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.

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

“…Inflammatory cytokines, proinflammatory cytokines and inflammation-associated myeloid cells are the three key inflammatory axes associated with stemness and EMT in breast cancer plasticity and malignancy [ 194 , 195 ]. Different components in the tumor microenvironment (TME) such as fibroblasts, macrophages, endothelial cells and infiltrating immune cells can conspire with the tumor cells to promote tumor cell plasticity [ 11 , 196 ]. In breast cancer, for example, cancer-associated fibroblasts (CAFs) were found to determine the molecular subtype of breast cancer by engaging in paracrine crosstalk with tumor cells via platelet-derived growth factor-CC signaling [ 197 ].…”

Interplay of Epidermal Growth Factor Receptor and Signal Transducer and Activator of Transcription 3 in Prostate Cancer: Beyond Androgen Receptor Transactivation

“…NED is a complex progression in which cellular reprogramming and epigenetic modulation are involved [ 14 , 91 , 92 ]. EGFR signaling induces NED via the following actions: repressing AR expression and initiating ENO2 expression, which are activated by GABAAR, heparin-binding EGF-like growth factor (HB-EGF), PTHrP autocrine/paracrine; or growth hormone-releasing hormone (GHRH)-mediated calcium flux [ 63 , 93 , 94 , 95 , 96 , 97 , 98 ] ( Figure 8 ).…”

Lineage Plasticity in Cancer: The Tale of a Skin-walker

“…Inflammatory cytokines, proinflammatory cytokines and inflammation associated myeloid cells are the three key inflammatory axises associated with stemness and EMT in breast cancer plasticity and malignancy [190,191]. Different components in the tumor microenvironment (TME) such as fibroblasts, macrophages, endothelial cells and infiltrating immune cells can conspire with the tumor cells to promote tumor cell plasticity [11,192]. In breast cancer, for example, cancer associated fibroblasts (CAFs) were found to determine the molecular subtype of breast cancer by engaging in paracrine crosstalk with tumor cells via platelet-derived growth factor-CC signalling [193].…”