UCLA scientists have identified for the first time a cell-of-origin for human prostate cancer, a discovery that could result in better predictive and diagnostics tools and the development of new and more effective targeted treatments for the disease.
The researchers, from UCLA's Jonsson Comprehensive Cancer Center, proved that basal cells found in benign prostate tissue could become human prostate cancer in mice with suppressed immune systems, a finding that bucks conventional wisdom. It had been widely believed that luminal cells found in the prostate were the culprits behind prostate cancer because the resulting malignancies closely resembled luminal cells, said Dr. Owen Witte, a Jonsson Cancer Center member and director of the UCLA Broad Stem Cell Research Center.
"Certainly the dominant thought is that human prostate cancer arose from the luminal cells because the cancers had more features resembling luminal cells," said Witte, senior author of the study and a Howard Hughes Medical Institute Investigator. "But we were able to start with a basal cell and induce human prostate cancer and now, as we go forward, this gives us a place to look in understanding the sequence of genetic events that initiates prostate cancer and defining the cell signaling pathways that may be at work fueling the malignancy, helping us to potentially uncover new targets for therapy."
The study appears July 30, 2010 in the peer-reviewed journal Science.
The researchers took healthy tissue from prostate biopsies and separated the cells based on their surface marker expression into groups of luminal cells and groups of basal cells. Using viral vectors as vehicles, they then expressed altered genes known to cause cancer into both cell populations and placed the cells in mice to see which developed cancer, said Andrew Goldstein, a UCLA graduate student and first author of the study.
"Because of the widespread belief that luminal cells were the root of human prostate cancer, it would have been those cells examined and targeted to treat the disease," said Goldstein. "This study tells us that basal cells play an important role in the prostate cancer development process and should be an additional focus of targeted therapies."
In normal prostate tissue, basal cells have a more stem cell-like function, Goldstein said, meaning they proliferate more to re-grow human prostate tissue. Luminal cells don't proliferate as much, but rather produce major proteins that are important for reproduction. Something is going awry in the basal cells that results in cancer and Witte and Goldstein plan to study those cells to uncover the mechanisms that result in malignancy.
Currently, there is a dearth of knowledge about how prostate cancer develops to treat it effectively in a targeted way, as Herceptin targets an out-of-control production of growth factor receptors in breast cancer cells. The major targeted therapy used for prostate cancer is directed at the androgen receptor and it is not always effective, Witte said.
The new human-in-mouse model system developed in the study - created by taking healthy human prostate tissue that will induce cancer once it is placed in mice instead of taking malignant tissue that is already cancerous and implanting it - can now be used to evaluate the effectiveness of new types of therapeutics. By using defined genetic events to activate specific signaling pathways, researchers can more easily compare therapeutic efficacy. The new model, by deconstructing tissue and then reconstructing it, also will aid in analyzing how the cells change during cancer progression.