Current Molecular Medicine
Volume 5, Number 2, 2005
Contents
Telomeres
and Telomerase in Diseases, Aging, and Carcinogenesis
Executive
Editor: K. Lenhard Rudolph
Editorial
K.
Lenhard Rudolph
In the End, it’s all Structure Pp.135-143
Laure
Crabbe and Jan Karlseder
Telomere Induced Senescence: End Game
Signaling Pp.145-152
Aram
F. Hezel, Nabeel Bardeesy and Richard S. Maser
Modeling Premature Aging Syndromes with the
Telomerase Knockout Mouse Pp.153-158
Sandy
Chang
Dyskeratosis Congenita – A Disease of
Dysfunctional Telomere Maintenance Pp.159-170
P.J.
Mason, D.B. Wilson and M. Bessler
Skin Aging: A Role for Telomerase and
Telomere Dynamics? Pp.171-177
Petra
Boukamp
Telomere Dynamics in Hematopoietic Stem Cells
Pp.179-185
Stefan
Zimmermann and Uwe M. Martens
Telomere Dynamics in Response to Chemotherapy
Pp.187-196
N.
Beeharry and D. Broccoli
Telomeres as Biomarkers for Ageing and
Age-Related Diseases Pp.197-203
T.
von Zglinicki and C.M. Martin-Ruiz
Telomerase Therapeutics for Degenerative
Diseases Pp.205-211
Calvin
B. Harley
Telomeres, Crisis and Cancer Pp.213-218
R.A.
Greenberg
Telomeres, Telomerase and Malignant
Transformation Pp.219-226
Oliver
G. Opitz
Telomere and Telomerase Dynamics in Human
Cells Pp.227-231
W.C.
Hahn
Extratelomeric Functions of Telomerase Pp.233-241
Hee
Kyoung Chung, Cheolho Cheong, Jaewhan Song and Han-Woong Lee
Telomerase-Dependent Gene Therapy Pp.243-251
Thomas
Wirth, Florian Kühnel and Stefan Kubicka
Telomere Maintenance and Tumorigenesis: An
“ALT”ernative Road Pp.253-257
Sheila
A. Stewart
Abstracts
[Back to top] Editorial
K.
Lenhard Rudolph
Research work in
the last decade has revealed that telomeres and telomerase influence the course
of human diseases, aging, and carcinogenesis. The present selection of experts’
reviews in this special edition highlights several areas of basic and clinical research
in this field, which will heighten our understanding of the role of telomeres
and telomerase in these processes as well as its therapeutic potential for
treatment of regenerative disorders and cancer.
There is
accumulating evidence that beside the telomere length, the telomere structure
is crucial for telomere function (Crabbe and Karlseder). Exploration of the
proteins controlling telomere structure formation, maintenance and the
regulation of these proteins during physiological processes in vivo
represents an important area of current research. To date, it is
unpretentiously accepted that telomere shortening limits the regenerative
capacity of human cells in vitro by induction of replicative senescence
– a stage of proliferative arrest induced by dysfunctional telomeres generating
a DNA-damage type of response (Hezel et al.). There is growing
experimental evidence that senescence has an impact on the regenerative
capacity of cells and organs during aging in vivo (Chang). In telomerase
knockout mice premature aging predominantly affected highly proliferative
organs, but there was also evidence for an impact on cardiac function, stem
cell differentiation, and insulin resistance (Chang).
Beside the bulk of
data demonstrating telomere shortening in different tissues during human aging
and disease, most direct evidence for a causative role of telomere shortening
during human aging comes from studies in the premature aging disease
Dyceratosis Congenital (DC), which on a molecular level is characterized by
telomerase and telomere dysfunction (Mason et al.). In fact, the
autosomal dominant form of this disease, which is caused by a mutation of the
telomerase RNA component, might be one of the first diseases where a telomerase
activating gene therapy can be implemented. Such an approach might help to
elongate the lifespan of such DC patients and could shed some light on the
therapeutic potentials and risks that come with telomerase activation
therapies. During the course of aging in healthy individuals, the influence of
telomeres appears to be diverse in different organs and tissues. Two reviews
highlight the complexity of telomere biology in two telomerase positive
compartments of the human body: the skin (Boukamp) and the hematopoietic stem
cells (Zimmermann and Martens). In both compartments telomere shortening occurs
during aging. However, it remains a debate to what extent telomere shortening
impacts on the regenerative capacity of these organs during aging. The recent
data on accelerated telomere shortening in human HSC as a consequence of
chemotherapy might help to clarify the impact of telomere shortening on the
function of the hematopoietic system during aging (Beeharry and Broccoli).
