Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewMeans to the ends: The role of telomeres and telomere processing machinery in metastasis
Introduction
When considered as a single disease, cancer is one of the leading causes of global mortality, with an estimated 14.9 million new cases and 8.2 million deaths attributable to cancer each year [1]. The incidence of many cancers is increasing in both developed and developing nations due in part to the prevalence of risk factors (e.g., tobacco and obesity) in an expanding and increasingly aging population [2]. Metastasis, while comprising only a fraction of this growing clinical burden, is responsible for the overwhelming majority of cancer mortality. Indeed, although the rates of diagnosing metastatic disease are typically low in many cancers (< 10–30%; [3], [4], [5]), approximately 90% of cancer-related deaths are attributable to metastasis [6]. The underlying lethality of metastasis reflects its molecular complexity, which has greatly limited the success of therapies targeting this process in both overt disease and adjuvant settings [7], [8], [9]. Thus, there remains a significant unmet need for novel therapeutic approaches to target metastasis.
Metastasis is most accurately thought of as a cascade of systemic and cellular events undertaken by a subset of cells within the primary tumor [10], [11]. Generally speaking, metastatic cells become liberated from well-vascularized, angiogenic primary tumors and undergo intravasation to gain access to the circulation, where they persist in the blood, lymph, or bone marrow. Upon reaching their target tissue, disseminated cells extravasate and initiate growth of pre-angiogenic “micrometastases” before fully colonizing the metastatic niche upon reinstatement of angiogenesis [10]. The classical view of metastasis as the terminal stage of cancer progression suggests that a subpopulation of primary tumor cells progressively acquire genetic alterations necessary for their dissemination and colonization, and that these cells remain rare until clonally expanded within secondary organs [12]. However, recent evidence indicates that the capacity of tumor cells to metastasize is present in the earliest stages of primary tumor development [13], [14] and that these variant cells are often genetically divergent from their primary tumor counterparts and from one another [15], [16], [17], [18]. In many respects, metastases may be considered as discrete entities from their primary tumors of origin due in part to their acquisition of genomic alterations during dissemination and distant organ colonization, suggesting that distinct regulatory pathways are operant during metastasis versus those active in primary tumor development [19].
Telomeres have long been implicated in driving tumorigenesis, yet emerging evidence indicates that the established concept whereby telomeres and their homeostatic machinery serve solely as cellular “immortalizers” may be drastically oversimplified. Indeed, telomeres and telomeric proteins subserve diverse functions in many of the stages that define the metastatic cascade. Herein we examine the varying roles that telomeres play in driving the dissemination and interaction of cancer cells with the metastatic microenvironment. We also discuss the therapeutic potential of targeting telomeres as a novel means to alleviate metastatic disease.
Section snippets
Metastasis at the cellular level
The metastatic cascade is defined by the following sequence of events: (i) primary tumor angiogenesis; (ii) cancer cell migration away from the primary tumor and intravasation into the tumor vascular supply; (iii) cancer cell survival within the circulation; (iv) extravasation of circulating tumor cells at secondary organs; and (v) proliferation of disseminated tumor cells (DTCs) at these secondary sites [19]. Each of these stages is spatially and temporally regulated by a host of cancer
Telomeres: dynamic structures with dynamic functions
Telomeres function as determinants of cellular age and replicative potential [62]. Consequently, aberrant telomere length imparts cells with replicative immortality, one of the hallmarks of cancer [63]. Indeed, abnormal telomere elongation is found in nearly all human cancers, with the vast majority of these exhibiting activation of the reverse transcriptase telomerase, while the remaining cases accomplish this task via the recombination-based Alternative Lengthening of Telomeres (ALT; [64],
Telomerase: more than a telomere machine
Telomerase is an RNA-dependent DNA polymerase that is composed of two moieties: (i) a RNA component (TR) that serves as a template for telomeric DNA replication, and (ii) a protein component (TERT) that is responsible for polymerase activity. The TERT protein contains four domains, and regions of the N- and C-terminal domains are sufficient to induce cell immortalization, even in the absence of catalytic activity [101]. Indeed, alternative splice variants of TERT lacking its catalytic domain
Telomere homeostasis: determinant or consequence of metastatic progression?
Associations between cancer and mutations in various telomeric proteins are continually being discovered (Table 1). However, the extent to which these aberrations specifically influence metastatic progression remains unclear. To date, many studies that have examined the association between cancer progression and telomere homeostasis have employed descriptive readouts of telomere dynamics, primarily differences in either telomere length or telomerase expression or activity that are then
Future directions: telomere-directed therapy for metastasis
The deadly nature of metastatic disease necessitates the development of therapies that specifically target essential pathways operant during dissemination. Current efforts aimed at anti-telomerase therapy have adopted several approaches, including direct enzyme inhibition, telomere destabilization, anti-telomerase immunotherapy, and telomerase-driven suicide gene therapy [147]. Enzyme inhibitors include both small molecules and RNA template antagonists, both of which have demonstrated robust
Financial disclosures/conflicts of interest
The authors declare that they have no competing interests, nor conflicts of interest.
Transparency document
Acknowledgements
Research support was provided in part by the National Institutes of Health to NJR (T32GM007250 and TL1TR000441) and WPS (CA129359, CA177069, and CA194518), and by METAvivor to WPS.
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