Abstract
Metastatic progression of advanced prostate cancer is a major clinical problem. Identifying the cell(s) of origin in prostate cancer and its distant metastases may permit the development of more effective treatment and preventive therapies. In this study, aldehyde dehydrogenase (ALDH) activity was used as a basis to isolate and compare subpopulations of primary human prostate cancer cells and cell lines. ALDH-high prostate cancer cells displayed strongly elevated clonogenicity and migratory behavior in vitro. More strikingly, ALDH-high cells readily formed distant metastases with strongly enhanced tumor progression at both orthotopic and metastatic sites in preclinical models. Several ALDH isoforms were expressed in human prostate cancer cells and clinical specimens of primary prostate tumors with matched bone metastases. Our findings suggest that ALDH-based viable cell sorting can be used to identify and characterize tumor-initiating and, more importantly perhaps, metastasis-initiating cells in human prostate cancer.
Highlights
Prostate cancer is the most commonly diagnosed cancer in males and the second leading cause of death
We show that a subpopulation of human prostate cancer cells with high aldehyde dehydrogenase (ALDH) activity correlates with enhanced clonogenicity and invasiveness in vitro
Before the functional testing of clonogenicity, subsets of ALDHhi and ALDHlow cells were isolated from PC-3M-Pro4luc and C4-2B human prostate cancer cell lines by flow cytometry using the ALDEFLUOR assay
Summary
Prostate cancer is the most commonly diagnosed cancer in males and the second leading cause of death. Bone metastases occur in ∼90% of patients with advanced disease and are leading causes of morbidity. The identification of the cell(s) of origin of prostate cancer as well as the neoplastic cells involved in the formation of distant metastases is, fundamental to a full understanding of this disease and the development of treatment and preventive therapies. Most carcinomas comprise of a heterogeneous cell population with marked differences in their ability to proliferate and differentiate as well as their ability to reconstitute the tumor upon transplantation.
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