Research

Cellular Replicative Potential: Telomere/telomerase

Research Topic
Unlimited replicative potential is the hallmark of cancer cells. Telomere/telomerase interplay is the major driver  of replicative potential. Understanding the value of costitutive telomere  length and circulating levels of TERT, the catalytic component of telomerase, as prognostic/predictive factors may allow us to design new approaches for minimally invasive monitoring of tumor onset/progression and response to therapy, and new therapeutic strategies against cancer.
Telomere shortening, which occurs at each cell division, restricts cell proliferation in normal somatic cells. Maintenance of telomere length, required for the unlimited cell proliferation displayed by cancer cells, is provided by telomerase activity, expressed in the vast majority of tumors. Many studies have demonstrated that neoplastic cells generally have shorter telomeres than their adjacent non-cancerous mucosa, strongly supporting the concept that telomere erosion is a critical event in carcinogenesis, by promoting genetic instability. TERT, usually absent in normal somatic cells, is expressed at variable levels in tumors, and specific mutations in its promoter influence TERT levels.

Research activities
Our research group has set up molecular methods based on multiplex PCR and Digital PCR to estimate telomere length, levels of TERT mRNA and telomerase activity. The main results of our studies, performed in collaboration with clinical centers, have demonstrated that: telomere length and/or  TERT levels are independent prognostic factors in chronic lymphocytic leukemia  (Leukemia 2007; Haematologica, 2012;Haematologica 2017) and in  solid tumors (Clin Cancer Res 2008;  Brit J Cancer,  2013); telomere length in cells of mucosa adjacent to head and neck tumors may be a  marker of field cancerization and prognostic of local relapse (Oral Oncol 2015); quantification of TERT in plasma may represent a minimally invasive tool for monitoring malignancies (Clin Cancer Res 2008) and response to neoadjuvant therapy (Br J Cancer 2018).
In addition, in vitro studies demonstrated that high levels of TERT improve resistance to apoptosis in tumor cells exposed to antineoplastic agents, and that TERT inhibition induces  DNA damage randomly  and death  of treated cells, thus suggesting that TERT, besides  maintaining  telomere length, may have extra-telomeric  functions in tumor cells  and its  inhibition may cause cell death, independently of telomere length (Clin Cancer Res 2013, Cell Death  Dis 2016) .

Ongoing Studies
a) evaluation of  predictive/prognostic role of tumor and constitutive telomere length in response to therapy/ disease progression;b) evaluation of prognostic role of circulating TERT in patients with solid tumors; c) studies of extra-telomeric functions of TERT in in vitro models of  viral-driven and viral-independent malignancies

5  selected publications
Rampazzo E, Del Bianco P, Bertorelle R, Boso C, Perin A, Spiro G, Bergamo F, Belluco C, Buonadonna A, Palazzari E, Lonardi S, De Paoli S, Pucciarelli S, De Rossi A. The predictive and prognostic potential of plasma Telomerase Reverse Transcriptase (TERT) RNA in Rectal Cancer. Brit  J Cancer  2018;118:878-886.

Celeghin A, Giunco S, Freguja R, Zangrossi M, Nalio S, Dolcetti R, De Rossi A. Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells. Cell Death Dis 2016; 12:e2562. doi: 10.1038/cddis.2016.425.

Giunco S, Dolcetti R, Keppel S, Celeghin A, Indraccolo S, Dal Col J, Mastorci K, De Rossi A. hTERT inhibition triggers Epstein-Barr virus lytic cycle and apoptosis in immortalized and transformed B cells: a basis for new therapies. Clin Cancer Res 2013; 19: 2036-2047.

Rampazzo E, Bonaldi L, Trentin L, Visco C, Keppel S, Giunco S, Frezzato F, Facco M, Novella E, Giaretta I, Del Bianco P, Semenzato G, De Rossi A. Telomere length and telomerase levels delineate subgroups of B-cell chronic lymphocytic leukemia with different biological characteristics and clinical outcomes. Haematologica  2012; 97:56-63.

Terrin L, Rampazzo E, Pucciarelli S, Agostini M, Bertorelle R, Esposito G, Del Bianco P, Nitti D, De Rossi A. Relationship betwen tumor and plasma levels of hTERT mRNA in patients with colorectal cancer: implications for monitoring of neoplastic disease. Clin Cancer Res  2008; 14, 7444-7451.

Funding
AIRC
Ricerca Finalizzata-Ministero della Salute

Pesonnel  involved
Anita De Rossi, Full Professor

Group members
Silvia Giunco,  Fellow IOV
Raffaella Petrara, Research fellow
Enrica Rampazzo, Research Fellow
Manuela Zangrossi, PhD student