Dynamics of Cellular Plasticity in Prostate Cancer Progression

Abstract

Despite the current advances in the treatment for prostate cancer, the patients often develop resistance to the conventional therapeutic interventions. Therapy-induced drug resistance and tumor progression have been associated with cellular plasticity acquired due to reprogramming at the molecular and phenotypic levels. The plasticity of the tumor cells is mainly governed by two factors: cell-intrinsic and cell-extrinsic. The cell-intrinsic factors involve alteration in the genetic or epigenetic regulators, while cell-extrinsic factors include microenvironmental cues and drug-induced selective pressure. Epithelial-mesenchymal transition (EMT) and stemness are two important hallmarks that dictate cellular plasticity in multiple cancer types including prostate. Emerging evidence has also pinpointed the role of tumor cell plasticity in driving anti-androgen induced neuroendocrine prostate cancer (NEPC), a lethal and therapy-resistant subtype. In this review, we discuss the role of cellular plasticity manifested due to genetic, epigenetic alterations and cues from the tumor microenvironment, and their role in driving therapy resistant prostate cancer.

Keywords: ADT; EMT; NEPC; cellular plasticity; drug resistance; prostate cancer; stemness.

Figure 1

Schematic representing the multifaceted role of cellular plasticity in progression of prostate cancer. Prostate tumor comprises of heterogenous cell populations where both cell-intrinsic and -extrinsic factors confer cellular plasticity to enable transition between different cell fates by facilitating different mechanisms like epithelial-mesenchymal transition (EMT), stemness and drug resistance. Prostate tumor cell plasticity imparts resistance toward androgen deprivation therapy (ADT) during the progression of prostate adenocarcinoma (ADPC) to castrate-resistant prostate cancer (CRPC) stage, which may also transdifferentiate to neuroendocrine prostate cancer (NEPC).

Figure 2

Schematic showing interplay between key molecular players involved in cellular plasticity in prostate cancer. Molecular markers associated with epithelial-mesenchymal transition (EMT), cell-intrinsic factors and tumor microenvironment are deployed for imparting plasticity in prostate cancer cells. These EMT and cell-intrinsic factors are regulated by cytokines and other growth factors released in the tumor microenvironment, which in turn are modulated by different transcription factors, transcriptional/post-transcriptional events and dysregulated signaling pathways in the cancer cells.