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.
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. 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. Metastasis is most accurately thought of as a cascade of systemic and cellular events undertaken by a subset of cells within the primary tumor. Thus, there remains a significant unmet need for novel therapeutic approaches to target metastasis. 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. Indeed, although the rates of diagnosing metastatic disease are typically low in many cancers (<10–30 percent ), approximately 90 percent of cancer-related deaths are attributable to metastasis. Metastasis, while comprising only a fraction of this growing clinical burden, is responsible for the overwhelming majority of cancer mortality. 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. 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. 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. 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.
Both telomerase and ALT are activated in various human cancers, with more recent evidence implicating both pathways as potential mediators of metastasis.
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). Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. 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.
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