Thomas Jefferson University researchers discover new pathways that drive metastatic prostate cancer

Elevated levels of Cyclin D1b could function as a novel biomarker of lethal metastatic disease in prostate cancer patients, according to a pre-clinical study published ahead of print on December 21 in the Journal of Clinical Investigation by researchers at the Kimmel Cancer Center at Jefferson.

The group, headed by Karen E. Knudsen, Ph.D., Professor and Hilary Koprowski Chair, Departments of Cancer Biology, Urology, and Radiation Oncology at Thomas Jefferson University and Deputy Director for Basic Science at the KCC, found that Cyclin D1b, a variant of the cell cycle regulator Cyclin D1a, functions independently of the cell cycle to promote metastasis in both early and late stage prostate cancer.

Rather, Cyclin D1b, but not Cyclin D1a, regulates a large gene network, the researchers found, which was shown to cooperate with androgen receptor (AR) signaling to fuel metastatic progression in multiple models of prostate cancer.

Studies have shown that Cyclin D1b expression is elevated in early stages of prostate cancer (in up to 30% of primary disease), and researchers have now demonstrated that this occurs more frequently in late stage castration-resistant prostate cancer: up to 80%.

Cyclin D1b expression is also highly correlated with that of the pro-metastatic gene SNAI2 (Slug), which the group identified as regulated by cooperative signaling between Cyclin D1b and AR.

"Numerous clinical and pre-clinical studies have effectively demonstrated that AR signaling is critical for progression to metastatic disease, but our knowledge of AR targets which can induce metastatic phenotypes is limited," said Dr. Knudsen. "Our data describe how cross talk between the cell cycle and AR can rewire the AR signaling axis to enhance the expression of genes which elicit metastasis in both early and castration resistant prostate cancer models."

Prostate cancer facts Prostate cancer is the most common form of the disease affecting Canadian men, at about 25,500 new cases annually.

Although more than 4,000 patients were expected to die from prostate cancer last year, the chances of survival are improving as more men get tested — and tested earlier.

It still means about 70 men will be diagnosed with prostate cancer each day and 11 will die per day. Or one in seven men will develop the disease and one in 28 may not beat it.

These are the sobering numbers and all the more reason men should get the facts, understand the risk factors and get a checkup, especially as more than 90 per cent of the cases are curable when detected in the earliest stages.

Knowing the facts and eliminating confusion is the first step.

"We found that Cyclin D1b can directly promote AR dependent expression of the gene SNAI2 (Slug), which dramatically increased metastatic events to soft tissues in animal models," she added.