Chapter 4 - Telomeres, Telomerase, And Cancer

7/22/2019 Chapter 4 - Telomeres, Telomerase, And Cancer

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Chapter 4: Telomeres, Telomerase, and Cancer

Telomeres, Telomerase, and Cancer: Introduction

Maintenance of most adult organ systems requires extensive cell renewal, typified most

strikingly by the replacement of the intestinal lining on a weekly basis and the production of

trillions of new blood cells daily. Yet a lifetime of factors including continual telomere erosion,

errors in DNA replication, intrinsic and carcinogen-induced somatic mutations, cancer-

relevant germline variants, and epigenetic insults conspire to endow cells with the large

number of changes needed for malignant transformation. How is it that replicating tissues,

showered with myriad cancer-relevant somatic alterations, resist malignant transformation?

That these mutations are indeed present in normal human tissues is reflected by the

remarkable observations that roughly 1% of neonatal cord blood collections contain

significant numbers of myeloid clones harboring oncogenic fusions such as the AML1-ETO

fusion associated with acute leukemia,1and that approximately one-third of adults possess

the IgH-BCL2translocation associated with follicular lymphomagenesis.2As the prevalence

of these cancers is far lower in the general population, these observations imply that potent

tumor suppressor mechanisms must be operating to constrain the growth and survival of

these aspiring cancer cells.

The most prominent biologic manifestations of an activated tumor suppressor response are

apoptosis (cell death) and senescence (permanent cell cycle arrest). These biologic processes

are linked to powerful checkpoint effector molecules involving the p16INK4a-Rb pathway, the

ARF-p53 pathway, and specialized chromosomal DNA ends termed telomeres. These genetic

elements comprise powerful tumor suppressor barriers and act cooperatively to eliminate or

to place a limit on the replicative lifespan of rogue would-be cells. The importance of

apoptosis in preventing cancer is further discussed in Chapter7.The focus of this chapter will

be on the role of telomere dynamics and associated telomere-related cellular checkpoint

processes, particularly senescence, in the regulation of neoplastic transformation. A

significant body of clinical and translational science now supports such a role for telomeres

and cellular senescence, and in this chapter, we present rapidly increasing clinical data

pointing to the relevance of these processes in human disease, particularly cancer. Indeed, it

is worth noting that the Nobel Prize for physiology or medicine in 2009 was awarded to

Blackburn, Greider, and Szostak for their pioneering and seminal work in telomere biology

that advanced our present understanding of aging and cancer.

Telomeres and Telomerase

Telomere dysfunction is a principal tumor suppressor mechanism manifesting most

prominently as apoptosis and senescence. At the same time, when accompanied by

functional p53 loss, the genome-destabilizing impact of telomere dysfunction can cause

widespread mutations that propel normal cells toward malignant transformation. Thus, the

telomere-based anticancer mechanism can actually fuel tumorigenesis in certain contexts.

The knowledge of the basic biology of telomeres and telomerase has yielded fundamental

insights into both cancer prevention and cancer promotion. The powerful and complex impact
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of telomere dynamics in model organisms and humans reflects the crucial role of telomere

function in processes of genomic instability, organ homeostasis, chronic diseases, aging, and

tumorigenesis. With respect to tumorigenesis, the study of telomeres in the mouse has

provided insight into how advancing age in humans fuels the development of epithelial

cancers as well as how chronic inflammation and degeneration may engender increasedcancer risk in affected organs. These advances in the basic understanding of telomere

maintenance are now being translated into clinically relevant applications that may have an

impact on the diagnosis and management of a broad spectrum of cancers as well as aging,

age-related disorders, and degenerative conditions. The important role of telomere biology in

aging and degenerative diseases has been reviewed elsewhere.3,4

Telomeres

Telomeres are specialized nucleoprotein complexes at the ends of linear chromosomes

consisting of long arrays of double-stranded TTAGGG repeats, a G-rich 3 single-strand

overhang, and associated telomeric repeat binding57(Fig.4.1). The work of Muller andMcClintock in the 1930s led to the concept that telomeres function to cap chromosomal

termini and prevent end-to-end recombination, thereby maintaining chromosomal integrity.

Subsequent work has substantiated this model across the animal and plant kingdom,

underscoring the critical roles served by the telomere complex.

Figure 4.1. Human telomere structure.

A: Human telomeres form telomere loop (T loop) and displacement loop (D loop) secondary

structures. Long stretches of telomeric repeats create a loop-back structure (T loop),

completed by the invasion of the single GT-rich 3 overhang into the double-stranded DNA

molecule (D loop), thus protecting the chromosome terminus. B: In human cells, double-

stranded telomeric repeats are bound directly by two proteins, TRF1 (TTAGG repeat binding

factor 1) and TRF2. Cell culture studies have suggested that the main function of TRF1 is to

regulate telomere length, whereas TRF2 functions to protect telomeres from activating

nonhomologous end-joining (NHEJ) and other DNA repair or DNA damage responsepathways. TRF2 also interacts with the human Rap1 protein (hRap). Biochemical studies also

suggest that the formation of the T loop depends on TRF2. Another protein, POT1 (protection

of telomere 1), has been shown to bind to the single-stranded human telomeric 3 overhang.

