Microenvironmental modulation of asymmetric cell division in human lung cancer cells

Abstract

Normal tissue homeostasis is maintained through asymmetric cell divisions that produce daughter cells with differing self-renewal and differentiation potentials. Certain tumor cell subfractions can self-renew and repopulate the heterogeneous tumor bulk, suggestive of asymmetric cell division, but an equally plausible explanation is that daughter cells of a symmetric division subsequently adopt differing cell fates. Cosegregation of template DNA during mitosis is one mechanism by which cellular components are segregated asymmetrically during cell division in fibroblast, muscle, mammary, intestinal, and neural cells. Asymmetric cell division of template DNA in tumor cells has remained elusive, however. Through pulsechase experiments with halogenated thymidine analogs, we determined that a small population of cells within human lung cancer cell lines and primary tumor cell cultures asymmetrically divided their template DNA, which could be visualized in single cells and in real time. Template DNA cosegregation was enhanced by cell-cell contact. Its frequency was density-dependent and modulated by environmental changes, including serum deprivation and hypoxia. In addition, we found that isolated CD133+ lung cancer cells were capable of tumor cell repopulation. Strikingly, during cell division, CD133 cosegregated with the template DNA, whereas the differentiation markers prosurfactant protein-C and pan-cytokeratins were passed to the opposing daughter cell, demonstrating that segregation of template DNA correlates with lung cancer cell fate. Our results demonstrate that human lung tumor cell fate decisions may be regulated during the cell division process. The characterization and modulation of asymmetric cell division in lung cancer can provide insight into tumor initiation, growth, and maintenance.cancer stem cell | CD133 | immortal DNA | template DNA

Evidence of asymmetric cell division and centrosome inheritance in human neuroblastoma cells

“…In addition, ACD has been reported in human hematopoietic stem and progenitor cells and lung cancer cells (8,9). A stem cell will divide asymmetrically, with one of its daughters retaining self-renewal potential, whereas the other proceeds to differentiate into transit-amplifying cells.…”

CD133 is a modifier of hematopoietic progenitor frequencies but is dispensable for the maintenance of mouse hematopoietic stem cells

“…17) and solid cancers (18). From a cell biological point of view, CD133 is a unique marker of both plasma membrane protrusions (6,8) and cholesterol-based membrane microdomains (19,20) and could be differentially inherited to daughter cells upon cell division as demonstrated in murine neural stem cells (2), human HSCs (11,12), and human lung and brain cancer cells (21,22). Furthermore, a link between the asymmetric cell distribution of CD133 and the cellular fate has been elegantly demonstrated in neural stem cells (2).…”

Drosophila male germline stem cells do not asymmetrically segregate chromosome strands

“…Supporting evidence for immortal strand segregation comes from studies of cells in the small and large intestine (Potten et al, 2002;Quyn et al, 2010), neural stem cells (Fei and Huttner, 2009;Karpowicz et al, 2005), mammary epithelial cells (Smith, 2005), fibroblasts (Merok et al, 2002), skeletal muscle satellite cells (Conboy et al, 2007;Shinin et al, 2006), human lung cancer cells (Pine et al, 2010) and female germline stem cells in the Drosophila ovaries (Karpowicz et al, 2009). Other studies using similar techniques have failed to observe evidence for asymmetric chromosome strand segregation in mouse hematopoietic stem cells (Kiel et al, 2007), epidermal basal cells (Sotiropoulou et al, 2008), hair follicle stem cells (Waghmare et al, 2008) and neocortical precursor cells (Fei and Huttner, 2009).…”