Abstract
New therapies for late stage and castration resistant prostate cancer (CRPC) depend on defining unique properties and pathways of cell sub-populations capable of sustaining the net growth of the cancer. One of the best enrichment schemes for isolating the putative stem/progenitor cell from the murine prostate gland is Lin-;Sca1+;CD49fhi (LSChi), which results in a more than 10-fold enrichment for in vitro sphere-forming activity. We have shown previously that the LSChi subpopulation is both necessary and sufficient for cancer initiation in the Pten-null prostate cancer model. To further improve this enrichment scheme, we searched for cell surface molecules upregulated upon castration of murine prostate and identified CD166 as a candidate gene. CD166 encodes a cell surface molecule that can further enrich sphere-forming activity of WT LSChi and Pten null LSChi. Importantly, CD166 could enrich sphere-forming ability of benign primary human prostate cells in vitro and induce the formation of tubule-like structures in vivo. CD166 expression is upregulated in human prostate cancers, especially CRPC samples. Although genetic deletion of murine CD166 in the Pten null prostate cancer model does not interfere with sphere formation or block prostate cancer progression and CRPC development, the presence of CD166 on prostate stem/progenitors and castration resistant sub-populations suggest that it is a cell surface molecule with the potential for targeted delivery of human prostate cancer therapeutics.
Highlights
Despite advances in the early detection and management of prostate cancer, castration resistant prostate cancer (CRPC) remains the second most common cause of male mortality in the United States [1]
We mined publically available databases describing gene expression profiles of murine prostates at day 0 and day 3 post-castration [22,23]. We focused on those genes that fell in the gene ontology category of ‘plasma membrane’ and identified CD166/ALCAM as one of only two common castration-enriched cell surface molecules (Table S1)
Few surface markers are currently available for enriching both murine and human prostate tissue stem/progenitor cells and for identifying prostate cancer initiating cells. By searching for those cell surface molecules that are upregulated in castrated murine prostate and castration resistant prostate cancers (CRPC) of murine and human origins, we identified CD166 as a surface marker for enriching both murine and human prostate tissue stem/progenitor cells based on in vitro sphere forming and in vivo tissue regeneration analyses
Summary
Despite advances in the early detection and management of prostate cancer, castration resistant prostate cancer (CRPC) remains the second most common cause of male mortality in the United States [1]. Mounting evidence suggests that a subpopulation of prostate cells can initiate prostate cancer and may be responsible for the castration resistance [2,3,4,5]. These cancer initiating cells [6] may serve as promising cellular targets for prostate cancer and identification of this subpopulation has become the necessary step toward future effective therapy. Using the tissue regeneration approach, basal cells have proved to be more efficient oncogenic targets for both human and mouse prostate cancer initiation [12,13]. Xin’s group demonstrated that adult murine prostate basal and luminal cells are selfsustained lineages that can both serve as oncogenic targets for prostate cancer initiation [14]
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