Prostate basal cells are intrinsically enriched in gene sets normally associated with stem cells, report researchers based at The University of Texas MD Anderson Cancer Center. These researchers also found that the basal cell gene signature was “enriched” in the gene signatures that characterize the most aggressive prostate cancer subtypes.
These findings not only speak to a controversy over the role of stem cells in prostate cancer, they also suggest strategies for treating aggressive and therapy-resistant forms of prostate cancer.
“It has become very controversial as to whether the human prostate contains adult stem cells or not and where they are located within the basal or luminal cell compartments,” said Dean G. Tang, M.D., Ph.D., professor of epigenetics and molecular carcinogenesis at MD Anderson. “Our study provided definitive evidence that the prostate basal cell layer harbors self-renewing adult stem cells that are enriched in stem-cell genes.”
The researchers realized that to date, large-scale sequencing studies have relied on heterogeneous tissue samples as the material for DNA and RNA extraction. Because these samples typically contain both epithelial and nonepithelial cells, they may leave obscure gene expression differences between basal and luminal cell lineages and hence miss fresh insights into the cells of origin for different types of prostate cancer.
Accordingly, the researchers undertook a detailed transcriptome analysis of human benign prostatic basal and luminal cells by deep RNA sequencing (RNA-seq). They presented the results of this work February 29 in the journal Nature Communications, in an article entitled “Stem Cell and Neurogenic Gene-Expression Profiles Link Prostate Basal Cells to Aggressive Prostate Cancer.” Essentially, the researchers found that basal and luminal cells expressed genes differently and that some basal cells represented self-renewing adult stem cells.
“Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis,” the authors detailed. “Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers.”
These proneural genes seem to play important functions in conferring stem cell-like properties upon some basal cells, noted Dr. Tang. This finding is important because a subset of prostate cancers (less than 5%) is highly aggressive and does not respond to current anti-prostate cancer treatments such as endocrine therapy.
“Surprisingly, these hard-to-treat cancers also express a gene signature that overlaps with our normal basal stem cell gene expression profile, suggesting that basal stem cells may represent the cell-of-origin for these prostate cancers,” explained Dr. Tang. “Of significance, the basal stem cell gene expression profile is also linked to endocrine therapy-resistant cancer, which is lethal to virtually all advanced prostate cancer patients.”
Dr. Tang's team also found that basal stem cells are enriched in a genetic component that is partially regulated by MYC, offering hope that the deadliest of prostate cancers and therapy-resistant prostate cancers may have a new therapeutic option.
“Our studies,” Dr. Tang added, “establish that therapy that combines Pol-I and MYC inhibitors may be a potential new line of treatment for highly metastatic and endocrine therapy-resistant prostate cancer.”