No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Stem cell aging and cancer Immortal but vulnerable
Cell Cycle
Abstract
Comment on: Vicente-Dueñas C, et al. Aging 2010; 2: 908-13.
... Normal animal cells undergo aging and eventually die of it [465,474,[764][765][766][767][768][769][770][771][772][773][774], and so do cells in overt outgrowths from many animal models, more often in morphologically-benign than in morphologically-malignant ones [769,[771][772][773]. This type of cell death has established "cancer cell senescence" as a popular research bailiwick [474], although many relevant studies do not involve lesions from animals but, peculiarly, use cancer cell lines that are immortal. ...
Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.
... There is hardly any other field in medicine in which so much potential therapeutic effort (from simple substances to high-technology genetic and rejuvenation techniques) has been invested. Enormous interest has been put into research on molecules that could influence the ageing process, whether whole-body ageing [1,2] and/or cellular ageing [3,4]. However, it seems that the desired effect has not been yet reached [4][5][6][7][8][9][10]. ...
Ageing is a progressive process that according to available knowledge cannot be effectively reversed, slowed or stopped. Here we propose a new anti-ageing approach that may lead to the design of effective therapeutic intervention. First, we hypothesize that the “organ system” oriented anti-ageing approach represents a better anti-ageing target than the “whole body” or “cellular ageing” concepts. The arterial system is the most suitable target, as it interconnects all the organs in the body, thus influencing them all. Second, we propose that an anti-ageing approach could be more successful in early than late ageing stages; middle-aged people seem to be the most appropriate candidates. Third, we believe that instead of searching for new medication, we should rely on already established medications with beneficial effects on the arterial wall. Renin-angiotensin system inhibitors and statins fulfill these criteria and are potential cornerstones of the new approach. The fourth hypothesis is based on the concept that in the early stages of arterial ageing only slight injury is present and therefore subtherapeutic, low-dose treatment would be effective. Fifth, we hypothesize that slight initial age-related arterial wall changes are reversible and could be corrected by a short-term (one month) treatment. Sixth, we hypothesize that the effects would be present for a certain period of time even after treatment termination. The listed assumptions combined represent the basis for a new, original anti-ageing approach – a subtherapeutic low-dose combination of a renin-angiotensin system inhibitor and a statin for one month (followed by approximately 6–12months without treatment) could delay or even reverse the arterial ageing process and consequently decrease the incidence of cardiovascular disorders.
... From this point of view, it has recently been shown, using a BCR-ABLp190inducible transgene 179 or by transfecting mouse cells of different ages, 180 that cells from old mice develop leukemias at a much faster rate than those from young animals, therefore suggesting some kind of competitive advantage of aged B-cell progenitors that could explain the more aggressive nature of B-ALL in advanced ages. 181,182 ...
The latest scientific findings in the field of cancer research are redefining our understanding of the molecular and cellular basis of the disease, moving the emphasis toward the study of the mechanisms underlying the alteration of the normal processes of cellular differentiation. The concepts best exemplifying this new vision are those of cancer stem cells and tumoral reprogramming. The study of the biology of acute lymphoblastic leukemias (ALLs) has provided seminal experimental evidence supporting these new points of view. Furthermore, in the case of B cells, it has been shown that all the stages of their normal development show a tremendous degree of plasticity, allowing them to be reprogrammed to other cellular types, either normal or leukemic. Here we revise the most recent discoveries in the fields of B-cell developmental plasticity and B-ALL research and discuss their interrelationships and their implications for our understanding of the biology of the disease.
So what might be the biological basis of the age-associated incidence of B-ALL with p190 BCR-ABL1? Vicente-Dueñas et al [5] designed a novel experiment to address this question which conveniently bypassed uncertainties over required exposures for the natural disease and age-associated alterations in the host tissue micro-environment. Using an inducible p190 BCR-ABL transgene, they found that ‘old' (= 20 months) cells develop leukemias at a much faster rate (~2x) than young' (= 4 months) cells when transplanted into recipients of the same age (4 weeks). The key to the experiment is that BCR-ABL1 expression is not activated until after the transplant.
Although all mice eventually developed ALL, this result is compatible with the notion that ‘old' B progenitors have some competitive advantage when expressing BCR-ABL1. What might this be? A plausible explanation is offered in another paper recently published by Henry et al [6]. This group have previously suggested that age-related fitness decline in stem and progenitor cells might increase selective pressure for oncogenic mutations [7]. In their new study [6], they also evaluated the impact of age on the transformability of hematopoietic cells by p190 BCR-ABL1. In their case, this was performed by transfecting ‘young' (2 months) versus ‘old' (22-24 months) bone marrow cells with a p190 BCR-ABL retrovirus and transplanting these into recipients which were selected to provide either ‘young' (2 months) or ‘old' (22-24 months) competitor normal cells. They observed higher rates of leukemia (up to 200 days post-transplant) with transfer of ‘older' cells. More rapid onset of leukemia in aged p190 BCR-ABL1 cells or more efficient leukemogenesis probably reflects more ‘target' cells being transformed which, in turn, would increase the probability of the acquisition of secondary genetic abnormalities such as IKZF1 deletion which, at least for leukemia in patients with BCR-ABL1+ ALL, appear to be critical for malignant progression [8]. This interpretation accords with the observation of Henry et al [6] that ‘older' mouse cells transfected with BCR-ABL1 undergo more rapid polyclonal expansion early after transplantation.
