Scientists identify prostate cancer stem cells among low-PSA cells

Prostate cancer cells that defy treatment and display heightened tumor-generating capacity can be identified by levels of prostate specific antigen (PSA) expressed in the tumor cells, a research team led by scientists at The University of Texas MD Anderson Cancer Center reports in the May 3 edition of Cell Stem Cell.

"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 study senior author Dean Tang, Ph.D., professor in MD Anderson's Department of Molecular Carcinogenesis.

Hormone therapy is used to block production of testosterone, which fuels prostate cancer growth, via either chemical or physical castration. Tumors eventually resist this approach.

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 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," Tang said. "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."

Their 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.

Low-PSA tumors associated with advanced prostate cancer

Previous research by others indicated that low-PSA tumor cells are rare in early stage disease but become more abundant in advanced prostate cancer. And patients whose tumors were composed of more than 50 percent PSA-positive cells enjoyed longer survival.

This made Tang and colleagues wonder whether the two cell types fundamentally differ from each other and so play different roles in prostate cancer progression.

They analyzed 20 untreated prostate cancer samples staged at varying degrees of aggressiveness on the Gleason scale and 23 samples where treatment had failed. High-PSA tumor cells composed on average about 80 percent of the Gleason 7 tumors, about 60 percent of the higher grade Gleason 9/10 tumors but only about 15 percent of the treatment-failed tumors.

A database analysis of gene expression in prostate cancer was consistent with the tumor experiments, indicating an association between low levels of PSA in tumors and disease recurrence, spread to lymph nodes, metastasis and shortened patient survival.