Two shelterin proteins, TIN2 and TPP1, connect POT1 to TRF1 and TRF2. POT1 has been

proposed to interact with TRF1 complexes to regulate telomere length. Thus, there is

significant interplay between telomeric binding proteins and the formation of the

secondary/tertiary structures that protect the ends of chromosomes.

Telomere structure and function have been studied extensively in mammals. Although the

overall structural features of telomeres are preserved among different mammalian

organisms, lengths can vary considerably from species to species: for example, 5 to 15 kb

for humans versus 20 to 80 kb for the laboratory mouse. On the structural level, electron
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microscopy and other studies have shown that telomeres form complex secondary and

tertiary structures via DNA-DNA interactions between the telomeric repeats, DNA-protein

interactions between the telomeric DNA and the telomeric repeat binding proteins (shelterins

or telosomes8,9), and protein-protein interactions between the telomeric repeat binding

proteins themselves and other associated proteins (Fig.4.1). The formation of this well-documented, higher-order DNA-protein complex has provided a working model of how the

telomere functions as a capping structure, preventing the ends of linear chromosomal DNA

from being recognized as either a DNA double-strand break (DSB) or DNA single-strand

break, thereby avoiding activation of the DNA damage response and the formation of

chromosomal end-to-end fusions through the DNA repair machinery.7

Many proteins involved in DNA DSB repair, including nonhomologous end-joining and

homologous recombination processes, have been found to be physically associated with the

telomeres.710These findings have fueled speculation that DSB repair proteins provide a

protective role at the telomere; for example, by sequestering the telomere end from the DNAdamage surveillance/repair machinery. Experimental support for this hypothesis has

emerged from the mouse, in which germ line inactivation of various repair proteins (e.g., Ku

and DNA-PK) results in reduced telomere length or loss of capping function, or both, leading

to increased end-to-end fusions.11Correspondingly, in cultured human cells, experimental

disruption of telomere-binding proteins results in the unraveling of higher-order

nucleoprotein structure and telomere localization of DNA DSB surveillance/repair proteins

(e.g., 53BP1, gamma-H2AX, Rad17, ATM, and Mre11), establishing that dysfunctional

telomeres can indeed serve as substrates for the classic DNA repair machinery.12Recently,

elegant in vitroand mouse genetic experiments have shown that subunits of the shelterin

complex actively repress the ATM and ATR DNA damage signaling pathways.7,13

A further understanding of the molecular mechanisms governing the repression versus

activation of the DNA DSB surveillance/repair apparatus at the telomere could lead to the

development of novel cancer therapeutic options. For example, the design of agents that can

uncap telomeres while preserving the DNA damage checkpoint response yet neutralize the

actual DNA damage repair process would be ideal because they would produce unrepaired

DSBs and elicit cell-cycle arrest or apoptosis responses. Lastly, in the near future, agents

designed to uncap the telomeres could be used in combination with conventional

chemotherapeutic agents that create DSB for cancer treatment, thereby simultaneously

targeting these intertwined pathways.

Telomerase

Conventional DNA polymerases operating in the S phase of the cell cycle require an RNA

primer for reverse-strand synthesis, resulting in incomplete DNA replication of telomeres

during each cell division. The solution to this end-replication problem is the telomere-

synthesizing telomerase enzyme, a specialized ribonucleoprotein complex with reverse

transcriptase activity. The functional telomerase holoenzyme is a large multisubunit complex

that includes an essential telomerase RNA (hTERC) component serving as a template for the

addition of telomere repeats and a telomerase reverse transcriptase (hTERT) catalytic

subunit.14In some normal human somatic cells, telomerase levels are insufficient to
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maintain telomere length, resulting in progressive attrition with each cell division. This forms

the basis for the theory that the metered loss of telomeres can serve as a cellular mitotic

clock that ultimately limits the number of cell divisions and cellular lifespan. In support of

this view, shortening of telomere length with aging can be demonstrated in human peripheral

blood cells,1517and the rate of shortening can be associated with conditions of increasedhematopoietic stem cell turnover (e.g., in paroxysmal nocturnal hemoglobinuria).18

Many normal somatic human cells and differentiated tissues express readily detectable levels

of the hTERC component. In contrast, hTERT expression and activity are more restricted

because of stringent regulation on the levels of transcriptional initiation, alternative RNA

processing, posttranslational modification, and subcellular localization. With the identification

of an increasing number of TERT-associated proteins, it is likely that additional regulatory

mechanisms will surface, such as those governing the accessibility of the telomerase

holoenzyme onto the telomere end.19Here again, a more complete elucidation of these

regulatory mechanisms may provide additional therapeutic strategies that can preferentiallytarget telomerase-mediated telomere maintenance in cancer cells. Indeed, the development

of such selective strategies may become paramount and more challenging as recent studies

have revealed low telomerase levels in cycling somatic human cells that were previously

thought to have no telomerase activity.20Eradication of residual telomerase function in

these primary cells alters the maintenance of the 3 single-strand telomeric overhang without

changing the rate of overall telomere shortening, resulting in diminished proliferation rates

and overall reduction in proliferative capacity. These studies support an additional protective

function of telomerase at the telomeres21and raise concerns that generalized

antitelomerase therapy could lead to the immediate uncapping of telomeres in normal cells,

thus limiting the use of antitelomerase therapy in cancer patients.

