STOCHASTIC AND STATE SPACE MODELS OF CARCINOGENESIS: SOME NEW MODELING APPROACHES - Quantitative Medical Data Analysis Using Mathematical Tools and Statistical Techniques - page 68

changes cancer phenotype are equally important as genetic changes in gen-
erating the cancer phenotype.
2.4. Telomere, Immortalization and Cancer
It is well-documented that normal stem cells have nite life span and can
divide only a nite number of times whereas cancer tumor cells can prolifer-
ate indenitely (i.e. immortalized) 5;25;50 . Biological studies have shown that
this is related to telomeres which make up the ends of chromosomes to pro-
tect it from recombination and degradation activities. Telomeres are special
chromatin structures and are composed of tandem repeats of TTAGGG se-
quences and single stranded overhang of the G-rich strand. When each nor-
mal stem cell divides, telomeres shorten by 50-200 bp, due to the fact that
the lagging strand of DNA synthesis is unable to replicate the extreme 3 0
end of the chromosome. When telomeres are suciently shortened, cells en-
ter an irreversible growth arrest called cellular senescence; when the length
of the telomeres have shortened below some critical points resulting in loss
of telomere protection of the chromosomes, then the cells will die or lead
to chromosomal instability. In cancer cells, the telomerase helps to stabilize
telomere length so that cancer cells become immortalized and can divide
indenitely.
Telomerase is a reverse transcriptase and is encoded by the TERT
(Telomerase Reverse Transcriptase) gene. This gene recognizes the 3 0 -OH
group of the end of the G-strand overhang of telomere. It elongates telom-
eres by extending from this group using the RNA, which is encoded by
the TERT, as a template. Blasco 5 has shown that besides being substrate
for telomerase and the telomere repeat-binding factors, the telomeres are
also bound and regulated by many chromatin regulators and related pro-
teins, including TRF1, TRF2, TERT, TERC, DKC1, SUV39H1, SUV39H2,
SUV20H1, HP1, HP1, HP1 and the retinoblastoma family of proteins
(RB1, RBL1, RBL2). This implies that the telomere length and function are
also regulated by many chromatin and regulator proteins as given above.
For example, if the retinoblastoma gene has been inactivated so that the
RB1 function is lost, then trimethylation of H4-K20 is down, leading to
abnormally long telomeres; as shown by Blasco 5 , this telomere length elon-
gation can also be achieved by epigenetic regulation of telomeric chromatin.
Henson et al. 26 have shown that lengthening of telomere and hence immor-
talization can also be achieved by telomerase-independent mechanisms.