Cancer Stem Cell Division: When the Rules of Asymmetry Are Broken

Abstract

Asymmetric division of stem cells is a highly conserved and tightly regulated process by which a single stem cell produces two daughter cells and simultaneously directs the differential fate of both: one retains its stem cell identity while the other becomes specialized and loses stem cell properties. Coordinating these events requires control over numerous intra-and extracellular biological processes and signaling networks. In the initial stages, critical events include the compartmentalization of fate determining proteins within the mother cell and their subsequent passage to the appropriate daughter cell. Disturbance of these events results in an altered dynamic of self-renewing and differentiation within the cell population, which is highly relevant to the growth and progression of cancer. Other critical events include proper asymmetric spindle assembly, extrinsic regulation through micro-environmental cues, and noncanonical signaling networks that impact cell division and fate determination. In this review, we discuss mechanisms that maintain the delicate balance of asymmetric cell division in normal tissues and describe the current understanding how some of these mechanisms are deregulated in cancer.The universe is asymmetric and I am persuaded that life, as it is known to us, is a direct result of the asymmetry of the universe or of its indirect consequences. The universe is asymmetric.-Louis Pasteur

Drosophila Brat and Human Ortholog TRIM3 Maintain Stem Cell Equilibrium and Suppress Brain Tumorigenesis by Attenuating Notch Nuclear Transport

“…The following primary antibodies were used for the immunohistochemistry: NICD (1:100) [Cell signaling Technology], Miranda (1:100) and Deadpan (1:100) [a gift from Dr. Renee Read], Phospho-Histone H3 [Abcam], Musashi (1:100) [a gift from Dr. Hideyuki Okano] and Brat (1:100) [a gift from Dr. Jorgen Knoblich]. Alexa flour 488, 555 and 647 were used as secondary antibodies.…”

“…Glioma stem cells (GSCs) are a driving force underlying the clinically devastating growth properties of glioblastoma (GBM) (1). While GSCs account for only a small fraction of total GBM cells, they confer a disproportionate influence on malignant behavior and therapy resistance (2-4).…”

Cancer Stem Cells: Cellular Plasticity, Niche, and its Clinical Relevance

“…To maintain this intrinsic homeostatic state, a stable balance between the rates of CSC self-renewal, differentiation, and asymmetric division and the rates of interconversion between non-CSCs to CSCs must be maintained within the individual tumor [39]. One critical aspect of normal stem cell function and identity is asymmetric division, in which the cell creates descendants that retain the parental stemness characteristics as well as give rise to progeny cells that are committed to differentiation into multiple lineages [40]. The symmetrical division is also a fundamental feature of the tissue generation of normal adult stem cells in which two daughter cells preserve their stemness.…”

“…Any disruption of this process throws off the equilibrium ratio of number of stem cells to non-stem cells. The dedifferentiation of non-CSCs into CSCs has been attributed to cellular reprogramming during oncogenic transformations and initiates subsequent development of aggressive cancers [3,6,9,40,41]. These unprecedented rates of plasticity allow normal cancer cells to acquire stem-like states and in this way increase the intratumoral CSC frequency.…”

Concise Review: Asymmetric Cell Divisions in Stem Cell Biology

“…According to this revised model of human hematopoiesis (Figure 4a MPPs divide asymmetrically with regard to CD133 to create two daughter cells, a lymphomyeloid-primed progenitor (LMPP) and an erythromyeloid-primed progenitor (EMP) [67,69]; (b) Hypothetical model assuming the existence of further ACD during human hematopoiesis. In addition to the asymmetric differentiation mode described in (a), there are probably further branching points being regulated by ACD, e.g., the previously postulated asymmetric renewal type of ACD [37,38,53,70] Since the kinetics of CD133 expression initially enabled us to discover the asymmetrically segregating proteins, we investigated whether LMPPs and EMPs arise by means of ACD of MPPs, next. In previous studies we noticed that the CD133 epitopes that are recognized by classically used anti-CD133 antibodies (AC133, AC141), which previously had shown symmetric CD133 distributions in mitotic HSPCs [59], are sensitive to fixation [58].…”