Lastly, in addition to forming the telomerase holoenzyme complex with TERC, TERT was

recently shown to be able to interact with the RNA component of mitochondrial RNA

processing endoribonuclease (RMRP). This distinct TERT/RMRP ribonucleoprotein complex

has RNA-dependent RNA polymerase activity and produces double-stranded RNAs that can

be processed into small interfering RNAs.22Also, there is compelling experimental evidence

that TERT can interact and engage the Wnt signaling pathway.23,24These results suggest

that TERT contributes to cell physiology independently of its ability to elongate telomeres, a

fact that further complicates efforts to specifically target telomerase enzymatic activity as an

anticancer therapy.

Senescence

Primary human cells, even when cultured under optimal conditions, will eventually encounter

a cell division barrier, termed cellular senescence,triggered by critically shortened

telomeres. Senescence is a specific cell biologic phenotype composed of a permanent and

durable growth arrest, alterations in cellular morphology, expression of characteristic

markers of senescence such as senescence-associated (SA) -galactosidase activity, and

alterations of chromatin structure to a growth-repressive state.25Induction of senescence is

intimately associated with p16INK4a

and p53 activation, and when induced in vitroas a resultof telomere dysfunction, this barrier is termed the Hayflick limit(M1) in honor of the
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discoverer of senescence.26Because loss of p16INK4a-RB and/or p53 pathway function in

primary human cells permits additional cell divisions beyond the Hayflick limit, these

pathways appear to be involved in the activation of this senescence program brought about

by the shortened telomere signal.

Beyond the connection with telomeres, cellular senescence appears to be a general

anticancer mechanism, induced by a variety of oncogenic stresses. In addition to telomere

erosion or structural uncapping (see later discussion), senescence is also induced by forms of

DNA damage, oxidative stress, suboptimal growth conditions, and activation of certain

oncogenes (reviewed in refs. 8 and 13). Senescence requires activation of the Rb and/or p53

protein; and expression of their regulators such as p16INK4a, p21CIP, and ARF (Fig.4.2).27

30An important form of senescence is induced by p53, which has several antiproliferative

activities including stimulation of the expression of p21CIP, a cyclin-dependent kinase

inhibitor. These inhibit progression through the cell cycle by inhibiting cyclin-dependent

kinases that phosphorylate and thereby inactivate Rb and related proteins p107 andp130.31The activation of p53 is predominantly effected by specific posttranslational

modifications and its stabilization, which are prompted by the same stimuli that induce its

expression, including telomere dysfunction, DNA damage, and oncogene activation (reviewed

in refs. 18 through 20), as well as inappropriate cell cycle entry.32,33A major sensor of

oncogene activation and inappropriate cell cycle entry is ARF (also designated p14ARFin the

human or p19ARFin the mouse), which binds to and blocks MDM2-mediated degradation of

p53.3336

Figure 4.2. The INK4a/ARF/INK4blocus (also calledCDKN2aand CDKN2b) and

downstream pathways.The locus contains three open reading frames encoding the ARF, p15INK4b, and p16INK4atumor

suppressor proteins. p16INK4aand p15INK4binhibit the activity of the proliferative kinases

CDK4/6, which phosphorylate RB and related proteins p107 and p130.

Therefore, INK4expression induces RB-family hypophosphorylation, which in turn represses

E2F-regulated transcription and cell-cycle arrest. ARF inhibits the MDM2-mediated

degradation of p53; and p53 stabilization in turn induces a number of targets including many

proteins involved in cell-cycle arrest or apoptosis. The entire locus spans a mere 35 kb in the

human genome, and inactivation of all three genes by a single genetic deletion is common in

many human and murine cancers.
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Another prominent molecular correlate of senescence is up-regulation of the cyclin-

dependent kinase inhibitor, p16INK4a, which increases markedly in senescent cells on passage

in culture or advancing age in tissues.37Correspondingly, ectopic expression of p16INK4ais

sufficient to induce senescence in some cell types,38and senescence can be delayed or

prevented in some cell types by p16

INK4a

silencing or neutralization by antisense or siRNA.3943The regulation of p16INK4ais not as well understood as that of p53, although it appears to

be induced by several stimuli, including oncogene activation and growth in

culture.37Activation of p53 (and hence p21CIP1) and/or accumulating levels of p16INK4ais able

to produce Rb-family member protein hypophosphorylation and activation, which leads to

repression of cell-cycle progression,27,30enabling initiation of the senescence process.

Recent data have suggested that Rb may be of particular importance in the promotion of

senescence compared with its related family members p107 and p130, likely explaining the

frequent inactivation of Rb in human cancers relative to the other Rb-family members.44

Senescence as a Cancer Prevention MechanismSeveral lines of evidence have suggested an important role for senescence in the prevention

of cancerin vivo. It is important to note that the field has been limited by the lack of

robust in vivobiomarkers of senescence. Although (SA)--galactosidase and

p16INK4aexpression have been used as markers of in vivosenescence, both have certain

limitations and neither can be considered unequivocal proof of senescent state in vivo. These

technical shortcomings notwithstanding, a growth arrest important for the prevention of

tumorigenesis with characteristic features of senescence (p16INK4aexpression and (SA)--

galactosidase expression) has been noted in several murine and human in vivotumor

systems, and we believe the data suggest bona fide senescence occurs in the intact

organism.

