Telomere Length Influences Cancer Cell Differentiation In Vivo

Abstract

dLimitless reproductive potential is one of the hallmarks of cancer cells. This ability is due to the maintenance of telomeres, erosion of which causes cellular senescence or death. While most cancer cells activate telomerase, a telomere-elongating enzyme, it remains elusive as to why cancer cells often maintain shorter telomeres than the cells in the surrounding normal tissues. Here, we show that forced telomere elongation in cancer cells promotes their differentiation in vivo. We elongated the telomeres of human prostate cancer cells that possess short telomeres by enhancing their telomerase activity. The resulting cells had long telomeres and retained the ability to form tumors in nude mice. Strikingly, these tumors exhibited many duct-like structures and reduced N-cadherin expression, reminiscent of well-differentiated adenocarcinoma. These changes were caused by telomere elongation and not by enhanced telomerase activity. Gene expression profiling revealed that tumor formation was accompanied by the expression of innate immune system-related genes, which have been implicated in maintaining tumor cells in an undifferentiated state and poor-prognosis cancers. In tumors derived from the telomere-elongated cells, upregulation of such gene sets is not observed. Our observations suggest a functional contribution of short telomeres to tumor malignancy by regulation of cancer cell differentiation.

Microenvironmental Regulation of Telomerase Isoforms in Human Embryonic Stem Cells

“…Induction of differentiation upon telomerase inhibition by TI-IX occurred within a matter of days, and is therefore not due to critical shortening of telomeres [27,89]. Interestingly, TI-III-mediated telomerase inhibition in hESCs appeared to improve stem-celllike phenotype compared with nontreated hESC controls.…”

Telomere Length and Recurrence Risk after Curative Resection in Patients with Early-Stage Non–Small-Cell Lung Cancer: A Prospective Cohort Study

“…A different study by Hirashima and colleagues demonstrated that forced elongation of the telomeres in cancer cells promoted their differentiation in vivo . 53 The resulting cells had longer telomeres and were capable of forming tumors in nude mice that surprisingly exhibited many duct-like structures, consistent with adenocarcinoma. We could speculate that long telomere length could potentially contribute to tumor recurrence by regulation of cancer cell differentiation, especially into adenocarcinoma subtype.…”

Mutations, Cancer and the Telomere Length Paradox

“…These include dysregulation during carcinogenesis in the shelterin proteins [41]. In vitro studies also showed that engineered telomere elongation in prostate cancer cells promoted their differentiation, suggesting selection of cancer cells [42]. However, these alternatives do not contradict the premise that individuals with constitutively long TL are more likely to sustain the 2 nd Hit, which is crucial for carcinogenesis in the two-stage telomere model we propose.…”