+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Neuroendocrine Differentiation in Prostate Cancer: A Mechanism of Radioresistance and Treatment Failure

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Neuroendocrine differentiation (NED) in prostate cancer is a well-recognized phenotypic change by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cells. NE-like cells lack the expression of androgen receptor and prostate specific antigen, and are resistant to treatments. In addition, NE-like cells secrete peptide hormones and growth factors to support the growth of surrounding tumor cells in a paracrine manner. Accumulated evidence has suggested that NED is associated with disease progression and poor prognosis. The importance of NED in prostate cancer progression and therapeutic response is further supported by the fact that therapeutic agents, including androgen-deprivation therapy, chemotherapeutic agents, and radiotherapy, also induce NED. We will review the work supporting the overall hypothesis that therapy-induced NED is a mechanism of resistance to treatments, as well as discuss the relationship between therapy-induced NED and therapy-induced senescence, epithelial-to-mesenchymal transition, and cancer stem cells. Furthermore, we will use radiation-induced NED as a model to explore several NED-based targeting strategies for development of novel therapeutics. Finally, we propose future studies that will specifically address therapy-induced NED in the hope that a better treatment regimen for prostate cancer can be developed.

          Related collections

          Most cited references 91

          • Record: found
          • Abstract: found
          • Article: not found

          Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer.

          The murine Pten prostate cancer model described in this study recapitulates the disease progression seen in humans: initiation of prostate cancer with prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma, and subsequent metastasis with defined kinetics. Furthermore, while Pten null prostate cancers regress after androgen ablation, they are capable of proliferating in the absence of androgen. Global assessment of molecular changes caused by homozygous Pten deletion identified key genes known to be relevant to human prostate cancer, including those "signature" genes associated with human cancer metastasis. This murine prostate cancer model provides a unique tool for both exploring the molecular mechanism underlying prostate cancer and for development of new targeted therapies.
            • Record: found
            • Abstract: found
            • Article: not found

            High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development.

            Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank of transplantable patient-derived prostate cancer xenografts that capture the biologic and molecular heterogeneity currently confounding prognostication and therapy development. Xenografts preserved the histopathology, genome architecture, and global gene expression of donor tumors. Moreover, their aggressiveness matched patient observations, and their response to androgen withdrawal correlated with tumor subtype. The panel includes the first xenografts generated from needle biopsy tissue obtained at diagnosis. This advance was exploited to generate independent xenografts from different sites of a primary site, enabling functional dissection of tumor heterogeneity. Prolonged exposure of adenocarcinoma xenografts to androgen withdrawal led to castration-resistant prostate cancer, including the first-in-field model of complete transdifferentiation into lethal neuroendocrine prostate cancer. Further analysis of this model supports the hypothesis that neuroendocrine prostate cancer can evolve directly from adenocarcinoma via an adaptive response and yielded a set of genes potentially involved in neuroendocrine transdifferentiation. We predict that these next-generation models will be transformative for advancing mechanistic understanding of disease progression, response to therapy, and personalized oncology. ©2013 AACR.
              • Record: found
              • Abstract: found
              • Article: not found

              The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration.

              Prostate cancer (PCa) is heterogeneous and contains both differentiated and undifferentiated tumor cells, but the relative functional contribution of these two cell populations remains unclear. Here we report distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (PSA(+)) and low (PSA(-/lo)) levels of the differentiation marker PSA. PSA(-/lo) PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division to generate PSA(+) cells. Importantly, PSA(-/lo) PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and they harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH(+)CD44(+)α2β1(+) phenotype. In contrast, PSA(+) PCa cells possess more limited tumor-propagating capacity, undergo symmetric division, and are sensitive to castration. Altogether, our study suggests that PSA(-/lo) cells may represent a critical source of castration-resistant PCa cells. Copyright © 2012 Elsevier Inc. All rights reserved.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                14 April 2015
                : 5
                1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University Center for Cancer Research, Purdue University , West Lafayette, IN, USA
                2Department of Radiation Oncology, Mayo Clinic , Rochester, MN, USA
                3Department of Pathology, David Geffen School of Medicine at UCLA , Los Angeles, CA, USA
                Author notes

                Edited by: Mercedes Salido, University of Cadiz, Spain

                Reviewed by: Simon J. Crabb, University of Southampton, UK; Ping Mu, Memorial Sloan Kettering Cancer Center, USA

                *Correspondence: Chang-Deng Hu, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, 575 Stadium Mall Dr., West Lafayette, IN 47907, USA e-mail: hu1@ 123456purdue.edu

                This article was submitted to Genitourinary Oncology, a section of the journal Frontiers in Oncology.

                Copyright © 2015 Hu, Choo and Huang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 108, Pages: 10, Words: 9088
                Funded by: U.S. Army Medical Research Acquisition Activity
                Funded by: Prostate Cancer Research Program
                Award ID: PC073098
                Award ID: PC11190
                Award ID: PC120512
                Funded by: Purdue University Center for Cancer Research Small Grants Program
                Funded by: Indiana Clinical and Translational Science Institute funded
                Award ID: RR-25761
                Funded by: National Institutes of Health
                Funded by: National Center for Research Resources
                Funded by: Clinical and Translational Sciences Award
                Funded by: NCI CCSG
                Award ID: CA23168
                Funded by: Purdue University Center for Cancer Research
                Review Article


                Comment on this article