Cellular Replicative Potential: Telomere/telomerase

Research Topic
The unlimited replicative potential is the hallmark of cancer cells. Telomere/telomerase interplay is the major driver of replicative potential playing a critical role in tumor formation and progression. Telomere shortening, which occurs at each cell division, restricts cell proliferation in normal somatic cells and reflects cell turnover and exposure to oxidative and inflammatory damage, crucial events in cellular senescence and biological ageing. Many tumour-based studies have shown that cancer cells generally have shorter telomeres than those of the adjacent non-cancerous mucosa, strongly supporting the concept that telomere erosion is a critical event in carcinogenesis. Maintenance of telomere length, required for the unlimited cell proliferation displayed by cancer cells, is provided by reactivation of TERT, the catalytic component of telomerase. TERT, usually absent in normal somatic cells, is expressed at variable levels in tumors, and specific mutations in its promoter influence TERT levels. Besides maintaining of telomere length, TERT has other biological activities contributing towards a more aggressive phenotype of cancer cells. Understanding the mechanisms affecting proliferative potential and cellular senescence may allow us to identify new prognostic and predictive biomarkers and develop innovative therapeutic approaches.

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: tumor telomere length and/or TERT levels and /or promoter mutation are independent prognostic factors of adverse oncological outcome in both solid and hematological malignancies (Terrin L et al, Leukemia 2007; Rampazzo E et al, Haematologica, 2012; Rampazzo E et al, Haematologica 2017; Terrin L et al, Clin Cancer Res 2008;  Bertorelle R et al, Brit J Cancer, 2013; Giunco S et al, Front Oncol 2021); telomere length in cells of mucosa adjacent to head and neck tumors may be a marker of field cancerization and prognostic of local relapse (Rampazzo et al, Oral Oncol 2015; Boscolo-Rizzo et al, Sci Rep 2019); quantification of TERT in plasma may represent a minimally invasive tool for monitoring malignancies (Terrin L et al, Clin Cancer Res 2008) and response to neoadjuvant therapy (Rampazzo E et al, Br J Cancer 2018; Rampazzo E et al, Cancers 2020) as well as an early biomarker of tumor onset (Cangemi M et al, Front Onco 2021); in elderly patients an accelerated aging profile identify subjects more susceptible to cancer onset and progression (Falci C et al, Exp Gerontol 2013; Giunco S et al, Aging 2019). In addition, in vitro studies demonstrated that high levels of TERT improve resistance to apoptosis in tumor cells exposed to antineoplastic agents and that telomerase inhibition, both in vitro and in vivo models, induces DNA damage randomly and cell death, thus suggesting that, besides maintaining telomere length, telomerase may have extra-telomeric functions and its inhibition can be exploited for therapeutic purposes also in the in vivo context, independently of telomere length and erosion. (Giunco S et al, Clin Cancer Res 2013, Celeghin A et al, Cell Death Dis 2016; Giunco S et al, Cancers 2020).

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 of viral-driven and viral-independent malignancies in in vitro and in vivo models; d) assessment of TERT as a biological target leading to short-term therapeutic benefit, regardless of telomere length of cancer cells.

5 selected publications

Giunco S et al, Cancers  2020; 12:2052
Celeghin A et al, Cell Death Dis 2016; 12:e2562.
Giunco S et al, Clin Cancer Res 2013; 19: 2036-2047.
Rampazzo E et al, Haematologica 2012; 97:56-63.
Terrin Let al, Clin Cancer Res 2008; 14, 7444-7451.

Ricerca Finalizzata-Ministero della Salute
IOV 5x1000

Personnel involved
Anita De Rossi, Full Professor

Group members
Silvia Giunco, Researcher (RTDa)
Maria Raffaella Petrara, Research fellow
Marzia Morello, IOV Fellow
Beatrice Rizzo, IOV Fellow