Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Dec;1866(2):320-329.
doi: 10.1016/j.bbcan.2016.10.005. Epub 2016 Oct 18.

Means to the ends: The role of telomeres and telomere processing machinery in metastasis

Nathaniel J Robinson  1 , William P Schiemann  2
Affiliations
Review

Means to the ends: The role of telomeres and telomere processing machinery in metastasis

Nathaniel J Robinson et al. Biochim Biophys Acta. 2016 Dec.

Abstract

Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origin to distant secondary sites. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions. Although telomere shortening occurs in nearly all somatic cells, telomeres may be elongated via two seemingly disjoint pathways: (i) telomerase-mediated extension, and (ii) homologous recombination-based alternative lengthening of telomeres (ALT). Both telomerase and ALT are activated in various human cancers, with more recent evidence implicating both pathways as potential mediators of metastasis. Here we review the known roles of telomere homeostasis in metastasis and posit a mechanism whereby metastatic activity is determined by a dynamic fluctuation between ALT and telomerase, as opposed to the mere activation of a generic telomere elongation program. Additionally, the pleiotropic nature of the telomere processing machinery makes it an attractive therapeutic target for metastasis, and as such, we also explore the therapeutic implications of our proposed mechanism.

Keywords: Alternative lengthening of telomeres; DNA damage; DNA repair; Epithelial-mesenchymal transition; Metastasis; Signal transduction; Telomere homeostasis; Telomeres.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Overview of the metastatic cascade. The ability of carcinoma cells to disseminate is dependent on the presence of a vascular supply and the cellular responses to multiple signaling inputs. Cancer cells secrete pro-angiogenic factors, such as vascular endothelial growth factor (VEGF; denoted by V), that facilitate tumor invasion of existing vasculature and recruit endothelial cells for neovascularization. These cells similarly secrete matrix metalloproteinases (MMPs), which remodel the surrounding extracellular matrix (ECM). MMPs also cleave and activate latent signaling molecules, including transforming growth factor-β (TGF-β; denoted by T). TGF-β binds and activates its receptors (TβR) to promote cancer cell migration, intravasation, and epithelial-mesenchymal transition (EMT). ECM proteins and secreted growth factors, including epidermal growth factor (EGF) and Wnt (denoted by W), activate convergent signaling pathways that further stimulate cancer cell growth and invasiveness and impart these cells with mesenchymal properties. Once in the circulation, disseminated tumor cells (DTCs) persist in isolation, in small clusters, or in association with macrophages (denoted M) until they reach distant organs that are amenable to DTC outgrowth. Metastatic outgrowth is determined in part by the relative activities of the protein kinases ERK1/2 and p38 MAPK. ERK1/2 are activated downstream of EGF receptor (EGFR) and integrin stimulation, while p38 MAPK is activated in response to environmental stressors, such as hypoxia. In addition, DTCs secrete pro- (VEGF) and anti-angiogenic (thrombospondin-1; Tsp) factors that control vascular supply and tumor growth. DTC growth at metastatic sites is further influenced by cells of the surrounding tissues, including cancer-associated fibroblasts (CAFs) that release Wnt and other factors into the microenvironmental milieu. In response, DTCs negatively regulate Wnt signaling in an autocrine manner. Dkk1, Dickkopf-related protein 1; E-cad, epithelial cadherin; FAK, focal adhesion kinase; PI3K, phosphatidylinositide 3-kinase.
Fig. 2
Fig. 2
Extratelomeric functions of TERT coupled to cancer cell dissemination and tumor formation. (Left Panel) Schematic representation of the metastatic cascade, encompassing (A) primary tumor formation, (B) endothelial cell (EC) recruitment and angiogenesis, (C) cancer cell migration and invasion into surrounding tissue, (D) cancer cell intravasation and survival within the system circulation, and (E) extravasation and colonization of distant organs either as single cells/micrometastases or (F) overt metastatic lesions. (Right Panel) Depicts the pathways regulated by telomerase TERT (denoted by T) that influence specific stages of the metastatic cascade. Canonical TERT activity is responsible for amplifying telomeric repeat DNA, an event that is essential for malignant transformation, and for tumor growth and development (A). In addition to its role in telomere elongation, TERT also controls gene expression by acting as a transcription factor. In doing so, TERT targets the expression of vascular endothelial growth factor (VEGF), as well as genes governed by the Wnt:β-catenin axis (Wnt denoted by W; β-catenin by β). VEGF orchestrates multiple stages of the metastatic cascade, particularly tumor angiogenesis (B), intravasation (D), and proliferation of disseminated cells at distant sites (F). Wnt signaling promotes EMT-mediated cancer cell migration (C) and intravasation (D). Additionally, Wnt signaling regulates the proliferation and outgrowth of DTCs in part by governing various features of the metastatic niche (F). Activation of Wnt-responsive genes, which includes VEGF, by TERT is dependent on its association with the chromatin remodeler SMARCA4 (SM4). In turn, TERT expression is reciprocally regulated by β-catenin-dependent transcription. TERT function and localization are controlled by both stimulatory (e.g., AKT) and inhibitory (e.g., bone morphogenetic proteins, BMPs) signals present in the metastatic microenvironment. AKT is an important regulator of cancer cell dissemination and survival in circulation (D), doing so by preventing the death of CTCs. In contrast, BMPs inhibit DTC outgrowth and maintain these cells as subclinical micrometastases (E). Under conditions of oxidative stress, TERT may translocate to mitochondria and regulate the expression of mitochondrial genes (Mitochondrion, left arrow) related to glucose metabolism and energy production; it also mediates an antioxidant response to reactive oxygen species (ROS; Mitochondrion, right bar). ROS are ordinarily present as a defense mechanism against disseminated tumor cells both in the circulation (D), and in the metastatic niche (F). Thus, expression of TERT in these cell may provide them with a selective advantage in colonizing metastatic sites.
Fig. 3
Fig. 3
Hypothetical model of TMM selection and therapeutic targeting during metastasis. The top row (blue box) depicts the dissemination of a telomerase-positive cancer cell from the primary tumor site to a distant organ, while the bottom row (pink box) depicts these same events in an ALT-positive cell. See Section 5. “Telomere homeostasis: Determinant or consequence of metastatic progression?” for details.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, Allen C, Hansen G, Woodbrook R, Wolfe C, et al. The Global Burden of Cancer 2013. JAMA Oncol. 2015;1:505–527. - PMC - PubMed
    1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108. - PubMed
    1. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO, Gelmon K. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28:3271–3277. - PubMed
    1. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94:2698–2705. - PubMed
    1. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244:254–259. - PMC - PubMed

Publication types

LinkOut - more resources