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

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.

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.