Telomere length maintenance: a factor to be considered in personalized medicine?

Abstract

telomerase is required to sustain their growth. The fact that cancer cells have shorter telomeres than normal cells, together with the fact that cancer growth appears to depend on telomerase reactivation, indicates that therapeutic strategies that are aimed at inhibiting telomerase will preferentially kill the tumor cells and have no toxicity on normal cells [3]. Since telomerase and telomere maintenance play a key role in the development of malignancies, several approaches targeting either the telomerase enzyme or the telomeres have been developed. However, while many efforts have been carried out to discover new anti-telomere/telomerase drugs, to date, very few compounds are exploitable for clinical use owing to low effectiveness or toxicity in vivo and also because of our partial knowledge on telomere and telomerase regulation and its functions [4]. There is growing evidence that telomere length carries information that may be of clinical importance for cancer patients. It is well established that telomere length is important for senescence in normal cells and there appears to be a connection between telomere shortening, genetic aberrations and the risk of cell transformation. Interests in investigating telomere length as a potential clinical biomarker in cancer has grown considerably in recent years. For hematogical malignancies, published data demon strate that short telomeres indicate progressive disease and a poor outcome [5]. For solid tumors the data are more heterogeneous. Thus, in colorectal cancer (CRC) telomere reduction appears to occur in parallel in noncancerous mucosa and colon cancer, with a correlation between both. Functional studies have implicated human TRF1 in telomere length Telomeres form specialized structures at the ends of eukaryotic chromosomes, preventing them from being wrongly recognized as damaged DNA. In normal cells, the DNA replication machinery is unable to completely duplicate telomeric DNA; thus, telomeres are shortened after every cell division. When telomeres become critically shortened and compromise genomic stability, chromosome ends activate DNA damage response pathways that can induce apoptosis. In cancer, these mechanisms are often inactivated, and telomeres can become dysfunctional via several mechanisms, such as loss or alteration of telomere-binding proteins involved in telomere maintenance. These proteins are critical for the functions of telomeres as they prevent unwanted DNA repair activity [1]. Tumor cells acquire the hallmark properties of cancer during the carcinogenic selection process. Cell immortality is one of the principal features acquired, which involves the stabilization of telomere length. It is achieved mainly by telomerase activation. Thus, the discovery of telo meres and telomerase allowed an understanding of the mechanisms by which cells can become immortalized [2]. Generally tumors have shorter telomeres than the surrounding normal tissue, owing to the fact that they have had a longer proliferative history in the absence of telomerase activity. Telomere shortening can eventually lead to increased cell death and loss of cell viability within the tumor. However, telomerase is reactivated in more than 90% of all types of human tumor, thereby rescuing and perpetuating cells with short telomeres and high chromosomal instability. Similarly, most metastases also contain telomerase-positive cells, which indicate that