Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity

Abstract

It is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we focus on alternate mechanisms—those without mutations, such as phenotypic plasticity and stochastic cell-to-cell variability that can also evade drug attacks by giving rise to drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria and has also recently garnered attention in cancer. We draw a parallel between bacterial persistence and resistance against androgen deprivation therapy in prostate cancer (PCa), the primary standard care for metastatic disease. We illustrate how phenotypic plasticity and consequent mutation-independent or non-genetic heterogeneity possibly driven by protein conformational dynamics can stochastically give rise to androgen independence in PCa, and suggest that dynamic phenotypic plasticity should be considered in devising therapeutic dosing strategies designed to treat and manage PCa.

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

“…These STN dynamics are governed by stochastic expression levels and signals (e.g., cytokines, receptor ligands) received from a cell's microenvironment . Cancer cells employ these plasticity mechanisms to achieve “bet‐hedging”—maintaining two or more concomitant phenotypes (e.g., cancer stem‐like and noncancer stem‐like) within a population, either a priori or in response to stressors, thereby enabling the population to better absorb environmental insults and to persist until genetically adaptive traits emerge …”

“…43 Cancer cells employ these plasticity mechanisms to achieve "bet-hedging"-maintaining two or more concomitant phenotypes (e.g., cancer stem-like and noncancer stem-like) within a population, either a priori or in response to stressors, thereby enabling the population to better absorb environmental insults and to persist until genetically adaptive traits emerge. 3 Epigenetic factors such as DNA methylation, histone modification, nucleosome occupancy and noncoding RNA play a role in all human malignancies and have been demonstrated to cooperate with mutations to drive the cancer phenotype. 44 Epigenetic regulation of phenotypic plasticity involves a balancing act between functional promoter and enhancer elements that control gene expression and are themselves modulated by repressive chromatin (e.g., H3K27me3, H3K9me3, promoter CpG methylation) that inhibits transcription signal transduction networks, versus activating chromatin (e.g., H3K4me3, H3K27ac, 5hmC) that promotes these networks.…”

“…This adaptive tumor evolution has been traditionally cast in the form of new DNA mutations that confer selective growth advantage and lead to clonal disease spread . However, it is now recognized that even within genetically homogeneous cell populations, significant phenotypic differences can exist or arise in response to environmental cues . In particular, many tumors contain subpopulations of aggressive, drug‐resistant cells, sometimes termed “tumor‐initiating cells” due to their high serial tumorigenicity in mice, or “cancer stem cells” due their self‐renewal capacity and active transcriptional networks of pluripotency genes …”

“…2 However, it is now recognized that even within genetically homogeneous cell populations, significant phenotypic differences can exist or arise in response to environmental cues. [3][4][5] In particular, many tumors contain subpopulations of aggressive, drug-resistant cells, sometimes termed "tumor-initiating cells" due to their high serial tumorigenicity in mice, or "cancer stem cells" due their self-renewal capacity and active transcriptional networks of pluripotency genes. 6 Initially, these subpopulations were conceptualized hierarchically, mirroring normal tissue stem cells, with self-renewing, pluripotent cancer cells giving rise to more differentiated transit amplifying cells and their progeny.…”

“…[6][7][8] However, a significant body of work including results from our group has demonstrated that cancer cells can, in fact, reacquire tumor-initiating, drug-resistant, stem-like properties and that this phenotypic reprogramming does not necessarily require clonal emergence of new DNA mutations. 3,5,[9][10][11] For example, we reported that bladder and breast cancer cell lines contain a highly tumorigenic, drug-resistant, cancer stem-like subpopulation that fluctuates in size cyclically and predictably through serial passages in culture. 12 This spontaneous conversion was mediated at least in part by PIK3CA/AKT signaling and CBP/β-catenin transcriptional activation.…”