Telomere shortening of epithelial cells characterises the adenoma-carcinoma transition of human colorectal cancer

Abstract

Background and aims: Chromosomal instability is one of the most consistent markers of sporadic colorectal cancer in humans. There is growing evidence that telomere shortening is one of the mechanisms leading to chromosomal instability and cancer initiation. Methods: To test this hypothesis, the telomere length of colorectal epithelial cells and cells from connective tissue was determined at the adenoma-carcinoma transition at the cellular level by quantitative fluorescence in situ hybridisation. Results: Our study showed that the telomere fluorescence intensity of epithelial cells was significantly weaker at the earliest morphologically definable stage of carcinoma-high grade dysplasia with minimal invasive growth-compared with the surrounding adenoma. In contrast, cells from connective tissue had a similar telomere signal intensity at the carcinoma stage compared with the adenoma, and in turn cells from connective tissue had overall significantly stronger telomere fluorescence signals compared with epithelial cells.Conclusions: These results demonstrate that short telomeres of epithelial cells characterise the adenoma-carcinoma transition during human colorectal carcinogenesis, suggesting that carcinomas arise from cells with critical short telomeres within the adenoma. Since the adenoma-carcinoma transition in colorectal cancer is characterised by an increase in chromosomal instability and anaphase bridges, our data support the hypothesis that short telomeres initiate colorectal cancer by induction of chromosomal instability.

Zinc deficiency or excess within the physiological range increases genome instability and cytotoxicity, respectively, in human oral keratinocyte cells

“…Telomere stability has been extensively correlated with the risk of cancer (Callen and Surralles 2004;Engelhardt et al 1997;Griffith et al 1999;Meeker 2006;Plentz et al 2003;Sieglova et al 2004), and few studies have investigated the relationship of Zn with telomere stability (Nemoto et al 2000;Bae et al 2007;Liu et al 2004). Accumulation of cells with short telomeres, which may lead to telomere end fusions, was found to be associated with reduced Zn status in hypertensive patients (Cipriano et al 2009).…”

Benign metastasizing leiomyoma: clonality, telomere length and clinicopathologic analysis

“…However, the meaning of telomere length is a complicated subject. While it has been shown that telomere length correlates inversely, and telomerase activity directly, with malignancy in epithelial tumors, [6][7][8][9] only a couple of studies address this question in soft tissue tumors. 22,23 Bonatz et al measured telomere length in 107 uterine leiomyomas using a Southern blot method and found that telomeres were significantly shorter in tumoral tissue compared to adjacent uterine smooth muscle.…”

“…However, since there is a 50% chance that the same X-inactivation could occur incidentally between two tumors, more cases should be analyzed using this method. Telomere shortening, a possible crucial event leading to chromosomal instability and development of malignancy, has been reported in multiple types of human cancer [6][7][8][9] and can be demonstrated with telomerespecific fluorescence in situ hybridization (FISH) probes.…”

Contrasting effects of telomere shortening on organ homeostasis, tumor suppression, and survival during chronic liver damage

“…In line with this hypothesis over 80% of human malignant tumors show reactivation of telomerase (Satyanarayana et al, 2004) and many genes of the senescence pathway are mutated in human cancer, for example, p53, p21 (Stewart and Weinberg, 2000). In contrast, human cancers including HCC are characterized by the presence of critical short telomeres compared to longer telomeres in noncancerous surrounding tissue (Plentz et al, 2003(Plentz et al, , 2004. Studies in mTERC À/À mice have revealed an explanation for this apparent paradox showing that telomere shortening has a dual role in cancer formation (Rudolph et al, 1999;Artandi et al, 2000).…”