Asymmetric Cell Division and Tumor Heterogeneity

Abstract

Asymmetric cell division (ACD) gives rise to two daughter cells with different fates after mitosis and is a fundamental process for generating cell diversity and for the maintenance of the stem cell population. The cancer stem cell (CSC) theory suggests that CSCs with dysregulated self-renewal and asymmetric cell division serve as a source of intra-tumoral heterogeneity. This heterogeneity complicates the diagnosis and treatment of cancer patients, because CSCs can give rise to aggressive clones that are metastatic and insensitive to multiple drugs, or to dormant tumor cells that are difficult to detect. Here, we review the regulatory mechanisms and biological significance of asymmetric division in tumor cells, with a focus on ACD-induced tumor heterogeneity in early tumorigenesis and cancer progression. We will also discuss how dissecting the relationship between ACD and cancer may help us find new approaches for combatting this heterogeneity.

Keywords: asymmetric cell division; drug resisitance; symmetric cell division; tumor heterogeneity; tumorgenesis.

FIGURE 1

(A) Distinct regulatory machineries are involved in the two daughter cells during ACD of stem cells. Stem cell at the apical pole: formation of the aPKC/PAR6/PAR3 complex plays a crucial role for the establishment of the ‘self-renewal’ identity at the apical pole. Aurora-A protein kinase activates aPKC, which then phosphorylates L (2)GL; then L (2)GL is released from the complex and replaced by PAR3. The aPKC/PAR6/PAR3 complex phosphorylates Numb, releasing it from the apical membrane. PON brings Numb to the basal pole that will become the differentiated daughter cell. By removing Numb, Notch signaling is active to maintain the stemness of the daughter cell at the apical side. Wnt signaling also participates in promoting self-renewal in the daughter cell, though details of the mechanism are not known. Differentiated cell at the basal pole: the adapter protein Miranda recruits Prospero and Brat. As a translational repressor, Brat suppresses the synthesis of proteins necessary for proliferation. The transcription factor Prospero promotes the expression of genes that drive differentiation after Miranda is degraded. Ubiquitination-dependent degradation of P53 is inhibited by Numb, while the miR-34-Numb-Notch feedback loop suppresses Notch level and favors differentiation in the daughter cell. (B) The relationship between tumor progression and the ratio of CSCs that undergo ACD versus SCD. When SCD and ACD are balanced, tumor generates heterogeneity while maintaining the pool of CSCs. On the other hand, a switch from ACD to SCD in CSCs results in the expansion of the stem cell pool.