EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers

Abstract

Neuroendocrine/Aggressive Variant Prostate Cancers are lethal variants of the disease, with an aggressive clinical course and very short responses to conventional therapy. The age-adjusted incidence rate for this tumor sub-type has steadily increased over the past 20 years in the United States, with no reduction in the associated mortality rate. The molecular networks fueling its emergence and sustenance are still obscure; however, many factors have been associated with the onset and progression of neuroendocrine differentiation in clinically typical adenocarcinomas including loss of androgen-receptor expression and/or signaling, conventional therapy, and dysregulated cytokine function. "Tumor-plasticity" and the ability to dedifferentiate into alternate cell lineages are central to this process. Epithelial-to-mesenchymal (EMT) signaling pathways are major promoters of stem-cell properties in prostate tumor cells. In this review, we examine the contributions of EMT-induced cellular-plasticity and stem-cell signaling pathways to the progression of Neuroendocrine/Aggressive Variant Prostate Cancers in the light of potential therapeutic opportunities.

Keywords: Cancer stem cells; Neuroendocrine trans-differentiation; Plasticity; Variant prostate cancers.

Figure 1.. Incidence of AVPCs (Aggressive Variant Prostate Cancers) and NEPCs (Neuroendocrine Prostate Cancers).

Around 10–20% of advanced prostate cancer patients develop CRPCs (castration resistant prostate cancers). Among these, AVPCs are observed in about 10% of CRPC patients, and NEPCs are observed in 10–20%. AVPCs and NEPCs are highly aggressive and may express neuroendocrine markers. These tumors are characterized by clinical androgen indifference, and simultaneous loss of AR (androgen receptor) and PSA (prostate-specific antigen) expression.

Figure 2.. Models explaining potential evolution of AVPCs/NEPCs.

This schematic depicts potential origin of cells that possibly populate various NEPC tumors. The cellular origin of de novo AVPCs/NEPCs is still debated. There is considerable consensus that widespread use of chemotherapy as well as secondary anti-androgen (abiraterone or enzalutamide) therapy of CRPCs results in trans-differentiation of epithelial adenocarcinoma cells into treatment-induced aggressive cancers (tNEPCs/tAVPCs) that lack AR-, PSA- or REST expression, but instead express various neuroendocrine markers (CgA, SYP, or NSE) as well as anti-apoptotic gene products such as Bcl2 and Survivin. Several recent mechanistic studies have shown that the EMT program plays a critical role in bestowing tumor cells with “plasticity” required to successfully adopt alternate states such as the neuroendocrine phenotype. Prostate cancer cells may transition through multiple intermediary cell states (of varying degrees of stemness/differentiation) during neuroendocrine tumor evolution. The luminal epithelial AR⁺ adenocarcinoma (AR⁺/PSA⁺/REST⁺) and the neuroendocrine AR⁻ variants (AR⁻/PSA⁻/REST⁻/CgA⁺/SYP⁺/NSE⁺/Bcl2⁺/Survivin⁺) represent the two ends of this continuum. While distinct molecular markers are often associated with the two extreme cell states, it is important to note that not all of these markers are simultaneously expressed/absent in every case. Clonal selection within adenocarcinomas may also preferentially enrich for neuroendocrine stem-cell traits. There is lesser evidence that these aggressive variants might potentially arise via transformation of normal adult prostate tissue stem cells. The role of radiotherapy in this context is also not substantiated in the clinic. The colors depicted in the NEPC tumors in this schematic (on the right) are meant to reflect on potential origin of cells responsible for populating the ultimate NEPC tumor bulk. Green represents adeno-CRPC cells; Red represents NE cells; Brown represents tissue-resident stem-cells. AR, androgen receptor; PSA, prostate-specific antigen; REST, Repressor Element-1 Silencing Transcription factor; adeno-CRPC, castration-resistant adenocarcinomas; AVPC, aggressive variant prostate carcinoma; NE, neuroendocrine; NEPC, neuroendocrine prostate cancer; CRPC, castration-resistant prostate cancer; EMT, epithelial-mesenchymal transition; NSE, neuron-specific enolase; CgA, chromogranin A; SYP, synaptophysin.

Figure 3.. Signaling pathways and molecular players implicated in AVPCs/NEPCs.

Attainment of the aggressive variant/neuroendocrine phenotype is presumably dependent on an extensive network of transcriptional reprogramming events that provide for the expression and maintenance of neuronal/stemness features. Various stem cell self-renewal pathways and molecules such as Wnt, Notch, Hedgehog, Sox2, Oct4, and CD44 have been shown to promote generation of AVPC/NEPC cells. Inhibition of miR200 and increase in EMT-inducing transcriptional factors (e.g., FOXC2, Snail, Twist, Zeb) induces an NEPC-like phenotype in prostate cancer cells. Multiple autocrine and paracrine signaling pathways (such as IL6, EGF, TGFβ, PI3K/AKT/mTOR, and p38 MAPK) facilitate induction and maintenance of the neuroendocrine phenotype. Genetic alterations including genomic amplifications of N-Myc and aurora kinase A, genomic loss of RB1 and PTEN, as well as genomic loss or point mutations of TP53 are also associated with the generation of these aggressive variants. AVPC, aggressive variant prostate carcinoma; NEPC, neuroendocrine prostate cancer.