Studies in telomerase deficient mice have shown a reduction in stem cell number
and function as a consequence of telomere shortening (Chang). It remains to be
elucidated whether stem cells have tighter checkpoints against DNAdamage
induced by telomere dysfunction compared to somatic cells as it has been
proposed for other types of DNA damage. Tight DNA damage checkpoints in stem
cells might be necessary to protect this long living cell compartment against
cellular transformation; on the other hand it could result in stem cell
exhaustion as a consequence of telomere shortening during aging. There is
strong evidence that telomere shortening in peripheral blood cells is an
indicative marker of aging (von Zglinicki and Martin-Ruiz). Telomere shortening
in peripheral blood cells correlates to the prevalence of several diseases affecting
different organ systems during human aging. In addition, shortened telomeres in
PBCs were linked to various types of organ cancer. The changes in population’s
demography, with a constantly increasing percentage of aged people makes the
area of aging marker identification a very important area of future research
that will help to optimize our clinical observation programs and individualized
therapeutic interventions for the elderly. Experimental data from mouse models
and the premature aging observed in DC patients indicate that shortened
telomeres not only represent a consequence of aging that can be used as an
aging marker but in fact functionally influence this process. Understanding of
senescence signaling at molecular level could lead to the identification of
novel therapeutic targets to improve regenerative capacity of cells in aged
tissues and could at the same time disclose tumor suppressor checkpoints
protecting against cancer in aged tissues. Alternatively, aiming towards
maintaining the telomere structure could stabilize telomeres and thus help to
prevent induction of senescence signaling when telomeres become critically
short. The most direct approach, however, would be to re-activate telomerase in
human cells and tissues (Harley). Experimental data from mouse models suggest
that such an approach could help to improve regeneration and survival during
aging especially in the setting of chronic organ damage. Therefore, first
clinical trials should focus on disease stages where survival is limited by
regenerative exhaustion and organ failure. However, the broader use of
telomerase activating therapies during aging will ultimately depend on its
impact on cancer formation.
The classical
telomere hypothesis suggested that telomere shortening as a consequence of cell
division induces senescence thus representing a tumor suppressor mechanism to
halt the growth of transformed cells. However, experimental data have revealed
a dual role of telomere shortening in carcinogenesis. On one hand, shortened telomeres
induce chromosomal instability – the number 1 cause of cancer initiation during
aging (Greenberg) – and on the other hand telomere stabilization is required
for tumor progression (reviewed by Greenberg, by Hahn, and by Opitz). The tumor
initiating activity of shortened telomeres appears to be relevant for human
carcinogenesis given the increased cancer incidence in DC-patients with short
telomeres (Mason et al.)
and also the accumulating data on drastic telomere shortening and sharply
increasing telomere dysfunction in pre-neoplastic disease stages and during
carcinogenesis in humans (Greenberg). The initiation of chromosomal aberrations
by telomere shortening might contribute to the increased cancer rates during
aging. Further understanding of the genetic alterations that cooperate with
telomere dysfunction to induce chromosomal instability could help to identify
new tumor marker genes and therapeutic targets to prevent and treat cancer in
the elderly.
