Neuroendocrine differentiation in prostate cancer: Current and emerging therapy strategies

https://doi.org/10.1016/j.critrevonc.2014.05.008Get rights and content

Abstract

Neuroendocrine differentiation (NED) secondary to androgen deprivation therapy (ADT) may be frequent in various stages of prostate cancer (PC), particularly in castration-resistant PC (CRPC). NED generally involves more aggressive PC clinical behavior and an unfavorable prognosis. The identification of neuropeptides secreted by NE cells and of different proliferative and anti-apoptotic pathways has led to attention being focused on probable diagnostic targets and therapeutic options for a subtype of PC. Emerging evidence suggests that the acquisition of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype are associated with the development of NED in PC, responsible for a complex interaction between ADT, the onset of CRPC and NED, in which EMT and CSC could play a central role, providing potential therapeutic targets. In this article, we review the pathogenetic, prognostic and predictive significance of NED in human PC, providing an insight into innovative agents capable of treating and perhaps preventing NED occurrence.

Introduction

Increasing knowledge of the pathophysiology of prostate cancer (PC) has recently led to the identification of novel mechanisms of androgen independence and progression which, in turn, have allowed for numerous drug discoveries with an increasing therapeutic armamentarium for PC, particularly in the advanced stages. However, despite much progress, some aspects of PC – remain largely unknown. In recent years, increasing attention has been focused upon neuroendocrine differentiation (NED), above all for castration resistant prostate cancer (CRPC) patients, in which the identification of NED might be helpful mainly for tailoring therapeutic strategies, increasing survival rates and ameliorating quality of life.

Section snippets

Features of neuroendocrine differentiation in prostate cancer

NED is a common feature of prostatic adenocarcinomas. Pure neuroendocrine prostate cancer (NEPC) and a small cell PC represent rare and aggressive tumors, such as primary carcinoids, which are also very rare, but usually not aggressive. In most cancers, the NE component coexists with non-NE component, displaying a variable extension of the two components, potentially ranging from 1 to 99%. NE component usually occupies less than 5% of the overall tumor mass and, in general, in NEPC NE component

Pathogenetic mechanisms involved in neuroendocrine differentiation and progression in prostate cancer

NE cells of the prostate are widely distributed in normal prostatic acini and ducts. The origin of NE cells in PC is controversial. It is suggested that NEPC cells have the same origin as normal NE cells from neural crest and are differentiated from common pluripotent stem cells (as reported in the following paragraph). In fact, NE cells have some features of cancer stem cells (CSCs), such as the expression of CD44 and CD133, which may give resistance to hormonal therapy and lead to tumor

Cancer stem cells and neuroendocrine differentiation in prostate cancer

Cancer stem cells (CSC) consist of a minor subpopulation of tumor cells (typically less than 1–2%) possessing the ability to self-renew and recreate the entire tumor, inclusive of all cell types [41]. In PC, CSC are typically quiescent, resistant to traditional therapies that depend on continuous cell cycle activity, such as chemotherapy and radiotherapy, and do not express the luminal differentiation markers AR and PSA, while they express stemness markers, including β1 integrins, CD133, CD44,

Epithelial-to-mesenchymal transition and neuroendocrine differentiation in prostate cancer

Epithelial-to-mesenchymal transition (EMT) is characterized by the loss of epithelial differentiation and by acquisition of mesenchymal phenotype with increased cell motility and invasion. EMT is considered to be a normal physiologic process, but it is also implicated in the progression of early stage tumors into invasive malignancies and it is often associated with tumor recurrence [50]. Many stimuli in the tumor microenvironment, such as hypoxia and growth factors (e.g. TGF-β, FGF and IGF-1),

Current diagnostic procedures on neuroendocrine differentiation of prostate cancer

The diagnosis of NEPC is not straightforward and immediate; it can, therefore, sometimes be misdiagnosed. Low serum PSA value and clinical history can help clinicians but confirmation by way of tissue biopsy is often required. The measurement of serum NE markers and IHC positivity for NE markers support the diagnosis.

CgA is considered as a main specific NE tumor marker. It belongs to the secretogranin family and CgA plasmatic levels could reflect the NE activity present in different organs,

Prognostic and predictive significance of neuroendocrine differentiation in prostatic carcinoma

Just as NE cells are present in all stages of PC, NED can also be identified in different stages of PC with a corresponding prognostic impact. However, the prognostic significance of NED in hormone naive prostate cancers and after radical prostatectomy is controversial [73], [76], but only in CRPC NED could be associated with a poor prognosis [77], [78]. In addition, for Gleason 8–10 PC, the presence of NED even only more than 1% is associated with poor clinical outcome for CRPC patients

Chemotherapy

In the past, some phase II trials of PC patients with NED have evaluated, at various tumor stages, the efficacy of single drug, as oral estramustine [85], or the combination of different cytotoxic drugs, for example, the association of cisplatin, etoposide and doxorubicin [86] or the association of cisplatin and docetaxel [87], with disappointing results. Subsequently, other studies have looked into the association of carboplatin and etoposide on the basis of results obtained with the same

Conclusions

The exact pathogenesis of NED in the prostate tumor is still little known, although multiple pathways are involved. However, it has now been confirmed that PC patients treated with ADT, particularly those with advanced stage but lower serum PSA levels, should be evaluated for the presence of NED, which may represent one of the key mechanisms of CRPC. With the introduction of new highly potent AR-targeted agents into the clinic (i.e., abiraterone acetate, MDV3100, TAK700), ADT-related NEPC is

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Reviewers

Dr. Michal Mego, MD, PhD, National Cancer Institute, Department of Medical Oncology, Klenova 1, Bratislava, Slovakia.

Dr. Dominik R. Berthold, Medical Oncology, Rue Bugnon 46, CH-1011 Lausanne, Switzerland.

Vincenza Conteduca, M.D., graduated from the University of Bari, Italy and received her title of specialist in Oncology at the Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Italy. Now she is working at Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola (FC), Italy and she is attending a Ph.D. in clinical and experimental oncology at the University of Foggia. Her main research

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      Most recently, Aggarwal and colleagues have reported that prostatic metastatic bone cancer is made up of about 10–15% NEPC (small cell carcinoma) which is histologically similar to NE prostate cancer (NEPC) metastasis to the lung and liver [17]. Regardless NEPC develops from primary NE cells or prostatic adenocarcinoma cells that transdifferentiate to therapy-induced NEPC (tNEPC), the tumors express NE markers [11,18,19], NEPC/NED has a more aggressive clinical behavior, an unfavorable prognosis, and is a non-curable disease [20]. Therefore, developing a new treatment for CRPC and NEPC/NED is a critical challenge.

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    Vincenza Conteduca, M.D., graduated from the University of Bari, Italy and received her title of specialist in Oncology at the Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Italy. Now she is working at Department of Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola (FC), Italy and she is attending a Ph.D. in clinical and experimental oncology at the University of Foggia. Her main research interests focus on the diagnosis and treatment of solid tumors. She is co-author of some full papers, books and abstracts presented at national and international meetings.

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