Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure

Abstract

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.

Keywords: ATF2; CREB; EMT; cancer stem cell; neuroendocrine differentiation; prostate cancer; radiosensitization; radiotherapy.

Figure 1

Impact of neuroendocrine differentiation on prostate cancer progression and tumor recurrence. Neuroendocrine differentiation (NED) can be induced by fractionated ionizing radiation (FIR), cAMP, androgen-deprivation therapy (ADT), and IL-6 via distinct signaling pathways. The clinical impact of NED on prostate cancer progression and therapy response can be twofold. On the one hand, NE-like cells can produce peptide hormones and growth factors to promote tumor progression. On the other hand, the dormant and apoptosis-resistant NE-like cells may resume the ability to proliferate due to the reversibility of NED, and contribute to treatment failure and tumor recurrence.

Figure 2

Transcriptional regulation of radiation-induced neuroendocrine differentiation in prostate cancer cells. CREB and ATF2 belong to the same CREB/ATF family transcription factors to regulate gene transcription by binding to the same cAMP response element (CRE). ATF2 constantly shuttles as a monomric form between the nucleus and cytoplasm in prostate cancer cells, and its nuclear regulation is tightly regulated. CREB acts as a transcriptional activator and ATF2 functions as a transcriptional repressor of NED in prostate cancer cells. Fractionated ionizing radiation (FIR) induces NED by activating CREB and impairing the nuclear import of ATF2.

Figure 3

Process and targeting strategies of radiation-induced neuroendocrine differentiation in prostate cancer cells. Shown is a schematic view of several distinct phases of fractionated ionizing radiation (FIR)-induced NED in prostate cancer cells (PCa). The critical role of CREB in the acquisition of radioresistance and NED phases has been demonstrated, and identification of upstream regulators of CREB may lead to development of novel radiosensitizers. Targeting NE-like cells and inhibiting the reversal of the “dormant” NE-like cells to a proliferating state could also be clinically useful. Further, profiling radioresistant recurrent prostate cancer cells may allow identification of molecules contributing to cross-resistance of recurrent prostate cancer after radiotherapy failure, and ultimately may lead to the development of novel therapeutic agents for the treatment of recurrent prostate tumors.