The necessity of telomere
stabilization for tumor progression in most human cancers is achieved by
reactivation of telomerase (reviewed by Hahn and by Opitz in this issue). The
immortalization of primary human cells by telomerase re-activation allowed
beginning to delineate the molecular pathways governing the transformation of
primary human cells (Opitz). This experimental cellular transformation of
primary human cells will certainly be of great value in a variety of research
areas including drug development against genetically defined tumors. It remains
an opened discussion whether telomerase itself has some transforming activity
or it just allows the accumulation of genetic alterations leading to cellular
transformation under extensive passage of in vitro cultivated cells
(reviewed by Hahn, by Opitz, and by Harley in this issue). The observation that
telomerase is active in human stem cells and germ cells and that these cells
maintain a non-transformed phenotype throughout life make a strong argument
that telomerase itself does not lead to cellular transformation. However,
reports on increased cancer formation in telomerase transgenic mice suggested
some tumor promoting activity of telomerase. Since telomeres are very long in
mice the increased tumor incidence in telomerase transgenic mice is most likely
independent of telomere length. Recent observations on the presence of
telomerase in non-transformed human cells (Hahn) and extra-telomeric function
of telomerase (Chung et al.) might provide some explanation for the
tumor initiating activity of telomerase. In addition, these studies indicate
that targeting telomerase in anti-cancer therapies could have more effects than
simply accelerating telomere shortening in telomerase positive cell
compartments and tumors. A careful analysis of knockout mouse strains carrying
deletions of different components of the telomerase enzyme complex could
potentially help to delineate the extra-telomeric function of telomerase. The
incidence of high levels of telomerase in most malignant human tumors and the
absence of telomerase in most human somatic tissues has made it a very good
candidate for novel anticancer therapeutics. Two reviews summarize where we
stand in terms of pharmaceutical telomerase inhibition and telomerase
vaccination (Harley) as well as in regards to develop telomerase-directed gene
therapy approaches (Wirth et al.) for cancer treatment. All three
approaches have advanced quickly over the recent years and clinical trials have
been initiated. Such new therapies could especially be efficient in combination
with other anti-cancer therapies and might help to improve the survival rate of
cancer patients. A possible mechanism to escape from anti-telomerase therapies
is the activation of alternative lengthening of telomere (ALT) mechanisms
(Stewart). However, experimental data suggest that this mechanism cannot fully
compensate for telomerase and that ALT- tumors might have a milder progression
phenotype compared to telomerase-positive tumors. It remains to be investigated
whether ALT is also present in non-transformed tissues in vivo to extend
the regenerative capacity of organ systems with shortened telomeres.
The rapid advances
in the field of telomeres and telomerase biology have made it possible to begin
to translate this knowledge into clinical applications. Ongoing basic research
in this field will help to constantly define new targets and to increase the
specificity, safety and efficacy of existing therapeutic approaches directed
against telomeres and telomerase. Beside the clinical areas of disease and
cancer treatment the new developing areas such as regenerative medicine and
cell transplantation will surely benefit from the advances in the telomere
field. In the years 1975 –1980 the number of PubMed-listed basic research manuscripts
on “telomeres” were 3-6 articles per year, compared to 873 articles in the year
2004. First clinical trials on therapies targeting telomerase have been
reported in PubMed in 2004 on the use of antitelomerase vaccination for cancer
therapies. If the future development in the clinical field can match the
development in the research field, the impact of telomere and telomerase
biology on human health should be enormous.
[Back to top] In the End, it’s all Structure
Laure
Crabbe and Jan Karlseder
Chromosome end
protection is essential for all organisms with linear genomes. Specialized
structures, called telomeres, accomplish this protection by forming DNA-protein
complexes that hide the natural chromosome ends from the DNA damage machinery.
In mammalian cells protection takes place on several levels. Telomeric DNA
forms large duplex loops with the help of telomeric proteins, consequently
hiding the very tip of the telomere. Telomeric proteins play additional roles
in protecting the end from degradation, regulating telomere length, and
suppressing the DNA damage response machinery. Here we summarize the current
knowledge about telomere structure, and discuss the future directions of the
field.
