Asymmetric division of stem cells and its cancer relevance

Abstract

Asymmetric division is a fundamental process for generating cell diversity and maintaining the stem cell population. During asymmetric division, proteins, organelles, and even RNA are distributed unequally between the two daughter cells, determining their distinct cell fates. The mechanisms orchestrating this process are extremely complex. Dysregulation of asymmetric division can potentially trigger cancer progression. Cancer stem cells, in particular, undergo asymmetric division, leading to intra-tumoral heterogeneity, which contributes to treatment refractoriness. In this review, we delve into the cellular and molecular mechanisms that govern asymmetric division and explore its relevance to tumorigenesis.

Keywords: Asymmetric division; Cancer; Cell fate; Stem cell.

Fig. 1

The apical and basal determinants in asymmetric division. On the apical side, aPKC, PAR6 and L(2)GL form a complex that is phosphorylated by Aurora A. Then, aPKC phosphorylates L(2)GL. Phosphorylated L(2)GL is released from the complex and replaced by PAR3. The newly formed complex phosphorylates Numb and leads it releasing from the apical side to the basal side, increasing Numb levels at the basal side and maintainng Notch signaling activity at the apical side. Besides, Wnt signaling is also involved in the stemness maintenance. At the basal side, the accumulation of Numb suppresses the activation of Notch signaling. In addition, the adapter protein Miranda binds to Prospero and Brat at the basal side. After degradation of Miranda, Prospero and Brat are released. Prospero acts as a transcription factor to initiate differentiation. Brat works as a translational repressor to downregulate proteins associated with proliferation. Apical microtubule arrangement is also important during asymmetric division. Inscuteable forms a complex with Pins and Gai and then bind to MUD/DLG/KNC73 complex

Fig. 2

Cell extrinsic and intrinsic cues during asymmetric division. A Extracellular microenvironment (local niche) provides cell extrinsic cues to induce asymmetric stem cell division. B Cell intrinsic non-canonical pathway is involved in regulating asymmetric stem cell division. Some growth-signaling pathways are involved in regulating asymmetric division of stem cells, such as MYC. On the other side, Brat (Drosophila) or TRIM32 (mammalian) ubiquitinates c-MYC leading to cell differentiation (i). Some self-renewal or differentiation transcription factors are accumulated on the side of stem cell or differentiated cell to regulate asymmetric division (ii). microRNAs regulate asymmetric division of stem cells. miR-146a and Lnc34a accumulating in the stem cell side drives stem renewal, whereas miR-34a, Let-7 and LincGET accumulating in the other side drives cell differentiation (iii)

Fig. 3

Different partition of cellular components during asymmetric division. The organelles, including A the centrosome, B the mitochondria, C the lysosome, D the endosome, E the endoplasmic reticulum and other cellular components such as F the midbody, G the sister chromatids, H the histones are asymmetrically inherited by two daughter cells

Fig. 4

Asymmetric or symmetric division in tumor development. Asymmetric division of cancer stem cells happens frequently in early stage of cancer, which not only maintains the pool of cancer stem cells, but also creates tumor heterogeneity (left). Tumors at this stage are usually well differentiated. However, the balance between asymmetric and symmetric division is broken in late stage of cancer. Increased symmetric division of cancer stem cells enables tumor to have higher proliferative capacity thus contributes to tumor progression (right). Tumors at this stage are usually poorly differentiated