VAI researchers take on prostate cancer
By Joe Boomgaard | LabWork
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GRAND RAPIDS — With two major findings already this year, researchers at Van Andel Research Institute, the research arm of Van Andel Institute, are making waves in the international efforts to scientifically study prostate cancer, its causes and treatments.
The two studies on prostate cancer build on the institute’s research into the origins of certain cancers and mark one of the institute’s areas of study, alongside Parkinson’s disease, kidney cancer, osteoporosis, diabetes and others.
Prostate cancer is the most common cancer in males with more than 192,000 cases diagnosed in 2009 and more than 27,000 deaths, according to the National Cancer Institute. Moreover, treatments are usually only effective on early stages of the slow-growing cancer.
Research conducted by H. Eric Xu, VARI distinguished scientific investigator, and X. Edward Zhou, a postdoctoral fellow, has identified the ways in which two key proteins, androgen receptor (AR) and steroid receptor coactivator-3 (SRC3), interact at the molecular level inside prostate cancer.
For prostate cancer to form and develop, researchers say AR must be activated by hormones. Then, they work with coactivators like SRC3 to regulate the gene expression and bind to the DNA of cells. And while research has found that AR needs a coactivator, scientists don’t quite have a grasp on the details of that interaction, which Xu and Zhou studied.
AR has been the typical target for prostate cancer treatment, but it is only susceptible to therapies with early stage patients, and those treatments can lose effectiveness over time. Zhou said AR has many pathways in molecules, including via SRC3, which was first identified in breast cancer but was later determined to be found in other cancers as well. Identifying methods to disrupt those pathways can then help researchers with various drug targets and treatments.
“The important point is that by this, we can maybe develop some treatments and use the AR-SRC3 interface as the target,” Zhou told LabWork. “Then we can design more molecules or small peptides to stop (them) from working.”
Zhou said the findings, which were published in the Journal of Biological Chemistry, represent the biggest discovery he’s made in his five years at VARI.
“It’s a tough job to cure this stage of prostate cancer, but people are working hard to find some more therapies,” he said. “In the future, patients need to be treated with different methods that block those pathways. That way, you can really stop the working of AR and cure the patient.”
Meanwhile, Cindy Miranti, VARI scientific investigator, and postdoctoral fellow Laura Lamb uncovered a new technique to develop secretory prostate epithelial cells in the laboratory. These epithelial cells line and protect organs in the human body, and the prostate has two types — basal and secretory. According to researchers, cancers form when abnormal cells change from basal to secretory.
Up to this point, however, Miranti said scientists have only been able to culture basal cells, and because they lacked all the types of cells, their models didn’t exactly mimic conditions in the human body.
“We started with a normal cell and moved toward a tumor cell,” Miranti told LabWork, noting the research was recently published in the Journal of Cell Science. “To really understand cancer at a clinical point of view, we need to mimic better what (doctors) see in the patient.”
By reconstructing the natural process, researchers hope to get a better view of how to manipulate the process and drive therapies, she said.
“Previous attempts at this attempted to take a cell from a patient and isolate it or do a short-term exposure to some type of protocol,” Lamb said.
Researchers had hoped that by introducing androgen to basal cells that they would react and turn into secretory cells, but they didn’t. The secretory cells — which have AR — were necessary to mimic the process of cancer growth. Thus, Lamb and Moranti had to find a way to make the conversion process work in the lab.
But prostate cancers take a long time to develop. So, rather than a couple of quick hits of androgen, Lamb and Moranti exposed the basal cells to androgen over a period of weeks, instead of hours or days, and the process worked.
“We have a system where we can start to look at…how androgen receptor functions,” Moranti said. “Now we have the whole paradigm to make that comparison and (find) where in that process does that protein misfunction and be able to test that better. Once we have this system, we can do toxicity studies and prevention studies … in a system that is more real, like in vivo.” LW