[Back to top] Telomere Induced Senescence: End Game
Signaling
Aram
F. Hezel, Nabeel Bardeesy and Richard S. Maser
The telomere-based
model of cell aging has proven to among been among the most enduring hypotheses
in cell biology. This model, suggesting that the gradual loss of telomere
sequences during the proliferation of cultured human somatic cells imposes a
barrier on cellular replicative potential, has been strongly supported by
recent genetic and biochemical studies. In addition, evidence implicating
telomere dynamics in organismal ageing and cancer progression in vivo
suggest that such a process is likely to have considerable physiological
relevance in homeostasis and disease. What is the sensing mechanism for
shortened telomeres and what is the molecular basis for the ensuing checkpoint
response? Moreover, what is the outcome when such failsafe mechanisms are lost?
Here we will review the signaling pathways that are induced by alterations in
telomere length and integrity and illustrate how these processes provoke
downstream effects on cell proliferation and survival. In addition, we discuss
how the telomere-induced pathways intersect with the DNA damage response and
document how the failure in either process results in unrestrained chromosomal
instability.
[Back to top] Modeling Premature Aging Syndromes with the
Telomerase Knockout Mouse
Sandy
Chang
Understanding the
molecular basis of the aging process is a daunting problem, given the complex
genetic and physiological changes that underlie human aging and the lack of
genetically amenable primate model systems. However, analysis of mouse models
exhibiting aging phenotypes reminiscent of those observed in elderly humans has
enhanced our understanding of the biological mechanisms underlying mammalian
aging. In particular, these mouse models have brought to light the importance
of the DNA damage pathway during the aging process. Increased genomic
instability is associated with accelerated cellular decline and manifestation
of premature aging phenotypes in mice. Here I discuss how one form of genomic
instability, initiated by critically short telomeres in the telomerase knockout
mouse, perturb normal mammalian aging. Insights into the molecular pathways of
the aging process may offer unprecedented opportunities to delay the
deleterious effects of the aging process.
[Back to top] Dyskeratosis Congenita – A Disease of
Dysfunctional Telomere Maintenance
P.J. Mason, D.B. Wilson and M. Bessler
Dyskeratosis
congenita (DC) is a rare inherited bone marrow failure syndrome associated with
abnormalities of the skin, fingernails, and tongue. Other clinical
manifestations may include epiphora, lung fibrosis, liver cirrhosis,
osteoporosis, and a predisposition to develop a variety of malignancies. The
clinical picture often resembles that of a premature aging syndrome and tissues
affected are those with a high cell turnover. DC has been linked to mutations
in at least four distinct genes, three of which have been identified. The
product of these genes, dyskerin, the telomerase RNA (TERC), and the
catalytic unit of telomerase (TERT) are part of a ribonucleoprotein complex,
the telomerase enzyme, that is essential for the elongation and maintenance of
chromosome ends or telomeres. All patients with DC have excessively short
telomeres, indicating that the underlying defect in these individuals is an
inability to maintain the telomeres. The purpose of the current review is to
highlight recent insights into the molecular pathogenesis of DC. We discuss the
impact these findings have on our current understanding of telomere function
and maintenance, and on the diagnosis, management, and treatment of patients
with conditions caused by dysfunctional telomeres.
[Back to top] Skin Aging: A Role for Telomerase and
Telomere Dynamics?
Petra
Boukamp
Skin is a complex
tissue composed of two very different compartments – the continuously renewing
epidermis made up mostly by keratinocytes and the underlying matrix-rich dermis
with the resting fibroblasts as its major cellular components. Both
compartments are tightly interconnected and a paracrine mutual interaction is
essential for epidermal growth, differentiation, and tissue homeostasis. Skin
aging is commonly viewed as wrinkle formation, hair greying, and impaired wound
healing. Nevertheless, the epidermis as the outermost shield needs to remain
intact in order to guarantee an inside-out and outside-in barrier function
throughout life time of a human being. Furthermore, the epidermis is one of the
few regenerative tissues that express telomerase, the ribonucleoprotein complex
that can counteract telomere erosion, one of the presently mostly favoured potential
mechanisms causing cellular aging. This raises the question whether in the
epidermis telomerase is able to counteract telomere erosion and thereby to
prevents a telomere-dependent aging process and consequently which part of the
skin is responsible for the most obvious changes associated with skin aging.
