Hot Topics

Parallel between Adult Stem Cells and Cancer Development
through mechanisms involving p53

(Rambhatla L et al, Cancer Res 2005;65:3155-61)
Summary by Michelle Moh

SUMMARY

Cancer is the second leading cause of death in the US1 with over half a million citizens succumbing each year.  Although billions have been poured into research on causes and cures, a definitive answer has yet to emerge. The recent surge of interest in stem cell biology has revived earlier speculation that some human cancers may be a result of genetic mutations in adult stem cells (ASCs).  ASCs are long-lived cells that have the ability to renew themselves, and if mutated, may keep dividing indefinitely until their sheer proliferation constitutes a cancerous growth.

If carcinogenic (cancer-causing) mutations do arise in ASCs that result in tumors, two special characteristics of ASCs have been put forward to reduce their potential to initiate cancers. The first is asymmetric self-renewal, that is, when an ASC division produces an ASC like itself and another that continues to divide and form specialized cells. The cartoon below shows the difference between asymmetric and symmetric divisions. It should be noted that not all ASC exhibit asymmetric division. Some ASC show symmetric division. However, the hot topic of focus discusses ASC with asymmetric division.

By causing a shift to asymmetric division, the ASC are able to self-renew. The second unique property of ASC, are immortal DNA strand cosegregations. That is, at each cell division, the ASCs “choose” to inherit the original set of chromosomes (genetic/DNA material) and the newly formed chromosomes are placed in the cells that continue to divide into specialized cells. Through this molecular selectivity, ASCs avoid mutations that come from damaged, unrepaired or misrepaired DNA that could occur through replication errors or physical damage (e.g. from UV rays).

Through asymmetric self-renewal and immortal DNA strand usage, the ASCs reduce their risk of damage from insults such as carcinogens. Since stem cells could mutate and form cancers, it is important to understand how the ASCs are able to employ DNA immortalization. The researchers used genetically engineered mouse cell lines to shift their division from symmetric to asymmetric self-renewal (refer diagram above). They have found that such a shift depends on a protein normally linked to cancer, if it is mutated. This protein is referred as p53, and its gene is considered to be tumor suppressive. The authors found that in order for the p53 protein-dependent asymmetric shift to occur, another cellular molecule has to be decreased. This molecule is referred in scientific term as inosine monophosphate dehydrogenase (IMPDH). The function of IMPDH is to make one of the components of DNA called guanine ribonucleotide (rGNP). By decreasing IMPDH levels, we would also reduce the levels of rGNP, and at the same time, help in causing immortal DNA strand usage. These occurrences are specific to ASCs undergoing asymmetric division or self-renewal.

In summary, the two unique characteristics described above for ASCs (self-renewal and immortal DNA strand usage) are linked to methods by which cancers are formed. Thus, the biology of stem cells and cancer development are not isolated events.  In cancer, if p53 is mutated, there will be loss of self-renewal of ASC, and continual division. 

Comments:  Cancer exhibits multifaceted behavior that until recently has managed to evade attempts at reductionistic explanations for its underlying causes.  But with the painstaking work of researchers trying to piece together the puzzles of molecular, genetic and cell kinetic relationships of key targets and players, the field of stem cells might add to unravel the causes of cancer towards the road for cures.  

1US Mortality Public Use Data Tape 2002, National Center for Health Statistics, Centers for Disease Control and Prevention, 2004