The lines of evidence for senescence as a tumor suppressor mechanism are quite strong.

First, the aforementioned minimal residual disease data showing frequent oncogenic

translocations and other mutagenic events demonstrate a constant need for tumor

suppression, even in young animals. Additionally, several of the initially described tumor

suppressor proteins that are mutated in familial cancer syndromes (e.g., p16INK4a, p53, Rb)

are intimately involved in the induction of senescence. Mice lacking p16INK4aor p53 are prone

to spontaneous cancers,4547and mice with severe compromise of the senescence pathway

due to combined p16INK4aand p53 inactivation die of cancer, often harboring multiple

synchronous primary tumors, with a median age of 8 weeks (compared with a normal murine

lifespan of more than 100 weeks).19Importantly, mice and humans with impaired

p16INK4aand/or p53 function develop with only modest phenotypic alterations other than an

age-dependent increase in cancer and an increased susceptibility to cancer following

carcinogen exposure. Several groups have demonstrated a senescencelike growth arrest in

murine and human tissues in association with somatic oncogenic events.4854For example,

some forms of benign cutaneous nevi appear to be collections of senescent melanocytes,

suggesting that these common benign neoplasms would transform into melanomas were it

not for the successful interdiction of this process by the senescence tumor suppressor

mechanism. In aggregate, these data establish that senescence-promoting molecules are

critical to the prevention of mammalian cancer with advancing age.
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Lastly, although the concept of tumor maintenance is becoming well established with

regard to oncogene-activation,55a similarly important role for the persistent inactivation of

the senescence checkpoint has been established in cancer. Several groups have established

in genetically engineered murine models, for example, that persistent p53 inactivation is

required for tumor maintenance.51,52,56Therefore, just as the finding that tumors in murinemodels require persistent RAS activation presaged the successful development of therapeutic

compounds such as epidermal growth factor receptor inhibitors that target pathways

required for tumor maintenance in vivo,similarly, these data support the notion that

reactivation of senescence-promoting mechanisms such as p53 could be of therapeutic

benefit in some cancers. In fact, it is likely that certain chemotherapeutics exert their

therapeutic effects through the promotion of senescence by activating p53 and related

senescence-inducing pathways.57

Dysfunction of self-renewing somatic stem cell compartments has also been suggested to

play a role in organismal aging.25,58In this model, the activation of p16INK4a

and p53 inresponse to cellular stresses including telomere dysfunction causes a decline in tissue-

regenerative capacity (Fig 4.3). This model is supported by murine studies5963and makes

several predictions relevant to human disease. For example, this hypothesis suggests that

heritable differences in regulation of the senescence-promoting machinery should alter

individual susceptibility to human age-associated diseases, a concept that has been

supported by a plethora of recent genomewide association studies.64With regard to

oncology, this model predicts that some agents and ionizing radiation used to treat cancer,

for example, by inducing DNA damage, also can potentially induce senescence of important

self-renewing cells of nonmalignant tissues such as the bone marrow. Studies in irradiated or

chemotherapy-treated mice support such a role of senescence in the long-term

hematopoietic toxicities of these therapeutic approaches.65,66Likewise, somatic attrition of

regenerative self-renewing cells as a result of senescence activation may place an increased

replicative demand on the remaining functional cells of a given tissue, which may increase

the rate of telomere dysfunction and speed transformation in other stem cells of a tissue in a

cell nonautonomous manner (see later discussion).

In aggregate, these genetic and in vivodata support the view that senescence prevents

cancer in the intact organism on a near-daily basis and that reactivation of this mechanism in

fully established cancers can effect dramatically beneficial responses, but also has the

potential to produce long-term toxicity in nonmalignant tissues. It stands to reason that an

improved understanding of the molecular basis of senescence could lead to therapeutic

approaches designed to beneficially reawaken this potent tumor suppressor mechanism.

The INK4a/ARF/INK4bSenescence-Promoting Locus

Senescence is intimately associated with activation of the INK4a/ARFlocus (also known

as CDKN2a). This locus possesses an unusual gene structure that dually encodes p16INK4aand

ARF (or p14ARFin humans and p19ARFin mice) in nonoverlapping open reading frames

(Fig.4.2). The locus also harbors the neighboring CDKN2bgene, which encodes p15INK4b, a

protein highly related to p16INK4athat also activates Rb, which is located a short physical

distance (10 kb) from the first exon of ARF. In addition to the links of p15INK4b/p16INK4aand
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ARF to Rb and p53 pathways, respectively, data showing that these proteins play prominent

roles in the prevention of human cancer are strong. Activation of the locus in response to

stimuli, which may be both independent and dependent on telomere dysfunction, is thought

to promote tumor suppression through induction of senescence.

As the INK4a/ARF/INK4blocus at chromosome 9p21 is the most frequent site of single copy

or homozygous deletion in human cancers,67,68extensive analysis of this cytogenetic region

has been performed. As somatic deletions in cancer frequently abrogate expression of all

three INK4a/ARF/INK4bproteins (p15INK4b, p16INK4a, and ARF), debate has focused on which

member or members of the locus represents the principal tumor suppressor activity located

at human chromosome 9p21. A substantial body of human and murine data has now

unequivocally shown that all three proteins are human tumor suppressors.37For example,

p15INK4bappears mainly important in the suppression of hematopoietic malignancies, whereas

p16INK4aand ARF appear to play more general anticancer roles in several tumor types.