[Back to top] Telomere Dynamics in Hematopoietic Stem Cells
Stefan
Zimmermann and Uwe M. Martens
The hematopoietic
system has an outstanding regenerative capacity which depends on a relatively
small population of hematopoietic stem cells (HSC). In contrast to normal human
cells, blood-forming stem cells, like most of their counterparts from other
adult tissues, exhibit telomerase activity to a certain level. Nevertheless,
this telomerase activity does not prevent telomere shortening in HSC,
suggesting a restriction of their proliferative capacity. Here, we review
recent studies on telomere dynamics in HSC of humans and mice. Furthermore, we
discuss the impact of telomere manipulation in HSC for possible clinical
applications and speculate on functions of telomerase beyond telomere
lengthening.
[Back to top] Telomere Dynamics in Response to Chemotherapy
N.
Beeharry and D. Broccoli
The use of
chemotherapy provides an essential arm in the treatment of a number of cancers.
The biological feature common to all cancerous cells that sensitizes them to
chemotherapeutic agents is their elevated division rate. Rapidly dividing
cells, such as tumor cells, are more sensitive to chemotherapeutic agents that
act to initiate pathways leading to cell death, a process enhanced in cells
with compromised DNA damage responses. The toxicity accompanying chemotherapy
is due to side-effects induced in normal regenerative tissues which also have
relatively high replication rates, such as hair follicles, the hematopoietic
system, the gastrointestinal system, the germline and skin cells. While the
side-effects of chemotherapy may be tolerated by the patient, the long term
impact of the cytotoxic effects of chemotherapy on healthy tissues is only now
becoming apparent. Chemotherapy-induced cytotoxicity in regenerative tissues
requires multiple cell divisions in order to reconstitute the affected tissues.
At least in part as a consequence of these extra divisions, telomeres in
individuals treated with chemotherapy are shorter than age-matched control
individuals who have never been exposed to these drugs. Given the essential
role of telomeres in regulating cellular aging and chromosomal stability, it is
possible that the prematurely shortened telomeres that arise following
chemotherapy may impact the long-term replicative potential of these tissues.
This review is focused on how telomeres may be modulated, directly or
indirectly, by anticancer drugs and the potential long-term consequences of
accelerated telomere shortening in healthy tissue as a result of current cancer
treatment protocols.
[Back to top] Telomeres as Biomarkers for Ageing and Age-Related Diseases
T.
von Zglinicki and C.M. Martin-Ruiz
Telomeres in
telomerase-negative cells shorten during DNA replication in vitro due to
numerous causes including the inability of DNA polymerases to fully copy the
lagging strand, DNA end processing and random damage, often caused by oxidative
stress. Short telomeres activate replicative senescence, an irreversible cell
cycle arrest. Thus, telomere length is an indicator of replicative history, of
the probability of cell senescence, and of the cumulative history of oxidative
stress.
Telomeres in most
human cells shorten during ageing in vivo as well, suggesting that
telomere length could be a biomarker of ageing and age-related morbidity. There
are two distinct possibilities: First, in a tissue-specific fashion, short
telomeres might indicate senescence of (stem) cells, and this might contribute
to age-related functional attenuation in this tissue. Second, short telomeres
in one tissue might cause systemic effects or might simply indicate a history
of high stress and damage in the individual and could thus act as risk markers
for age-related disease residing in a completely different tissue. In recent
years, data have been published to support both approaches, and we will review
these. While they together paint a fairly promising picture, it needs to be
pointed out that until now most of the evidence is correlative, that much of it
comes from underpowered studies, and that causal evidence for essential
pathways, for instance for the impact of cell senescence on tissue ageing in
vivo, is still very weak.
[Back to top] Telomerase Therapeutics for Degenerative Diseases
Calvin
B. Harley
Telomerase is
active in early embryonic and fetal development but is down-regulated in all
human somatic tissues before birth. Since telomerase is virtually absent or
only transiently active in normal somatic cells throughout postnatal life,
telomere length gradually decreases as a function of age in most human tissues.
