There was a problem sending you an sms. Check your phone number or try again later.
We've sent a link to the Scribd app. If you didn't receive it, try again.
The unique biology of telomeres and telomerase plays important roles in many aspects of mammalian cell physiology. Over the past decade, several lines of evidence have con\ufb01rmed that the maintenance of telomeres and telomerase participate actively in the pathogenesis of human cancer. Speci\ufb01cally, activation of telomerase is strongly associated with cancer, and recent observations con\ufb01rm that telomeres and telomerase perform important roles in both suppressing and facilitating malignant transformation by regulating genomic stability and cell lifespan. In addition, recent evidence suggests that telomerase activation contributes to tumorigenesis independently of its role in maintaining telomere length. Here we review recent developments in our understanding of the relationships among telomeres, telomerase, and cancer.
One of the central characteristics of cancer is its complexity. Clinically, cancer encompasses a diverse set of illnesses that share the property of inappropriate cell growth, and biologically, cancer cells harbor thousands of molecular alterations that distinguish them from normal cells. Despite this complexity, it is clear that certain mutations play critical roles in programming the malignant state by imparting or facilitating particular biological phenotypes. Several lines of evidence now \ufb01rmly implicate
dysregulation of the normal homeostasis of telomeres and telomerase as a critical change necessary for the development of cancer[3\u20137].
Telomeres are nucleoprotein structures that termi- nate eukaryotic chromosomes. One of the primary functions of telomeres is to mark the ends of linear chromosomes as distinct from a broken DNA end and to facilitate chromosome replication. In addition, recent observations implicate the maintenance of telomeres as an important determinant of replicative lifespan in many types of eukaryotic cells[9 \u2013 11]. Telomeres are maintained by a specialized reverse transcriptase, the ribonucleoprotein telomerase, which is composed of a ubiquitously expressed RNA subunit, Telomerase RNA Component (TERC),
and a protein catalytic subunit, Telomerase Reverse Transcriptase (TERT), whose expression is highly regulated[13,14]. Although other proteins associate with the telomerase holoenzyme[15\u2013 18], these two subunits comprise the core catalytically active enzyme[19\u2013 21]. Activation of telomerase is strongly correlated with cancer, implicating the interplay of telomerase, telomeres, and telomere maintenance as a critical step in cancer development[3,22].
Here we focus on the roles of telomere mainten- ance and telomerase activation in the process of malignant transformation. Studies in both human and animal cancer models indicate that telomeres and telomerase serve dual roles in oncogenesis, serving both to suppress and facilitate neoplastic transform- ation. Understanding the context and mechanisms by which telomeres and telomerase contribute to cancer development will not only provide insight into the complex etiology of cancer but also promises to provide novel targets for cancer therapy.
It is a well-established principle that normal human cells exhibit a restricted replicative lifespan when propagated in culture. In fact, several laboratories have identi\ufb01ed at least two proliferative barriers that limit the lifespan of human cells. These replicative barriers are called replicative senescence or mortality stage 1 (M1) and crisis or M2. Since immorta- lization is required for experimental cell transform- ation[25,26], several investigators have proposed that the limited replicative capacity of human cells suppresses tumor formation by greatly reducing the available pool of nascent cancer cells[27\u2013 32].
In human\ufb01broblasts, the retinoblastoma (pRB) and p53 tumor suppressor pathways play critical roles in controlling the onset of cellular senescence. Neutral- ization of pRB and p53 function, most often accomplished experimentally by the expression of viral oncoproteins such as the Simian virus 40 (SV40) large T antigenor the human papillomavirus (HPV) E6 and E7 oncoproteins[34,35], permits such cells to bypass senescence and extends replicative lifespan. Such post-senescent cells continue to proliferate until they reach crisis, characterized by widespread apoptosis and chromosomal instability
including end-to-end chromosomal fusions and non- reciprocal translocations. Thus, in addition to their roles in regulating cell cycle progression and the response to agents that damage DNA, the p53 and pRB tumor suppressor pathways play important roles in governing cell lifespan. However, loss of function of these pathways, as occurs in most human cancers, fails to immortalize human cells.
In addition to these tumor suppressor pathways, the maintenance of telomeres contributes in essential ways to regulating cell lifespan. In primary human cells, telomeres shorten with progressive cell division, and telomere length has been correlated with replicative capacity of human\ufb01broblasts[9,37]. Since most asynchronously proliferating normal human cells fail to display telomerase activity, these observations have led some to propose that a speci\ufb01c telomere length triggers replicative senescence. Although recent evidence suggests that other aspects of telomere structure or telomere-associated proteins may trigger replicative senescence[38\u2013 40], these observations indicate that the particular telomere status of human cells regulates entry into replicative senescence.
