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Functions of Normal and Malignant Prostatic Stem/Progenitor Cells in Tissue Regeneration and Cancer Progression and Novel Targeting Therapies

Department of Biochemistry and Molecular Biology (M.M., P.P.M., R.H., S.K.B.), Department of Pathology and Microbiology (S.K.B.), Division of Hematology and Oncology, Department of Internal Medicine (R.H.), and Eppley Institute for Cancer and Allied Diseases (M.M., P.P.M., S.K.B.), University of Nebraska Medical Center, Omaha, Nebraska 68198-5870

Correspondence: Address all correspondence and requests for reprints to: Murielle Mimeault, Ph.D., and Surinder K. Batra, Ph.D., Department of Biochemistry and Molecular Biology, Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870. E-mail: mmimeault{at}unmc.edu or sbatra{at}unmc.edu

This review summarizes the recent advancements that have improved our understanding of the functions of prostatic stem/progenitor cells in maintaining homeostasis of the prostate gland. We also describe the oncogenic events that may contribute to their malignant transformation into prostatic cancer stem/progenitor cells during cancer initiation and progression to metastatic disease stages. The molecular mechanisms that may contribute to the intrinsic or the acquisition of a resistant phenotype by the prostatic cancer stem/progenitor cells and their differentiated progenies with a luminal phenotype to the current therapies and disease relapse are also reviewed. The emphasis is on the critical functions of distinct tumorigenic signaling cascades induced through the epidermal growth factor system, hedgehog, Wnt/β-catenin, and/or stromal cell-derived factor-1/CXC chemokine receptor-4 pathways as well as the deregulated apoptotic signaling elements and ATP-binding cassette multidrug transporter. Of particular therapeutic interest, we also discuss the potential beneficial effects associated with the targeting of these signaling elements to overcome the resistance to current treatments and prostate cancer recurrence. The combined targeted strategies toward distinct oncogenic signaling cascades in prostatic cancer stem/progenitor cells and their progenies as well as their local microenvironment, which could improve the efficacy of current clinical chemotherapeutic treatments against incurable, androgen-independent, and metastatic prostate cancers, are also described.