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The following is the first explanantion of what Dr Anthony Cesare has been researching into. His findings will be continually updated in this section.

The ends of human chromosomes are protected, or “capped”, by physical structures termed “telomeres”.  In healthy (non-cancerous) human cells, the telomeres shorten every time a cell divides.  The telomeres are thus a built-in clock that indicates the number of times a cell has divided; young cells have longer telomeres and old cells have shorter telomeres.  In older cells, the shortened telomeres turn on a permanent state of cellular growth arrest termed “replicative senescence”.  Once a cell enters “senescence”, it remains alive but is no longer able to divide.  Senescence is believed to act as a potent anti-cancer mechanism by preventing a cell from dividing too many times.  Limiting the number of times a cell divides protects that cell from accumulating the mutations that increase the chance of that cell becoming cancerous.

If the cellular pathways that initiate senescence have already become mutated, an old cell will by-pass senescence and continue to divide, despite having shortened telomeres.  Because the telomeres continue to shorten with every cell division, eventually the telomeres in these cells will be lost completely.  Once the telomeres are totally lost, the cells are in “crisis”.  During crisis, the chromosomes fuse to each other, leading to detrimental genetic re-arrangements and cell death. Crisis is also a potent anti-cancer mechanism, because it kills cells that have already developed pre-cancerous mutations that allowed those cells to by-pass senescence.  While, “senescence” and “crisis” may sound detrimental, they are normal and very-important mechanisms that human cells use to prevent cancer. 

To become cancerous a cell has to avoid senescence and/or crisis.  This is achieved by turning on a telomere length maintenance mechanism to elongate the shortened telomeres.  Once the short telomeres are elongated, the built-in clock is reset, and the cell is fooled into thinking it is young again.  If the telomeres are always maintained, a cell will always believe it is young and will continue to divide indefinitely.  The ability to divide forever, termed “immortalization”, is believed to be a necessary step in tumour development.

Two telomere length maintenance mechanisms have been identified in human cancers.  One of these mechanisms, termed “Alternative Lengthening of Telomeres” (or “ALT”) occurs in 10-15% of all cancers, with much higher instances in certain tumour types.  While much about how the telomeres are elongated in ALT-positive tumours remains unknown, it is known that these cells use a form of DNA repair termed “homologous recombination” to elongate shortened telomeres.  

My research focuses on elucidating how the telomere lengths are maintained in ALT cells.  My data indicate that in ALT-positive immortalized cells, many of the telomeres are not arranged into the same structure which telomeres form in non-cancerous cells.  Additionally, when we alter the function of telomere-associated proteins in ALT-positive cells we can restore the telomeres to their normal structure. When we do this, we also observe a reduction in the growth rate of these cells. I hypothesize that the altered structure of the telomeres in ALT-positive cancers lies at the root of the ALT telomere maintenance mechanism. Presumably healthy cells inhibit homologous recombination at the telomeres by assuming a certain structure. In ALT cells, all the telomeres do not assume this normal structure, and therefore they can no longer inhibit homologous recombination. If this hypothesis is correct, re-structuring the telomeres in ALT positive tumours to the proper shape should inhibit the ALT telomere length maintenance mechanism, and in turn inhibit the growth of these tumours.

My current focus is to apply several new experimental techniques I have developed to better understand what is occurring at the telomeres in ALT cells, and to determine if indeed the ALT mechanism can be inhibited by restoring normal telomere structure. Additionally, I believe that by understanding the nature of telomere dysfunction in ALT tumours, we will gain valuable insight into basic telomere function in healthy cells, specifically how normal human cells inhibit homologous recombination at their chromosome ends to prevent ALT (and cancer) from developing. 

To become cancerous, a cell must be able to divide indefinitely.  This is termed “immortalization” and is dependent on the cells turning on a length maintenance mechanism by elongating telomeres.

Inhibiting cell division through replicative senescence prevents the accumulation of mutations in aged cells that would predispose such cells to cancer development.  In the occurrence that pre-cancerous mutations have already developed that allow an aged cell to by-pass senescence, telomere shortening can still prevent cancer development by initiating crisis. Therefore, telomeres serve to prevent cancer by two separate mechanisms, first by inhibiting cells from dividing many, many times and accumulating mutations that increase the likelihood of cancer, and second by the ability of a cell to divide indefinitely, termed "immortalizaton" is therefore dependent on cells turning on a telomere length maintenance mechanism to prevent continued telomere shortening, and therefore senescence or crisis. Immortalization is a requisite for cancer development, and therefore understanding how telomere length is maintained is critical to the understanding of how healthy cells become cancerous.