NASHVILLE, Tenn.—Researchers at Vanderbilt University Medical Center and the University of Alberta in Canada have identified a biomarker for a cellular switch that accurately predicts which prostate cancer patients are likely to have their cancer recur or spread.
The study, posted online recently in advance of publication in Cancer Research, was led by co-investigators Dr. Andries Zijlstra, assistant professor of pathology, microbiology and immunology and cancer biology at Vanderbilt, and Dr. John Lewis, associate professor of oncology and Frank and Carla Sojonky Chair in Prostate Cancer Research at the University of Alberta.
Prostate cancer is the second-leading cause of cancer-related deaths among men in North America. While some prostate cancer spreads slowly and does not lead to serious symptoms, in other patients the cancer metastasizes to other parts of the body and proves fatal. Cancer researchers have been searching for biomarkers that indicate which patients should be treated aggressively and which patients can be followed through active surveillance.
Zijlstra and his colleagues have been investigating a protein called CD151 that facilitates the migration of cancer cells. In prostate cancer cell lines, they discovered that CD151 is free from its normal adhesion partner (integrin)—another protein that allows a cell to stick to the surrounding tissue. This form of non-sticky CD151 called “CD151free” proved to be functionally important in cancer.
In collaboration with Lewis and colleagues in Alberta, the group looked at tissue samples from 137 patients treated for prostate cancer in Canada over the past 12 years. The team determined that if patients tested positive for CD151free, their cancer recurred and spread earlier than patients without any detectable CD151free.
“Patients who tested positive for the biomarker developed metastasis an average of 10 years earlier than those who tested negative,” said Lewis.
Prior studies had demonstrated that a specific anti-CD151 antibody could inhibit tumor cell metastasis, Zijlstra notes. “Our 2008 study suggested that a unique molecular mechanism was in play. We subsequently determined that this antibody only interacted with integrin-free CD151 (to which no integrin alpha 3 was bound). This led to clinical validation and the discovery that it was clinically relevant. Both the Zijlstra and the Lewis lab are using clinical validation to confirm relevance of any molecular investigation. In this instance our collaboration was synergistic in the sense that the clinical observation not only confirmed the existence of integrin-free CD151 but also demonstrated that it had prognostic value in prostate cancer.”
“It was a big surprise that some of this CD151 protein was now free of that partner, and it turns out that it only occurs when a cancer is formed,” Zijlstra adds. “What’s so novel about this discovery is we’re not talking about changing protein expression, which is what we traditionally see. We’re talking about a protein that changes its molecular state and detection of that molecular state is an indication of disease progression.”
“Most, if not all, molecular mechanisms involved in adhesion are organized around complex partnerships involving an adhesion molecule which is engaged with other transmembrane partners and cytoplasmic signaling and structural scaffolding mechanisms,” Zijlstra explains. “Changes in the composition of these macromolecular complexes are expected to create rapid and dynamic changes in cell behavior. In this manuscript we are observing a dissolution of the CD151-integrin alpha3 complex. That complex is common in normal epithelial cells but appears to be disrupted during prostate cancer progression. Consequently, the CD151/integrin alph3/laminin axis is expected to have less impact. The control of migration is expected to switch to an as-yet-unknown adhesion mechanism.”
Preliminary work in other solid tumors besides prostate cancer suggests that this may be a universal mechanism important for cancer progression.
“It is increasingly clear that a molecular switch in cell migration corresponds to patient outcome in solid tumors,” said Zijlstra. “Consequently, the detection of that switch can assist in determining whether a patient is going to develop aggressive cancer or if the disease will remain benign. That information ultimately determines the type of care given to a cancer patient.”
The group is working on development of an antibody test for use in the clinic.