Elegant murine studies69have further shown that these tumor suppressor genes can playback-up roles to each other, suggesting that combined inactivation of the locus is more

oncogenic than deletion of any single member. Therefore, although the human and murine

genetic data considered as a whole establish that the INK4a/ARF/INK4blocus encodes three

major human tumor suppressor proteins, their relative and combinatorial importance in a

particular tumor type is a subject of ongoing study.

Crisis, Telomerase Reactivation, and Alternative Lengthening of Telomeres

Under circumstances of extended cell divisions beyond the Hayflick limit with inactivation of

the p16INK4aand p53 pathway, progressive telomere erosion ultimately leads to loss of

telomere capping function, resulting in increasing chromosomal instability. This leads to

progressive loss of cell viability and proliferative capacity across the cell population,

ultimately resulting in cellular crisis. The cellular phenotypes of massive cell death and

growth arrest are likely by-products of DNA damage checkpoint responses and rampant

chromosomal instability with associated loss of essential genetic material. Emergence from

crisis is a rare event in human cell culture and requires restoration of telomere function

either by up-regulation of telomerase activity or activation of the alternative lengthening of

telomeres (ALT) mechanism.70The restoration of functional telomeres serves to quell DNA

damage signaling and high levels of chromosomal instability, thereby enhancing the viability

of cells with procancer genotypes. Finally, the extent to which normal tissues experience

telomere-associated Hayflick and crisis transitions continues to be an area of ongoing

investigation. Nevertheless, although clear evidence of the presence of these events is still

lacking, strong support is mounting for telomere-based crisis, particularly during early stages

of neoplastic development.

Transcriptional up-regulation of the TERTgene seems to be a key rate-limiting step in

telomerase reactivation, whereas the telomerase-independent ALT pathway appears to be

executed via a poorly understood process involving activation of the homologous

recombination pathway.71,72The analysis of pathways regulating TERTgene transcription

has forged links to well-known oncoproteins and tumor suppressors including Myc, Mad, and

Menin, among others, demonstrating the capacity of these proteins to engage the TERTgene
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promoter directly.7375In contrast, the enigmatic ALT process has been variously

associated with p53 deficiency and with tumors of mesenchymal origin.76

Studies in yeast have also shown that ALT is enhanced in mismatch repair-deficient cells,

owing to increased homologous recombination between chromosomes. The rare use of ALT

by epithelial-derived tumors, coupled with functional comparisons of telomerase versus ALT-

mediated telomere maintenance, has shown that ALT may not be as biologically robust in

advancing malignancy, a finding that diminishes the theoretical concern that ALT may

provide a robust resistance mechanism to antitelomerase therapy in advanced

malignancy.77The idea that ALT may be a less effective telomere maintenance mechanism

derives additional support from studies in human cell culture and the mouse revealing that

telomerase per se is needed for full malignant transformation, including metastatic

potential.78The fundamental mechanistic differences between ALT and telomerase

reactivation in telomere maintenance may provide an explanation for the report of more

favorable clinical outcomes for ALT-positive compared with telomerase-positiveglioblastomas,79although analysis of 71 human osteosarcoma cases failed to show a more

favorable clinical outcome for the ALT-positive subset.80However, it should be noted that, in

the latter, the absence of any telomere maintenance mechanism was more associated with

improved survival than stage or response to chemotherapy, further emphasizing the general

importance of telomere maintenance in cancer.

Telomere Maintenance and Cancer

Robust telomerase activity is observed in more than 80% of all human cancers,81a profile

consistent with its role in promoting malignant progression. However, another side to the

telomerase-cancer connection has emerged from mouse models and correlative data in

staged human tumors. These data have indicated that a lack of telomerase and associated

telomere attrition during the early stages of neoplastic growth provides a potent mutator

mechanism that enables would-be cancer cells to achieve the high threshold of cancer-

promoting changes required to traverse the benign to malignant transition.

Indeed, telomeres of human cancer cells are often significantly shorter than their normal

tissue counterparts, suggesting that telomere attrition has occurred during the life history of

these cancer cells, apparently at very early phases of the transformation process when

telomerase activity is low. The subsequent reactivation of telomerase restores telomere

function, albeit at a shorter set length. Thus, although reactivation of telomerase is critical to

the emergence of immortal human cells, this preceding and transient period of telomere

shortening and dysfunction promotes the carcinogenic process through the generation of

chromosomal rearrangements. These chromosomal rearrangements are brought about

through breakage-fusion-bridge (BFB) cycles (Fig.4.4). A DSB created by these BFB cycles is

now known to provide a nidus for amplification and/or deletion at the site of breakage for the

resulting daughter cells. The broken chromosome may become fused to another

chromosome, generating a second dicentric chromosome and perpetuating the BFB cycle.

The accumulation of wholesale genetic changes via aneuploidy, nonreciprocal translocations,

amplifications, and deletions by the BFB cycles coupled with the reactivation of telomerase
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enables rare cells incurring a threshold number of carcinogenic changes needed to initiate

the transformation process.

Figure 4.3. Senescence and aging.

