Telomere length maintenance involvement in gastrointestinal cancer
Medical Oncology Unit, Human Pathology Department. University of Messina. Messina, Human Pathology Department., Italy
The length of telomeres, critical for chromosome stability and cellular life span, is mainly maintained by telomerase, that allows cell immortalization. Although telomerase activation is associated to more aggressive cell behaviour (motility and invasion), other mechanisms, which involve the telomere binding protein 1 (TRF1) and PARP (poly(ADP-ribose) polymerase), physiologically modulate the telomere length: TRF1 over-expression is associated to telomere shortening and its down-regulation to telomere length maintenance; on the contrary over-expression of PARP allows telomere elongation, probably trough the ADP-ribosylation of TRF1. Our previous data have shown variable expression of TRF1 by tumor cells, depending on the differentiation status and/or their histotype: 80% of meningiomas were TRF1 positive, 0% of astrocytomas grade 3 and 4, 30% of bladder cancers, 0% of prostate cancer, 5% of gastrointestinal cancers. AIM: To evaluate telomere length maintenance involvement in gastrointestinal cancer we evaluated the immunohistochemical expression of TRF1, of hTERT (human telomerase reverse transcriptase) and PARP in gastrointestinal tumor samples. METHODS: 20 endoscopic gastrointestinal tumor samples have been immunihistichemically stained by using polyclonal antibodies anti human TRF1 and hTERT and monoclonal anti PARP (Santa Cruz Biotechnology). As revealing system second antibody-biotin-streptavidine-peroxidase-AEC system (Universal Quick Kit, Vector) has been used. Paired normal mucosa at least 5 cm from the tumor were also evaluated. RESULTS: Tumor cells were TRF1 negative in all cases but one (95%); both PARP and hTERT were expressed in the 70% of gastrointestinal cancer samples examined (r=0.881; p<0.001). Non neoplastic tissues obtained at the same time at 5 and 10 cm from tumor, were stained by anti TRF1 antibody in almost all cases (80%), by anti-PARP in 36%, but they were always negative for anti hTERT. TRF1 correlated positively with histopathological grade in the normal mucosa (p<0.05) and not significantly negative in the tumor samples. No significant correlations of histopathological grade with respect to PARP and hTERT were observed. CONCLUSIONS: In conclusion these observations show that TRF1 expression is always down-regulated in gastrointestinal cancers and inversely related with respect to PARP and hTERT, that are up-regulated in 70% of cases. In the other 30% of cases in which telomerase (hTERT) is negative the proliferative potential and the prolonged life span of tumor cells may be sustained, as alternative mechanism (ALT), by the lack of TRF1. Long term follow-up will clear the prognostic impact of these findings.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 1091 (Immunobiology).