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."
"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.
Metastatic castration resistant prostate cancer represents the most lethal form of the disease, which arises when AR is reactivated despite continued hormone therapy.
Soft tissue metastasis to the liver and lung represents a particularly aggressive form of prostate cancer, whose presence predicts for decreased survival time in prostate cancer patients.
Currently, there is little knowledge as to how these metastatic events occur, and identification of pathways and biomarkers of this lethal event could greatly benefit prostate cancer patients.
Using various in vitro and in vivo models, researchers found that Slug enhances the ability of cells to colonize soft tissues, which resulted in a higher incidence of metastasis in the liver and lung.
Given the inability to manage AR signaling in metastatic castration resistant prostate cancer, Slug driven pathways could be leveraged to dramatically limit the incidence of soft tissue metastasis and improve patient morbidity and mortality, researchers believe.
"Identification of AR driven pathways which mediate metastatic progression represents a significant leap forward in our attempts to effectively manage prostate cancer progression," said Dr. Knudsen. "Cyclin D1b and Slug can likely be used as biomarkers to identify patients with an increased risk of metastasis, and will eventually provide us with novel "druggable" targets downstream of AR and Slug which can be exploited to dramatically reduce the incidence of these lethal metastatic tumors."
Journal reference: Journal of Clinical Investigation
Provided by Thomas Jefferson University
- Doubling up on advanced prostate cancer with PARP inhibitors Oct 09, 2012 | not rated yet | 0
- Researchers discover that same gene has opposite effects in prostate, breast cancers Oct 17, 2011 | not rated yet | 0
- Blocking signaling protein prevents prostate cancer spread Jun 02, 2008 | not rated yet | 0
- A potential new target for treatment of hormone refractory prostate cancer Apr 06, 2009 | not rated yet | 0
- Scientists identify KRAS rearrangements in metastatic prostate cancer Apr 03, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be a term called "intestinal metaplasia" of stomach
8 hours ago Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
- More from Physics Forums - Medical Sciences
More news stories
An attack on glioblastoma brain tumor cells that uses a modified poliovirus is showing encouraging results in an early study to establish the proper dose level, researchers at Duke Cancer Institute report.
Cancer 1 hour ago | not rated yet | 0
The surgical management of non-small cell lung cancer (NSCLC) in U.S. hospitals varies widely depending on the race of the patient, according to a new study.
Cancer 5 hours ago | not rated yet | 0
Treatment with an Alpha-1 proteinase inhibitor (A1-PI), a naturally occurring protein that protects lung tissue from breakdown and protects the lung's elasticity, is effective in slowing the progression of emphysema in patients ...
Cancer 5 hours ago | not rated yet | 0
Scientists from Nanyang Technological University (NTU) and Lund University, Sweden, have bioengineered a novel molecule which has been proven to successfully kill tumour cells.
Cancer 5 hours ago | 5 / 5 (1) | 0
Researchers at USC have found that a class of pharmaceuticals can both prevent and treat Alzheimer's Disease in mice.
40 minutes ago | not rated yet | 0 |
The decision to limit life support in patients in the intensive care unit (ICU) appears to be significantly influenced by physician practices and/or the culture of the hospital, suggests new findings from researchers at the ...
58 minutes ago | not rated yet | 0
Children with obstructive sleep apnea who had a common surgery to remove their tonsils and adenoids showed notable improvements in behavior, quality of life and other symptoms compared to those treated with "watchful waiting" ...
58 minutes ago | not rated yet | 0
(Medical Xpress)—Native peoples in regions where cameras are uncommon sometimes react with caution when their picture is taken. The fear that something must have been stolen from them to create the photo ...
3 hours ago | 4 / 5 (3) | 0 |
(Medical Xpress)—Despite spending billions of dollars on research and development, drug companies have been unable to come up with effective treatments for dementia and Alzheimer's Disease (AD). Now, A. ...
1 hour ago | 4.7 / 5 (3) | 0 |
Australian scientists have charted the path of insulin action in cells in precise detail like never before. This provides a comprehensive blueprint for understanding what goes wrong in diabetes.
3 hours ago | 4.5 / 5 (2) | 0 |