Activation of p53- and/or p16INK4a-mediated senescence pathways in stem cell compartments

in response to DNA damage, telomere dysfunction, or other unknown stimuli leads to

attrition of tissue-specific stem cells (e.g., hematopoietic stem cell and pancreatic -cells)

with attendant compromise of organ function and aging.

Figure 4.4. Dysfunctional telomere-induced genomic instability model of epithelial

carcinogenesis.

Continuous epithelial turnover during aging coupled with somatic mutations inactivating

checkpoint responses is thought to lead to critical telomere erosion, resulting in telomere

uncapping and the initiation of breakage-fusion-bridge (BFB) cycles. The double-strand

breaks created by the BFB cycles are nidi for amplifications and deletions for the resulting

daughter cells. The broken chromosome may become fused to another chromosome,

generating a second dicentric chromosome and perpetuating the BFB cycle. This facilitation

of the accumulation of genetic changes (via aneuploidy, nonreciprocal translocations,

amplifications, and deletions) by the BFB cycles coupled with the reactivation of telomerase

enables cells to emerge from crisis and proceed to malignancy.

Although at first glance the cancer-promoting effects of telomere-based crisis seem to

counter the established role of telomerase activation in cancer progression, this mechanism

is less paradoxical if one considers that many early-stage cancers deactivate pathways

essential for telomere checkpoint responses, thus increasing the survival and proliferation of

cells experiencing increasing chromosomal instability.75,82This hypothesis of episodic

instability derives additional support from genetic studies in the mouse showing that
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telomere-based crisis coupled with loss of the p53-dependent DNA damage response can act

cooperatively to effect malignant transformation. In humans, the accumulation of oncogenic

lesions during normal aging or accelerated accumulation of DNA damage (e.g.,

environmental carcinogen exposure or oxidative damage) may deactivate the telomere

checkpoint response, accelerate telomere attrition, and drive the affected premalignant cellsinto crisis. It is the rare transformed cell that emerges from this process, often with

reactivated telomerase. Thus, telomeric shortening can be viewed as a barrier to cancer

development in the presence of intact checkpoint response and as a facilitator for numerous

genetic changes necessary for the emergence of nascent cancer cells in the absence of the

checkpoint response pathways.

It has also been suggested that telomere dysfunction can be oncogenic in a cell

nonautonomous process.83Murine data in the hematopoietic system suggest that telomere

dysfunction leads to stem cell dysfunction.84,85Therefore, telomere dysfunction could

induce premature loss of stem cells (as described in Fig.4.3), which might induce acompensatory hyperproliferation of remaining functional stem cells. This increased

proliferative drive might facilitate mutagenesis in the remaining functional self-renewing

cells, and in turn select for clones with damaged genomes, in particular those harboring

defects in the senesce-promoting machinery.

Several recent lines of evidence have suggested that the oncogenic effects of telomere

dysfunction are an important determinant of susceptibility to human cancer. For example,

several human kindreds have been identified with congenital telomerase deficiency

syndromes due to inactivating mutations of TERTor other members of the shelterin

complex.4Such patients exhibit age-associated pathologies such as bone marrow failure andpulmonary fibrosis, but also appear to be at increased risk for several cancers including acute

myelogenous leukemia and cutaneous carcinomas.4,83,8688Likewise, human genomewide

association studies of large human cohorts have pointed to sequence variants in the

chromosome 5p15.33 locus as a susceptibility locus for many types of cancer, including

tumors of the skin, lung, bladder, prostate, and cervix.89The single nucleotide

polymorphisms associated with these cancers are near to both the CLPTM1L(cisplatin

resistance-related protein CRRP9) gene and the TERTgene. It is unclear whether one or both

of these genes are responsible for the association as there is limited functional biological

validation. These human data suggest that telomere dysfunction could be oncogenic, and

that hypomorphic alleles of TERT could contribute to human cancer susceptibility on a

population basis.

Telomere-Induced Chromosomal Instability

The study of senescence and telomeres has provided some insights into the link between

advancing age and increased cancer risk. In humans, there is a dramatic escalation in cancer

risk between the ages of 40 and 80, resulting primarily from a marked increase in epithelial

malignancies such as carcinomas of the breast, lung, colon, and prostate. A conventional

view is that the cancer-prone phenotype of older humans reflects the combined effects of

cumulative mutational load, decreased DNA repair capabilities, increased epigenetic gene

silencing, and altered hormonal and stromal milieus. Although these factors are almost
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certain to contribute to increasing cancer incidence in aged humans, it is less evident why

such processes would spur the preferential development of epithelial cancers. Moreover,

these mechanisms do not readily explain one of the cardinal features of adult epithelial

carcinomasnamely, a radically altered genome typified by marked aneuploidy and complex

nonreciprocal chromosomal translocations.

The study of telomere dynamics in normal and neoplastic cells of the mouse has provided a

potential explanation for the observed tumor spectrum and associated cytogenetic profiles in

aged humans. InTerc p53compound mutant mice, the presence of telomere dysfunction

results in a dramatic shift in the tumor spectrum toward epithelial cancers, including those of

the lung, colon, and skin.90Moreover, in contrast to the largely normal cytogenetic profiles

of cancers arising in mice with intact telomeres, the cancers generated in the Terc

p53compound mutant mice had highly complex cytogenetic profiles with a striking

resemblance to human epithelial cancer genomes.