In post-senescent cells expressing viral oncopro- teins, telomeres continue to shorten with cycles of cell division until these cells reach crisis, where telomere length is critically short. Although introduction of HPV E7 has been reported to elongate telomeres without telomerase activation, long-term cultivation of these cells also eventually results in crisis[42,43]. Studies in both human and murine cells indicate that shortened telomeres in these post-senescent cells no longer retain the capacity to protect chromosomes from degradation and damage, suggesting a plausible mechanism for the chromosomal instability and aneuploidy observed when cells enter crisis
constant telomere lengths and most express telomer- ase activity[48,49]. Consistent with these obser- vations, introduction of human TERT (hTERT) and activation of telomerase leads to immortalization of some primary human cells and all post-senescent cells
Recent work has provided support for this notion while elucidating some of the mechanisms respon- sible for a long-standing paradox in cancer biology. Although the introduction of cooperating oncogenes such asras andmyc or the adenovirus E1A protein andras into primary murine\ufb01broblasts ef\ufb01ciently converts such cells into tumorigenic cells[55,56], similar experiments in human cells consistently fail to produce immortalized, tumorigenic cell lines. These observations indicate that the biology of murine and human cell transformation differs in signi\ufb01cant ways; at least one of these differences is the regulation of telomere length and telomerase activity[58,59]. Telomeres are much longer in the mouse, and telomerase is expressed ubiquitously in adult murine somatic tissues[61,62], making it unlikely that appreciable telomere shortening occurs during normal proliferative history of murine cells. Although primary murine cells encounter a proliferative block similar to the senescence observed in cultured human cells with extended passage, this barrier is controlled by the actions of the p53 tumor suppressor pathway rather than by telomere attrition.
These observations suggest that the presence of telomerase is responsible for the relative ease with which murine cells are immortalized and rendered tumorigenic. Recent work demonstrates that co- expression ofhTERT together with the SV40 Early Region and an oncogenic allele of H-RAS was suf\ufb01cient to transform a wide variety of human cells
capable of anchorage-independent growth and tumor formation in animal hosts, suggesting that at least one important difference between human and mouse cells is the constitutive presence of active telomerase. Human cells that express only SV40 oncoproteins and H-RAS proliferate only for a short period of time, consistent with a role for telomere attrition in controlling replicative lifespan[4,65]. Importantly, when very early passage primary cells were used, expression of the SV40 Early Region and a mutant H- RAS protein suf\ufb01ced to permit focus formation, suggesting that initially long telomeres permitted adequate cell proliferation for this type of assay. Similarly, introduction of the adenovirus EIA onco- protein, MDM2, and mutant H-RAS into early passage human\ufb01broblasts suf\ufb01ces to allow growth in soft agar but tumors inevitably activated telomerase
. Taken together, these studies reinforce the notion that the immortalization of human cells is a prerequisite for the eventual progression to a tumori- genic state and that the telomere attrition serves as a mechanism of tumor suppression.
Although human and murine cells differ with respect to their telomere biology, several recent studies using mice in which telomerase activity was eliminated by a targeted deletion of the RNA component,mTerc, provide further evidence that loss of telomere maintenance leads to tumor suppres- sion. In such mice, germline deletion ofmTerc results in loss of telomerase activity, and after four to six generations of interbreeding, the telomeres of such mice eventually reach lengths similar to those of cells observed in human cells. Such late generation
known to induce skin papillomas, suggesting that loss of telomeres contributes to tumor suppression. Furthermore, when suchmTerc null mice were interbred with tumor prone p16INK4Anull mice, a marked decrease in the incidence of malignant tumors was observed in the doubly de\ufb01cient mice. Consistent with these observations, cells from such mice were also relatively resistant to cellular trans- formation in vitro. Taken together, these results indicate telomere attrition to critically short lengths serves to limit tumor progression both in cell and animal models of transformation.
Although telomere shortening appears to limit the replicative lifespan of human cells and suppresses cell transformation, telomere shortening also eventually leads to critically short telomere lengths and the onset of crisis. Although the most of the cells that enter crisis are eliminated by apoptosis[33,49], sporadic cells (, 1\u00a3 1027) survive crisis and become immor- tal. As described previously, such immortal cells typically exhibit aneuploidy and extensive non- reciprocal chromosomal translocations providing further support for the notion that telomeres lose their protective function at lengths associated with crisis. Despite exhibiting critical telomere short- ening upon entering crisis, cells that survive crisis
Now bringing you back...
Does that email address look wrong? Try again with a different email.