Although telomerase repression likely evolved as a tumor suppressor mechanism,
a growing body of evidence from epidemiology and genetic studies point to a
role of telomerase repression and short telomeres in a broad spectrum of
diseases: (a) Humans with shorter than average telomere length are at increased
risk of dying from heart disease, stroke, or infection; (b) Patients with Dyskeratosis
congenita are born with shortened telomeres due to mutations in telomerase
components, suffer from a variety of proliferative tissue disorders, and
typically die early of bone marrow failure; and (c) Individuals with long-term
chronic stress or infections have accelerated telomere shortening compared to
age-matched counterparts. Telomerase activation may prove useful in the
treatment of diseases associated with telomere loss. While human cells dividing
in culture lose telomeric DNA and undergo changes that mirror certain age- or
disease-associated changes in vivo, telomerase transduced cells have
extended replicative capacities, increased resistance to stress, improved
functional activities in vitro and in vivo, and no loss of
differentiation capacity or growth control. In addition, telomerase
transduction in vivo can prevent telomere dysfunction and cirrhotic
changes in liver of telomerase knockout mice. Thus, pharmacological activation
of telomerase has significant potential for the treatment of a broad spectrum
of chronic or degenerative diseases.
[Back to top] Telomeres, Crisis and Cancer
R.A.
Greenberg
Eukaryotic
chromosomes terminate in specialized nucleic acid-protein complexes known as
telomeres. Disruption of telomere structure by erosion of telomeric DNA or loss
of telomere binding protein function activates a signal transduction program
that closely resembles the cellular responses generated upon DNA damage.
Telomere dysfunction in turn induces a permanent proliferation arrest known as
senescence. Senescence is postulated to perform a tumor suppressor function by limiting
cellular proliferative capacity, thus imposing a barrier to cellular
immortalization. Genetic or epigenetic silencing of components of the DNA
damage pathway, allows cells to proliferate beyond senescence limits. However,
these cells eventually reach a stage of extreme telomere dysfunction known as
crisis that is characterized by cell death and the concomitant appearance of
cytogenetic abnormalities. Telomeric crisis produces significant chromosomal
instability, a hallmark of human cancer, and may thus be relevant to
carcinogenesis by increasing the occurrence of genetic alterations that would
favor neoplastic transformation. The following review examines the relationship
of telomere function during crisis in accelerating chromosomal instability and
cancer.
[Back to top] Telomeres, Telomerase and Malignant Transformation
Oliver
G. Opitz
Human cancer
arises in a stepwise process by the accumulation of genetic alterations in
oncogenes, tumor suppressor genes and other genes involved in the regulation of
cell growth and proliferation. Many genes, important for the pathogenesis of
various cancers and the pathways through which they act, have been
characterized over the past decades. Nevertheless, recent successes in experimental
models of immortalization and malignant transformation of human cells indicate
that the disruption of a limited number of cellular pathways is sufficient to
induce a cancerous phenotype in a wide variety of normal cells. In this
context, immortalization is an essential prerequisite for the formation of a
tumor cell. Besides classical cancer related pathways as the pRB and p53 tumor
suppressor pathway or the ras signaling pathway, the maintenance of telomeres
plays an essential role in both of these processes. Alterations in telomere
biology both suppress and facilitate malignant transformation by regulating
genomic stability and cellular life span. This review will summarize recent
advances in the understanding of the molecular mechanisms of malignant transformation
in human cells and the role of telomere maintenance in these processes. This
ultimately leads to the development of cellular models of human cancer that
phenocopy the corresponding disease. Furthermore, in the future these models
could provide an ideal basis for the testing of novel chemopreventive or
therapeutic approaches in the treatment of different types of human cancer.
[Back to top] Telomere and Telomerase Dynamics in Human Cells
W.C.
