How do cancer cells manage to grow and multiply while healthy cells seem to know better? Cell division is the normal process by which a single cell divides to produce two identical copies. Cell division requires a cell to first make chemical copies of the many molecules crucial to its survival, including all of its chromosomes, which contain the genetic material. This process is tightly controlled so that cells divide only when new cells are needed, such as during growth in childhood or to heal a wound. The control over cell division is so crucial that a single cell with the ability to divide uncontrollably often leads to cancer.
There are many failsafe mechanisms working in human cells to prevent the occurrence of a frenzied episode of division, which would result in multiple copies of the cell being produced at an inappropriate time. One of these mechanisms involves a short segment of DNA found on the end of chromosomes called a telomere. Each time a chromosome is copied (i.e. every time a cell divides), the telomeres on the end of the chromosomes get slightly shorter. After a number of divisions, the telomeres get so short that they prevent the cell from dividing altogether. Thus, the length of telomere a cell’s chromosomes has represents its lifetime “supply” of ability to divide.
It has been known for some time that most cancer cells are different from healthy cells in that a cancer cell can undergo division to produce two copies without causing shortening of its telomeres. Thus, cancer cells can divide without the failsafe that healthy cells have in their successively shortening telomeres, and so may divide unchecked, producing a tumor.
Until recently, it was not known how cancer cells manage to maintain long telomeres. A study by Bell et al., published on May 29th in the journal Science, has revealed how some cancer cells can maintain long telomeres despite repeated division. While all cells have a gene called TERT that can lengthen telomeres, this gene is tightly shut off in nearly all types of human cells. Bell & colleagues found that some cancer cells have a mutation in the “switch” that controls whether the gene TERT is on or off. Specifically, they discovered that the mutation in the “switch” gene causes the abnormal binding of a protein called GABP to the region of the chromosome very close where the TERT gene is found, which causes the TERT gene to be switched “on”. They also found that experimentally preventing GABP from binding to chromosomes near the TERT gene in cancer cells prevented cancer cells from growing.
It is by this mechanism that some cancer cells then have active TERT, which maintains abnormally long telomeres even when cells divide repeatedly. This is a fundamental requirement that allows cancer cells to continue dividing by over-riding the mechanism that normally stops cell division. This important breakthrough suggests a new strategy for developing anti-cancer drugs that would abolish the unlimited growth potential of some cancer cells by restoring the normal function of the TERT gene. This TERT-targeted treatment could then be used to halt tumour growth in cancer patients.
Bell et al. 2015. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer Science. 348: 1036-1039