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Telomeres and Telomerase in Cancer Development

Telomeres and Telomerase in Cancer Development. 28 February 2008 Hannah Yin. (www.biovita.fi). Telomere Structure and Function. Specialized chromosomal terminal structures – caps that guard the chromosome from recognition as a product of DNA fragmentation

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Telomeres and Telomerase in Cancer Development

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  1. Telomeres and Telomerasein Cancer Development 28 February 2008 Hannah Yin (www.biovita.fi)

  2. Telomere Structure and Function • Specialized chromosomal terminal structures – caps that guard the chromosome from recognition as a product of DNA fragmentation • Regulate chromosomal integrity and cell life span (Hahn, 2003)

  3. DNA End Replicationand Telomere Shortening (universe-review.ca) (Wikipedia.com)

  4. Telomerase Structure and Function Reverse transcriptase heterotetramer hTERC: RNA template portion hTERT: DNA polymerase enzymatic portion (Hahn, 2003)

  5. Telomeres and Telomerasein Normal vs. Immortal Cells In normal presenescent human cells • Telomerase activity is repressed • Telomeres shorten with successive cell divisions • Limited proliferative capacity in culture (Amazon.com) Hayflick Limit • In cancer cell lines • Telomerase activity maintains stable telomere lengths • Unlimited replicative potential

  6. IMMORTALIZATION Cells must… Overcome replicative senescence AND Escape regulation of the cell cycle

  7. Telomerase activity is NECESSARY…

  8. …butNOTSUFFICIENT

  9. The Path to Immortality (Hahn, 2003)

  10. Paradigm: Telomerase and Cancer During early stages of cell transformation, telomere attrition suppresses malignant tumor formation by limiting cell life span In later stages of cancer development, telomere maintenance by telomerase facilitates oncogenesis (Hahn, 2003)

  11. What happens if we Knock Out Telomerase?

  12. Tumor Formation in Nude Mice by mTR2/2 Transformed Cells (A) Tumor formation in nude mice from TAg and rasv12 transformed mTR1/1 and G1 mTR2/2 cells. (B) Tumor formation in nude mice injected with E1A and rasv12 transformed cells from wild type and mTR2/2 G1, G2, G3, and G4 embryos. (C) A second experiment was done similar to that described in (B) using wild type, mTR2/2 G4 cells, and two different isolates of mTR2/2 G6 cells. (Blasco, 1997)

  13. Diagnostics (Eiso Hiyama & Keiko Hiyama, 2002)

  14. Therapeutics • Small molecule inhibitors of telomerase reverse transcriptase RTIs already exist for treatment of HIV! • Specific inhibitors that target the active site of telomerase BIBR1532, a synthetic, non-nucleosidic drug (Pascolo et al, 2002) • Cellular immunotherapy “Data from both human and murine systems demonstrate that cytotoxic T-lymphocytes (CTL) can recognize peptides derived from TERT and kill TERT-positive tumor cells of multiple histologies. Given the vast overexpression of hTERT in human tumors and its low-level expression in rare normal tissues, clinical trials have begun that test the credentials of hTERT as a broadly applicable target for immunotherapy of cancer.” (Vonderheide, 2002)

  15. Considerations • Telomere lengths vary widely among different cancer cells, and the mechanisms that control the length of telomeres in cancer cells are not yet understood • Selection of non-telomerase-based mechanisms of telomere maintenance after prolonged treatment with telomerase inhibitors (evidence of ALT pathways) • Some normal cells, including those with stem cell-like properties, retain the ability to activate telomerase physiologically  side effects of long-term treatment with telomerase inhibitor or immunotherapy??

  16. Big Picture “Increasing our understanding of telomere biology will not only identify targets for drug development but will also aid the efficient design of clinical trials to identify effective anti-telomere- and antitelomerase-based therapies.” (Hahn, 2003) (GeneticsAndHealth.com) (www.lbl.gov)

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