Plasticity of Cancer Stem Cell: Origin and Role in Disease Progression and Therapy Resistance

Abstract

In embryonic development and throughout life, there are some cells, which can exhibit phenotypic plasticity. Phenotypic plasticity is the ability of cells to differentiate into multiple lineages. In normal development, plasticity is highly regulated whereas cancer cells reactivate this dynamic ability for their own progression. The re-activation of these mechanisms enables cancer cells to acquire a cancer stem cell (CSC) phenotype-a subpopulation of cells with the increased ability to survive in a hostile environment and resist therapeutic insults. There are several contributors, which fuel CSC plasticity in different stages of disease progression such as a complex network of tumour stroma, epidermal microenvironment and different sub-compartments within tumour. These factors play a key role in the transformation of tumour cells from a stable condition to a progressive state. In addition, flexibility in the metabolic state of CSCs helps in disease progression. Moreover, epigenetic changes such as chromatin remodeling, DNA methylation could stimulate the phenotypic change of CSCs. Development of resistance to therapy due to highly plastic behaviours of CSCs is a major cause of treatment failure in cancers. However, recent studies explored that plasticity can also expose the weaknesses in CSCs, thereby could be utilized for future therapeutic development. Therefore, in this review, we discuss how cancer cells acquire the plasticity, especially the role of the normal developmental process, tumour microenvironment, and epigenetic changes in the development of plasticity. We further highlight the therapeutic resistance property of CSCs attributed by plasticity. Also, outline some potential therapeutic options against plasticity of CSCs.

De-novo purine biosynthesis is a major driver of chemoresistance in glioblastoma

“…Tumor cell plasticity with regards to adaptation to therapeutic pressure has been hypothesized to play a significant role in disease recurrence 12,18,52 . However, delineation of such adaptation mechanisms and the identification of actionable targets to prevent the plastic behavior of cancer cells are lacking.…”

The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma

“…A growing body of information suggests that CSCs’ quiescence may contribute to therapy resistance, as some of the cytotoxic agents target only highly proliferating cancer cells [ 78 , 79 , 80 ]. These quiescent CSCs can re-enter the cell cycle after treatment and can accelerate tumour regeneration by activating cell growth and proliferative signalling pathways [ 11 , 81 ].…”

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

“…TME is not only essential for the shape, function, development, and growth of tissues [ 96 , 100 , 107 ], but also for maintaining the optimal conditions of CSCs [ 39 , 61 , 96 , 108 ] and promoting tumor growth [ 109 ]. Within the TME, CSCs reside in specific areas known as CSC niches, where they can survive, self-renew, reactivate [ 30 , 61 , 75 , 110 ], and maintain their plasticity due to the autocrine and paracrine signals provided by the TME [ 111 , 112 , 113 ].…”

“…During tumor growth, most solid tumors undergo hypoxia, which is responsible for a more aggressive tumor behavior [ 108 , 114 ] and resistance to radio- and chemotherapy because hypoxia promotes the CSC properties associated with EMT, maintains their plasticity, stimulates early EMT by suppressing E-cadherin and induces unfolded protein response (UPR) [ 61 , 64 , 111 , 114 ]. The effect of hypoxia on cells is controlled by a family of transcriptional regulators, hypoxia-inducible factors (HIF) [ 61 , 108 , 109 ], which can also inhibit cellular apoptosis [ 30 ].…”

“…Additionally, tumor cells in the TME are able to control the immune response by increasing the amount of myeloid-derived suppressor cells, tumor-associated neutrophils (TANs), dendritic cells, and tumor-associated macrophages (TAMs) [ 111 ]. TAMs, like CAFs, participate in tumorigenesis by promoting genetic instability and tumor growth, nurturing CSCs, paving the way to metastasis and suppressing the protective adaptive immunity [ 122 , 123 ].…”