Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Review article Cancer stem cell (a)symmetry & plasticity: Tumorigenesis and therapy relevance Masoud Najafi a , Keywan Mortezaee b, ⁎ , Reza Ahadi c a Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran b Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran c Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran ARTICLE INFO Keywords: Cancer stem cell (CSC) Niche Plasticity Asymmetric division (AD) Symmetric division (SD) Dedifferentiation Tumor microenvironment (TME) Resistance Stemness Quiescence Epithelial-mesenchymal transition (EMT) Numb ABSTRACT Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play critical roles in tumor initiation, recurrence and metastasis. Despite extensive research, challenges about identity of CSCs and combating them in cancer therapy still remain steady. Cellular plasticity is a cardinal feature of tumor micro- environment (TME) tremendously influencing tumor aggressive behavior. Plasticity and CSC a (symmetry) are interconnecting processes essential for shaping a cancer through nurturing a wide number of cells with tumor promoting capacities. The plastic nature of TME cellularity infers that destemming just CSCs is not sufficient in respect with therapy, especially for high-grade cancers—instead, deploying mechanisms to retard tumor type- dependent TME-CSC interplay is a suggested strategy for making a durable remission of cancer. This requires extending our understanding about CSC divisional profiling and plasticity in order to find critical drivers in cancer progression. 1. Introduction Cellular origin of cancer and the nature of cells responsible for maintenance and progression of tumor are still unsolved challenges in regard with cancer therapy [1]. It is predictive that cancer is originated from a single cell that expands upon cancer progression [2]. Cancer stem cells (CSCs) (also called cancer-initiating or tumor-propagating cells) are small population of self-renewing cells that have potential to initiate cancer [3,4] and to cause tumor recurrence (relapse) [2,3,5]. Common therapeutic approaches like radio- and chemotherapy can exert a counter-effect by potentiating CSC self-renewal and tumor re- lapse [1]. It has been proposed that only complete eradication of these cells will eliminate the chance of tumor recurrence [6]. This strategy is not always effective, especially for high-grade tumors, due in part to the existence of, intrinsic or extrinsic, cellular plasticity [7]. There is an intense reciprocal interplay between cancer cells with their nearby stroma required for maintaining CSC properties [8]. It is obvious that tumor microenvironment (TME) is distinct in primary tumors than metastatic cancers [9]. In fact, this TME adds variability and complexity to the evolutionary processes of tumorigenesis [2] through promoting adaptation and heterogeneity of CSCs, the two important drivers of therapy resistance [10] in which a cell type can take a variety of phe- notypical state switching in this milieu [11]. This perspective aims to unravel important values of CSC divisional profiling (i.e. symmetric division [SD] and asymmetric division [AD]) along with cellular plas- ticity in tumorigenesis and therapy. CSC plasticity is one of the major obstacles in cancer targeted therapies. Information provided in this review acknowledge the importance of dampening cross-talking be- tween CSCs and their nearby TME as a promising strategy for reducing the chance of cancer recurrence. CSCs can transition between multiple types of phenotypes (stem/non-stem) and conditions (quiescence/pro- liferation) enable them to easily evade from therapy. CSCs in close association with other cells within the TME could acquire such cap- ability, so in regard with plasticity it is reasonable to assert that not essentially CSCs but all cells within the TME have the capacity to in- itiate a tumor. Therefore, combating this high cellular turnover requires extending our understanding about CSC divisional profiling and plas- ticity in order to specifically address critical drivers in cancer pro- gression. https://doi.org/10.1016/j.lfs.2019.05.076 Received 11 May 2019; Received in revised form 22 May 2019; Accepted 28 May 2019 ⁎ Corresponding author. E-mail address: mortezaee.k@muk.ac.ir (K. Mortezaee). Life Sciences 231 (2019) 116520 Available online 31 May 2019 0024-3205/ © 2019 Elsevier Inc. All rights reserved. T