A new type of progenitor cell, found in the prostates of adult mice, can also give rise to carcinoma in some circumstances, researchers said.
The novel cells, called "castration-resistant Nkx3.1-expressing cells" or CARNs, are a form of luminal cell, one of the three types that make up the prostate epithelium, according to Michael Shen, PhD, of Columbia University Medical Center, and colleagues.
The finding may explain why prostate cancers are typically only composed of luminal cells, Shen and colleagues reported online in Nature.
Of the three cell types -- basal, luminal, and neuroendocrine -- only basal progenitor cells had been known. But, puzzlingly, human prostate cancer is "markedly" luminal, they said.
Indeed, the absence of basal cells is a diagnostic feature for prostate adenocarcinoma, which suggests that either the disease arises from a luminal cell, or that the oncogenic transformation of a basal progenitor leads to rapid production of luminal progeny.
To help clarify that issue, the researchers studied what happens during repeated cycles of androgen deprivation, which causes rapid cell death of about 90% of luminal cells and some basal cells.
When androgen is restored, the prostate epithelium regenerates over a short period of time, suggesting the tissue contains a population of castration-resistant cells.
One effect of androgen deprivation is to turn off expression of the Nkx3-1 homeobox gene, which regulates prostate epithelial differentiation. But, the researchers said, a small proportion of cells -- about 0.7% -- continues to express the gene despite the lack of androgen.
These cells -- the CARNs -- do not display markers typical of basal or neuroendocrine cells, but do express markers associated with luminal cells, Shen and colleagues found.
Moreover, after the restoration of androgen, the number of CARNs in the restored tissue increased nine-fold, from 0.37% to 3.3%, a rise that was significant at P<0.0001.
Indeed, even a single CARN was capable of reconstituting prostatic ducts. In an experiment in which single marked CARNs were transplanted into renal tissue, 37% gave rise to prostatic ducts, all of whose cells expressed the marker.
In contrast, only 3% of control luminal cells gave rise to prostatic ducts, a difference that was significant at P<0.001.
The cancer connection is associated with the tumor suppressor gene Pten.
The researchers genetically modified mice so that they could turn off Pten in CARNs at will and then deprived them of androgen, causing most of the luminal cells to die.
They turned off the gene in some of the mice before restoring androgen.
The six animals without active Pten rapidly developed high-grade prostatic intraepithelial neoplasia and carcinoma with evidence of microinvasion, they found, while the animals in which the tumor suppressor was working remained healthy.
The implication, they concluded, is that "the CARN population can act as a cell of origin for prostate cancer, and that the resulting carcinoma lesions have a luminal phenotype."
"Previous research suggested that prostate cancer originates from basal stem cells and that during cancer formation these cells differentiate into luminal cells," Shen said in a statement. "Instead, CARNs may represent a luminal origin for prostate cancer."
He cautioned, however, that it is unclear whether CARNs exist in the normal human prostate and if human prostate cancers can originate from these CARNs.
The research was supported by the National Institutes of Health, the Department of Defense, and the National Cancer Institute. The authors made no disclosures.