All Tumor Cells Are Not Created Equal

"This schematic representation depicts symmetric and asymmetric division of template DNA, and their correlation with cell fate within the daughter cells. Cells are grown in the DNA analog 5-bromo-2-deoxyuridine (BrdU) (labeled green) for a sufficient amount of time to allow incorporation into all of the chromosomes. During anaphase of the second cell division after BrdU is removed (the chase), the BrdU labeled template chromosomes are segregated either randomly (symmetric), or exclusively to one daughter ce

This schematic representation depicts symmetric and asymmetric division of template DNA, and their correlation with cell fate within the daughter cells. Cells are grown in the DNA analog 5-bromo-2-deoxyuridine (BrdU) (labeled green) for a sufficient amount of time to allow incorporation into all of the chromosomes. During anaphase of the second cell division after BrdU is removed (the chase), the BrdU labeled template chromosomes are segregated either randomly (symmetric), or exclusively to one daughter cell (asymmetric). The lung cancer stem cell marker CD133 is co-segregated with the template DNA and differentiation-specific markers, such as pro-surfactant protein C, are upregulated and passed to the other daughter cell.

Cell division is commonly thought of as a process whereby one cell gives rise to two identical daughter cells. However, rare cell divisions are asymmetric, generating daughter cells that may differ in size, developmental potential, or even DNA content. The ability of stem cells to undergo asymmetric division allows them to self-renew while simultaneously generate daughter cells committed to differentiating into specialized cell types.

The "immortal DNA strand hypothesis" states that when specific populations of cells, such as stem cells, asymmetrically divide they pass the "immortal" DNA template strand to one daughter cell and segregate the newly synthesized DNA strand to a second daughter cell that acquires a more differentiated fate. This type of asymmetric cell division is hypothesized to prevent potentially cancer-causing DNA replication mutations from being retained in the long-lived stem cell. There has been speculation that subpopulations of tumor cells—sometimes called cancer stem cells—can regenerate all the cell types of a tumor by undergoing asymmetric cell division; however, there is currently no direct evidence that any cancer cell is capable of undergoing asymmetric cell division.

Sharon Pine, Ph.D. and Bríd Ryan, Ph.D., M.P.H., both fellows in the CCR Laboratory of Human Carcinogenesis headed by Curtis Harris, M.D., and their colleagues sought to determine whether lung cancer cells have the ability to asymmetrically divide their template DNA and whether this process could be modulated and linked to cell fate. In a study recently published in the Proceedings of the National Academy of Sciences, they labeled newly synthesized DNA in replicating cells to track asymmetric cell division and demonstrated that lung cancer cells can asymmetrically divide their template DNA. In addition, the team showed that micro-environmental conditions could affect the frequency of asymmetric division: when starved of oxygen or nutrients, self-renewal is favored by increasing symmetric divisions and decreasing asymmetric divisions.

Asymmetric divisions of lung tumor cells were then verified to give rise to daughter cells with differing cell fates. The lung cancer stem cell surface marker CD133 was preferentially retained in the daughter cell that inherited the "immortal" template DNA strands, whereas, differentiation-specific markers were segregated to the other daughter cell. Additional experiments revealed that CD133-expressing cells grown in culture gave rise to a cell population that consisted primarily of cells lacking CD133. This suggests that the CD133 subpopulation has the ability to repopulate the entire original tumor population.

This study provides direct evidence that some tumor cells have the capacity to divide asymmetrically and that rates of asymmetric cell division can be influenced by environmental factors. A shift toward symmetric division leads to expansion of the cell population with stem-like properties, which could contribute to the exponential growth of tumors. Indeed, defects in asymmetric division genes can lead to abnormal cell growth and cancer in some model systems. Identifying the genes and pathways in human cells that regulate asymmetric cell division could reveal the secrets of cancer maintenance and provide new therapeutic targets.

Summary Posted: 02/2010

Reference

Proc Natl Acad Sci USA. 2010 Jan 13. [Epub ahead of print] PubMed Link