In attempting to assign relevance of these murine studies to humans, it is worth considering

that the typical adult cancer, an epithelial carcinoma, derives from a compartment that has

undergone continued renewal throughout the human lifespan. Against this backdrop of

physiologic cell turnover, combined with the occasional pro-proliferative oncogenic mutation,

telomere lengths would shorten in self-renewing progenitor cells of these epithelial tissues. If

somatic mutations also neutralize Rb/p16INK4a/p53-dependent senescence checkpoints,

continued growth beyond the Hayflick limit further drives telomere erosion and loss of the

capping function, culminating in cellular crisis with attendant genomic instability. In this

manner, telomere-based crisis provides the means to generate many additional mutations

required to reach the early stages of malignant transformation. The subsequent reactivationof telomerase in transformed clones would serve to stabilize the genome to a level

compatible with cell viability, allowing these initiated neoplasms to mature further.91It is

unclear whether additional somatic mutations, beyond telomerase activation, would be

needed to produce a fully malignant phenotype that includes invasive and metastatic

potential. Thus, a transient period of explosive chromosomal instability before telomerase

reactivation appears to be required for the stochastic acquisition of the relatively high

number of mutations thought to be required for adult epithelial carcinogenesis. Another line

of support is the fact that a proportion of early-stage epithelial cancers are hardwired for

lethal metastatic progression, suggesting that many cancers acquire a full profile of genome

change early in their life history.

The episodic instability model of epithelial carcinogenesis fits well with current knowledge

regarding the timing of telomerase activation and evolving genomic changes during various

stages of human carcinoma development, particularly those of the breast, esophagus, and

colon. Comparative genome hybridization has demonstrated that dysplastic human breast,

esophageal, and colon lesions sustain widespread gains and losses of regions of

chromosomes early in their development, often well before these tissues exhibit carcinoma in

situor invasive growth.9294The ploidy changes detected by comparative genome

hybridization appear to correlate tightly with the presence of complex chromosomal

rearrangements, and these markers of genomic instability are evident in the stages of

advanced dysplasia of these tissues (e.g., ductal carcinoma in situ, Barretts esophagus). As
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these cancers progress through invasive and metastatic stages, genomic instability

continues, apparently at a moderate rate, but further mutations would be predicted to derive

from nontelomere-based mechanisms. Correspondingly, the measurement of telomerase

activity in adenomatous polyps and colorectal cancers has established that telomerase

activity is low or undetectable in small and intermediate-sized polyps, reflecting less intacttelomere function. In contrast, telomerase increases markedly in large adenomas and

colorectal carcinomas, reflecting stabilization of telomere function.95Therefore, it appears

that widespread and severe chromosomal instability is present early on during human

tumorigenesis at a time when telomerase activity is low.

Additional support for this episodic instability model derives from the documentation of

anaphase bridging (a correlate of telomere-based crisis) in evolving human colorectal

cancers and in genomically unstable pancreatic cancers.96,97This suggests that the DSB-

induced conditions (including but not limited to telomere dysfunction), coupled with

mutations that allow survival in the face of a DSB, could provide amplification/deletionmechanisms across the genome. Biologic selection forces would in turn lead to the

emergence of clones with the amplifications and deletions that target cancer-relevant loci.

Studies in the telomerase mutant mouse have begun to provide mechanistic insight into how

BFB leads to cancer-relevant changes. In particular, telomerase-p53 compound mutant mice

with telomere dysfunction have increased end-to-end fusions, and the ensuing BFB process

is associated with chromosomal regional gains and losses that appear linked to nonreciprocal

translocations.55,75

In future human studies, it will be important to document telomere attrition in renewing

epithelial stem cells and to perform a simultaneous comparison of telomere status, telo-merase activity, and chromosomal instability in the same tumor samples, particularly during

the earliest stages of human epithelial cell transformation. Defining the temporal point at

which telomerase is reactivated in the genesis and progression of the different cancers may

also lead to the development of biomarkers for diagnosis, prognosis, and outcomes

prediction. Such studies are needed to more firmly establish a causal link between telomere

dysfunction and early chromosomal instability in human neoplasms.

Telomere Dynamics, Inflammatory Diseases, and Cancer

The telomere dysfunction-induced genomic instability model also suggests some

unanticipated opportunities for the therapies of other human diseases. For example, this

model provides a potential explanation for the high cancer incidence associated with diseases

characterized by chronic cell destruction and renewal as well as inflammation. One of the

most notable examples of this tight link is the high incidence of hepatocellular carcinoma in

late-stage cirrhotic livers. Cirrhosis is the phenotypic end point of prolonged cycles of

hepatocyte destruction and regeneration, and cirrhotic livers show a documented reduction

in telomere length over time. Humans with congenital telomerase deficiency may be

predisposed to fibrotic liver disease, including cirrhosis.87Mouse models involving the

telomerase-deficient mouse have shown that critical reductions in telomere length and

function can accelerate the development of cirrhosis and hepatocellular carcinoma in chronic

liver injury experiments.98100Another example of a telomere-based pathogenic
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relationship between chronic tissue turnover, telomere-based crisis, and increased cancer

risk is ulcerative colitis, a condition characterized by rapid cell turnover and oxidative injury

to the intestines, and a high incidence of intestinal dysplasia or cancer.97In addition to the

progressive telomere attrition resulting from the cell turnover, accelerated telomere attrition

might occur via increased oxidative stress and from the altered inflammatorymicroenvironment milieu. Together, such observations suggest the intriguing possibility that

early somatic reconstitution of telomerase could attenuate telomere attrition and

paradoxically reduce the occurrence of cancers in these high-turnover disease states, a

theory that requires additional preclinical studies. In addition, serial analyses of telomere

length from these tissues may provide prognostic information regarding the rising risk of

cancer development. Thus, progress in our understanding of telomere biology has

mechanistically connected diverse fields in medicine involving chronic inflammatory diseases,

degenerative diseases, geriatrics, and oncology.

