Lessons from development: A role for asymmetric stem cell division in cancer

Abstract

Asymmetric stem cell division has emerged as a major regulatory mechanism for physiologic control of stem cell numbers. Reinvigoration of the cancer stem cell theory suggests that tumorigenesis may be regulated by maintaining the balance between asymmetric and symmetric cell division. Therefore, mutations affecting this balance could result in aberrant expansion of stem cells. Although a number of molecules have been implicated in regulation of asymmetric stem cell division, here, we highlight known tumor suppressors with established roles in this process. While a subset of these tumor suppressors were originally defined in developmental contexts, recent investigations reveal they are also lost or mutated in human cancers. Mutations in tumor suppressors involved in asymmetric stem cell division provide mechanisms by which cancer stem cells can hyperproliferate and offer an intriguing new focus for understanding cancer biology. Our discussion of this emerging research area derives insight from a frontier area of basic science and links these discoveries to human tumorigenesis. This highlights an important new focus for understanding the mechanism underlying expansion of cancer stem cells in driving tumorigenesis.

Figure 1

Model illustrating how mutations in factors regulating asymmetric stem cell division in Drosophila neuroblast and germline cells result in uncontrolled expansion of stem cells. (A) Stem cells can undergo asymmetric division giving rise to both a stem cell (white) and a differentiated cell (gray), or symmetric division that produces two stem cells. (B) In the Drosophila germline stem cells (GSC) asymmetric cell division requires Adenomatous polyposis coli-2 (Apc2; green oval) and its partners DE-cadherin and Armadillo (Arm)/β-catenin (purple) at the HUB cell interface to support proper mitotic spindle orientation, as well as additional microenvironmental extrinsic cues (yellow arrows). This yields one GSC and one Gonialblast. However, mutations in tumor suppressors results in symmetric cell division that yields two GSCs and consequent hyperproliferation of the stem cell pool. (C) Asymmetric division of the Drosophila neuroblast requires correct localization of the apical complex (red crescent): atypical Protein Kinase C-Bazooka-Par6, Inscuteable, Partner of Inscuteable, and Gαi (aPKC-Baz-Par6, Ins, Pins and Gαi) and basal restriction of Lethal giant larvae-Discs large-Scribble, Brain tumor, Miranda, Prospero, Numb (Lgl-Dlg-Scrib, Brat, Mira, Pros, Numb; blue crescent). Normal asymmetric neuroblast division results in self-renewal of the stem cell and production of a differentiated ganglion mother cell (GMC). Mutations in tumor suppressors cause mislocalization of the basal proteins and thus generate two neuroblasts resulting in uncontrolled stem cell proliferation.