TELOMERES AND TELOMERASE IN COLORECTAL CANCER STEM CELLS: A CYTOGENETIC CHARACTERIZATION

Abstract

Current evidence suggests that small subpopulations of tumorigenic cells, known as cancer stem cells (CSCs), fuel tumor. CSCs share with stem cells some proprieties, such as self-renewal, long-term clonal growth and multipotency. CSCs are involved in tumor initiation, development, metastasis, relapse and resistance to conventional or targeted therapies (1). Molecular and cellular characterization of CSCs is thus necessary to develop novel effective anticancer therapies. In this project, we are performing a cytogenetic characterization of a panel of in vitro established colorectal cancer stem cells (CRC-SCs) derived from different primary/metastatic neoplasms, which we obtained through the collaboration with the CSC Biobank, ISS (Dr. Biffoni). Our main aim is to identify novel effective therapeutic strategies targeting CSCs. In the first part of this study, we have analyzed the genetic profile, ploidy status and the level of chromosomal instability (CIN) (2) of multiple CRC-SCs. Although the mechanisms leading to CIN are not fully elucidated, some findings seem to indicate that CIN may arise from loss or damage of telomeres (3). Driven by this evidence, in the second part of the project, we have analyzed telomere status and telomerase activity in our panel of CRC-SCs. Telomeres are structures involved in chromosome protection, whose shortening or instability triggers the DNA damage response (DDR), arrests cell cycle and induces cell death (4,5). A significant fraction of tumors reactivates the ribonucleoprotein telomerase, which, on the one hand, helps maintaining short or unstable telomeres and, on the other hand, increases CIN levels (6,7). Of note, in previous studies, telomerase was described as catalytically active in CSCs. The alternative lengthening of telomere (ALT) process contributes to telomere maintenance and is activated either as an alternative mechanism or in conjunction with telomerase (8). This project is aimed to shed light upon (and open a new horizon in the study of) chromosome and telomere biology of CSCs, which are the roots and chemo-resistant seeds of cancer, and thus they can have important implication providing fundamental insights for the development of novel telomere-based strategies for depleting CSCs. 1. Kreso A, Dick JE, Cell Stem Cell 14:275-291 (2014) 2. DJ Gordon, B. Resio, D. Pellman, Nat Rev Genet. 13:189-203 (2012) 3. De Lange T, Cold Spring Harb Symp Quant Biol 70:197-20(2005) 4. Cesare AJ Bioessays 36(11):1054-61 (2014) 5. Lechel A, Satyanarayana A, Ju Z, et al EMBO rep. 6(3):275-81 (2005) 6. Ponti D, Costa A, Zafaaroni N, et al. Cancer Res. 65:5506-5511 (2005) 7. Marian CO, Cho SK, Hatanpaa KJ, et al. Clin Cancer Res. 16:154-163 (2010) 8. Perrem K, Colgin LM, Neumann AA, et al. Mol Cell Biol. 21(12):3862-75 (2001)