Prostate cancer is one of the most commonly-diagnosed forms of cancer in men. In cases of advanced prostate cancer, Androgen deprivation therapy (ADT), which involves either actual castration or chemical castration whereby hormone therapy is used to block production of testosterone, which fuels prostate cancer growth, is an effective treatment route that results in remission of the disease in most cases. However within 6 to 20 months, most patients who initially benefit from ADT unfortunately relapse into resistant disease.
The journal Oncology CancerNetwork’s Zachary Hartman reports that according to preclinical results presented at the annual meeting of the American Association for Cancer Research, held April 6–10 in Washington, DC., that targeting prostate cancer stem cells may be a method of treating prostate cancer while avoiding the development of resistance to androgen deprivation therapy (ADT)
In his presentation in Washington, Dean Tang, MD, Ph.D., a professor in MD Anderson’s Department of Molecular Carcinogenesis, showed data that may help to explain why ADT resistance occurs and how it can best be combated.
A research team led by scientists at The University of Texas MD Anderson Cancer Center last year reported in the journal Cell Stem Cell that treatment-resistant prostate cancer cells that display heightened tumor-generating capacity can be identified by levels of prostate specific antigen (PSA) expressed in the tumor cells.
“Using a new technique, we were able for the first time to separate low-PSA and high-PSA prostate cancer cells. This led to the discovery of a low-PSA population of cancer stem cells that appears to be an important source of castration-resistant prostate cancer,” said Dr. Tang, the study’s senior author in a 2012 release.
In cell lines and mouse model experiments, the low-PSA cells resisted chemotherapy and thrived under hormone deprivation, the two main prostate cancer drug treatments , the MD Anderson Cancer Center researchers found. Low-PSA cells were found to be both self-renewing and capable of differentiating into other prostate cancer cell types upon division, a hallmark of stem cells called asymmetric cell division.
“Asymmetric cell division is the gold standard feature of normal stem cells,” Dr. Tang noted. “Using time-lapse fluorescent microscopy, we were able to show asymmetric cell division by filming a low-PSA cell dividing into one high-PSA cell and one low-PSA cell.”
A paper co-authored by Dr. Tang and colleagues at the University of Texas M.D. Anderson Cancer Center, entitled “The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44,” notes that cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis, and than microRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenes in cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary have been identified using the adhesion molecule CD44. The researchers report that they’ve identified and validated CD44 as “a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. The study shows that “miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.”
The researchers’ findings point to the need to develop new therapeutics to target low-PSA prostate cancer cells that can be combined with hormone therapy to wipe out cancer cells and prevent recurrence.
In another paper, entitled “The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration,” Dr. Tang’s team report that PSA(-/lo) PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH(+)CD44(+)21(+) phenotype. In contrast, PSA(+) PCa cells possess more limited tumor-propagating capacity, undergo symmetric division, and are sensitive to castration. Altogether, they say their our study suggests that PSA(-/lo) cells may represent a critical source of castration-resistant PCa cells.
Dr. Tang and colleagues analyzed tumor cell PSA expression in 556 human tumors and found low protein levels correlated with reduced overall survival. They separated the two types of cells in three primary human tumors and found that low-PSA cells did not express androgen receptor and have higher cell-generating and sphere-forming capabilities than high-PSA cells.
Future research will focus on developing therapeutic targets for low-PSA cells and illuminating the epigenetic landscapes of both cell types.
The research was financed by grants from the National Cancer Institute, the U.S. Department of Defense, the Cancer Prevention and Research Institute of Texas, the Elsa Pardee Foundation, the MD Anderson Cancer Center University Cancer Fund, MD Anderson Center for Cancer Epigenetics, the Laura and John Arnold Foundation and MD Anderson’s Cancer Center Support Grants.