Telomerase and Telomere Maintenance As Therapeutic TargetsSome evidence supports the view that telomerase-mediated telomere maintenance

represents a near-universal therapeutic target for cancer. Indeed, cell culturebased studies

of human cancer cells have established that inhibition of telomerase culminates in cell death

after extended cell divisions. The past few years have witnessed intense efforts to design

therapeutic strategies capable of targeting telomere structure and the telomerase

holoenzyme function.14,101,102Unfortunately, most of these compounds and agents are

still in preclinical and early clinical development and thus their safety and efficacy profiles in

human patients are not fully known.

Presently, the only clinically advanced telomerase-related cancer treatment strategy is

immunotherapy, targeting immune recognition and the destruction of cells that express telo-

merase. Immune responses, specifically cytotoxic T-cell responses, have been generated

against peptide sequences of the hTERT protein, and it has been demonstrated that these

cytotoxic T cells are capable of selectively lysing target cells that express TERT peptides

presented on the cell surface in the context of major histocompatibility complex class I

molecules. There have been several promising completed phase 1/2 trials using peptides

from telomerase as vaccines.103,104A large randomized phase 3 trial comparing

gemcitabine alone versus gemcitabine with a telomerase peptide vaccine (GV1001) showed

no difference in survival benefit in the first 360 enrolled patients, and the trial was stopped.

A second large 1,110 pancreatic cancer patient trial comparing gemcitabine/capecitabine

combination therapy with concurrent and sequential gemcitabine/capecitabine therapy with

GV1001 is still ongoing. Lastly, other TERT-based immune approaches, such as infusion of

patients primed antigen-presenting dendritic cellsex vivowith TERT mRNA, are also

currently in early clinical trials.105

As for the ongoing design of rational clinical trials of telomere-based therapeutics, such

efforts will be informed by the considerable body of knowledge accumulated in telomere

biology. Experience with the telomerase mutant mouse model and human cell culture

systems should serve to guide the design of human clinical trials. These studies suggest that

inhibitors of telomerase activity might be expected to exhibit a long lag time and might
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promote malignancy in some circumstances, but also may be particularly useful in the

setting of minimal residual disease after the administration of standard chemotherapeutic

agents and surgery. In addition, pharmacodynamic assays capable of assessing inhibition of

telomerase activity in individual patients are needed. Moreover, given that the activation of

senescence-promoting mechanisms such as p53 and p16

INK4a

has been associated with aging-like pathologies in several tissues,5963some caution is warranted regarding the toxicity

resulting from the induction of premature senescence in nondiseased tissues. This potential

is underlined by evidence of germ cell defects, defects in proliferative homeostasis of certain

tissues, and an increased rate of spontaneous malignancy in mice with telomere dysfunction,

suggesting that clinical trials of such agents will need to be actively monitoring patients for

these sequelae.

Furthermore, it seems prudent that the genetic profile of tumors enlisted into clinical trials

should be determined to assess the integrity of p53. This caution relates to mouse models

showing that the combination of p53 deficiency and telomere dysfunction drives greatergenomic instability and thus potential for emergence of therapeutic resistance. In contrast,

when p53 responses are intact, critical telomere shortening should induce p53-dependent

senescence and apoptosis. The final answers to these safety questions reside in the analyses

of current and future clinical trials with humans.

Conversely, the telomerase-deficient mouse model has also informed that cells and animals

with telomere dysfunction are more sensitive to ionizing radiation and DNA DSB

chemotherapeutic agents; thus, telomerase activity inhibitors may be more effective when

paired with radiation or certain classes of chemotherapy that produce DSBs, as they might

produce synergistic cytogenetic catastrophe. Again, however, particular care is warrantedhere as the combination of increased DNA damage with reduced capacity for normal repair

may also produce marked increases in the toxicity of chemoradiotherapy.

Recent years have witnessed significant progress in the telomere biology field that is now

maturing into new opportunities for improved diagnostics and novel therapeutic applications

in human diseases, including cancer. Discoveries in telomere biology, rewarded with the

2009 Nobel Prize, have provided new mechanistic insights into the pathogenesis of human

cancer and of inherited and acquired degenerative disorders. The role of telomere

dysfunction driving episodic genomic instability in epithelial cancersfirst seen in the

telomerase-deficient mousehas now been substantiated in the study of several humancancer types, with further support from genomewide association studies and kindreds with

congenital telomerase deficiency. The pivotal role of telomere attrition in the pathogenesis of

cancer and tissue aging provides potential avenues for the development of cancer risk

biomarkers, diagnostics, and rationally designed therapeutics.

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Chapter 4 - Telomeres, Telomerase, And Cancer