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Blocking telomerase kills cancer cells but provokes resistance, progression
Date:2/21/2012

In a series of experiments in a lymphoma mouse model, the team found:

  • Telomerase reactivation in malignant cells after genomic instability causes cancer progression.
  • Inhibiting telomerase caused tumor cell death but also led to alternative lengthening of telomeres (ALT) independent of telomerase.
  • ALT-positive cells increase both the expression and copy number of a gene called PGC-1, a key regulator of mitochondrial function, to compensate for mitochondrial and reactive oxygen species defense deficiencies.
  • Targeting PGC-1 to weaken mitochondria function enhances anti-telomerase therapy.

To study the impact of reactivated telomerase, DePinho and colleagues genetically modified mice to develop T cell lymphomas and to have telomerase reactivated when the mice are treated with 4-hydroxytamoxifen (4-OHT). They crossed the mice for several generations, treating some with 4-OHT and others with a control vehicle that did not trigger TERT activation.

Telomerase reactivation causes aggressive cancer

Third- and fourth-generation mice with telomerase activated by 4-OHT had a median survival of 30 days and more frequent tumor infiltration to the spleen, kidney, liver, lung, bone marrow and brain than did control-treated mice, 70 percent of which lived beyond 50 days. Tumor cells in control-treated mice were more likely to be detected and destroyed by tumor-suppressing p53 signaling.

"These findings are consistent with telomere crisis leading to genomic instability during early stage cancer, with reactivated telomerase protecting malignant cells later to ensure tumor progression," Hu said.

Telomere dysfunction causes cancer-promoting genetic changes

Later-generation mice with activated telomerase had 4,928 amplified genes and 2,297 deletions. The team compared these changes to those in human lymphoma tumors and found 565 matching amplified genes and 300 deletions.

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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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