are the most common site of prostate cancer metastases and are typically lethal in 72 percent of cases based on a five year survival rate (2). "If we can prevent prostate cancer metastasis to bone we would significantly enhance patient quality of life and increase survival rates," added Chu.

### (1) World Health Organisation (2008) World Cancer Report 2008 [Accessed 20/01/2014]

(2) Prostate Cancer Overview (2013) American Cancer Society [Accessed 21/01/2014]