Hahn
Accumulating evidence
now implicates telomeres and telomerase as critical regulators genomic
stability and replicative lifespan in mammalian cells. Disruption of telomere
maintenance and/or telomerase expression contributes to the etiology of some
degenerative diseases and may participate in the process of aging. Although
telomere dysfunction and aberrant telomerase expression clearly play important
roles in cancer development, the contribution of telomere biology to cancer is
complex and involves both positive and negative influences on tumor
development. Indeed, recent work from several laboratories suggests additional
roles for telomeres and telomerase in both normal and malignant physiology.
Understanding the complexity of telomere biology will provide further insights
into chromosome biology in both normal and malignant cells.
[Back to top] Extratelomeric Functions of Telomerase
Hee
Kyoung Chung, Cheolho Cheong, Jaewhan Song and Han-Woong Lee
Telomerase reverse
transcriptase (TERT), a catalytic subunit of telomerase, has been demonstrated
to exert a reverse transcriptase function when combined with telomerase RNA
component (TERC), the complex of which ensures the maintenance of telomere
length in all eukaryotes. Telomerase also prevents cell death, and promotes
survival in many types of cells, from various tissues or organs including
neurons, muscle, and immune cells, as well as a variety of tumor cells.
Recently, a new aspect of telomerase activity, independent of telomere
lengthening, has emerged to explain its protective effects on cell survival.
Consistent with this, TERT was found to enhance tumorigenesis, and to regulate
the expression of genes that control cell growth, which cannot be explained by
telomere stabilization per se. Furthermore, the observation that TERT
resides not only in the nucleus, but also in the cytosol, reinforces the notion
of possible telomere-independent functions. In this review, recent studies
regarding the extratelomeric functions of TERT have been comprehensively
summarized, and their implications discussed.
[Back to top] Telomerase-Dependent Gene Therapy
Thomas
Wirth, Florian Kühnel and Stefan Kubicka
Adenovirus-mediated
gene therapy approaches have evolved as promising means for cancer treatment
during the last decade. Utilizing a broad spectrum of tumor-specific promoters,
numerous oncotropic vectors have been created with exceptional properties
regarding tumor-restricted specificity. The discovery of telomerase, its high
prevalence in tumor tissues and the discovery of its transcriptional regulation
via the hTERT promoter have extended the applicability of adenoviral
gene therapy vectors to approximately 90% of all tumors. First generation
adenoviral vectors expressing transgenes under the control of the hTERT
promoter confirmed the therapeutic potential but were restricted to initially
transduced cancer cells. Recently, telomerase-dependent conditionally
replicative adenoviral vectors (CRADs) have been developed that combine the
specificity of hTERT promoter based expression systems with the lytic efficacy
of replicative viruses. To evaluate the potential for clinical applications,
various efforts have been made to establish combinative strategies including
systemic chemotherapy, radiotherapy and antiangiogenesis. This review
highlights the rapid advances of telomerase-based gene therapy and gives
insight into future prospects and future development of oncotropic vectors.
[Back to top] Telomere Maintenance and Tumorigenesis: An “ALT”ernative Road
Sheila
A. Stewart
The acquisition of
cellular immortality is a critical step in human tumorigenesis. While the vast
majority of human tumors activate the catalytic component of telomerase (hTERT)
to stabilize their telomeres and attain immortality, a significant portion
(7-10%) utilize a poorly defined alternative form of telomere maintenance
referred to as ALT. Interestingly, telomerase activation is often favored in
tumors arising from the epithelial compartment whereas ALT occurs in a more
significant portion of tumors that arise from tissues of mesenchymal origin.
This observation raises the possibility that cell type specific mechanisms
favor the activation of telomerase versus ALT in human tumorigenesis. Because
cellular immortality is critical to tumorigenesis it may represent an important
anti-neoplastic target. Indeed, several approaches have successfully eliminated
telomerase activity in human tumor models and some of these approaches are now
moving into clinical trials. While these results are encouraging, it is clear
that these approaches will have no impact on cells that utilize the ALT
mechanism for telomere maintenance. Furthermore, the existence of ALT raises
the possibility that telomerase-positive tumors undergoing anti-telomerase
therapies may escape by activating the ALT pathway. For these reasons a
detailed understanding of the ALT pathway is critical to the future design of
anti-neoplastic therapies.