The incidence, malignancy and treatment resistance of many types of human B-cell leukaemias (B-ALL) are directly related to patient age. A major obstacle to elucidate the contribution of age to the development and evolution of leukaemias is the lack of appropriate mouse models where precise control of the timing of oncogene expression is possible. Here we present proof-of-principle experiments showing how a conditional transgenic mouse model of BCR-ABLp190-driven B-ALL offers the opportunity to test the hypothesis that the age of the leukemic cells-of-origin of B-ALL influences B-ALL malignancy. B-ALLs generated from 12- and 20-month-old progenitors gave rise to a more invasive B-ALL than the one developed from 4-month old precursors. This was evidenced by survival analysis revealing the increased malignancy of B-ALLs generated from 20 or 12-month-old transformed progenitors compared with the 4-month equivalents (median survival of 88 days versus 50.5 and 33 days, respectively). Our study shows that the age of target cells at the time of transformation affects B-ALL malignancy.
Aging is associated with the functional decline of cells, tissues, and organs. At the same time, age is the single most important prognostic factor in the development of most human cancers, including chronic myelogenous and acute lymphoblastic leukemias initiated by Bcr-Abl oncogenic translocations. Prevailing paradigms attribute the association between aging and cancers to the accumulation of oncogenic mutations over time, because the accrual of oncogenic events is thought to be the rate-limiting step in initiation and progression of cancers. Conversely, aging-associated functional decline caused by both cell-autonomous and non-cell-autonomous mechanisms is likely to reduce the fitness of stem and progenitor cell populations. This reduction in fitness should be conducive for increased selection of oncogenic mutations that can at least partially alleviate fitness defects, thereby promoting the initiation of cancers. We tested this hypothesis using mouse hematopoietic models. Our studies indicate that the dramatic decline in the fitness of aged B-lymphopoiesis coincides with altered receptor-associated kinase signaling. We further show that Bcr-Abl provides a much greater competitive advantage to old B-lymphoid progenitors compared with young progenitors, coinciding with restored kinase signaling pathways, and that this enhanced competitive advantage translates into increased promotion of Bcr-Abl-driven leukemias. Moreover, impairing IL-7-mediated signaling is sufficient to promote selection for Bcr-Abl-expressing B progenitors. These studies support an unappreciated causative link between aging and cancer: increased selection of oncogenic mutations as a result of age-dependent alterations of the fitness landscape.
In human cancers, all cancerous cells carry the oncogenic genetic lesions. However, to elucidate whether cancer is a stem cell-driven tissue, we have developed a strategy to limit oncogene expression to the stem cell compartment in a transgenic mouse setting. Here, we focus on the effects of the BCR-ABLp210 oncogene, associated with chronic myeloid leukaemia (CML) in humans. We show that CML phenotype and biology can be established in mice by restricting BCR-ABLp210 expression to stem cell antigen 1 (Sca1)(+) cells. The course of the disease in Sca1-BCR-ABLp210 mice was not modified on STI571 treatment. However, BCR-ABLp210-induced CML is reversible through the unique elimination of the cancer stem cells (CSCs). Overall, our data show that oncogene expression in Sca1(+) cells is all that is required to fully reprogramme it, giving rise to a full-blown, oncogene-specified tumour with all its mature cellular diversity, and that elimination of the CSCs is enough to eradicate the whole tumour.
Cancer is a clonal malignant disease originated in a single cell and characterized by the accumulation of partially differentiated cells that are phenotypically reminiscent of normal stages of differentiation. Given the fact that human cancer is diagnosed at later stages and cannot be monitored during its natural evolution, the origin of tumors has been a subject of continuing discussion. Animal models provide a means to determine the identity of the cell-of-origin leading to malignancy and to develop new treatments. Recent findings in mice have shown that cancer stem cells could arise through a reprogramming-like mechanism, suggesting that genetic lesions that initiate the cancer process might be dispensable for tumor progression and maintenance. This review addresses the impact of these results toward a better understanding of carcinogenesis and proposes research avenues for tackling these issues in the future.
The effects of aging on the immune system are widespread and extend from hematopoietic stem cells and lymphoid progenitors in the bone marrow and thymus to mature lymphocytes in secondary lymphoid organs. These changes combine to result in a diminution of immune responsiveness in the elderly. This review aims to provide an overview of age-related changes in lymphocyte development and function and discusses current controversies in the field of aging research.
The aging of tissue-specific stem cell and progenitor cell compartments is believed to be central to the decline of tissue and organ integrity and function in the elderly. Here, we examine evidence linking stem cell dysfunction to the pathophysiological conditions accompanying aging, focusing on the mechanisms underlying stem cell decline and their contribution to disease pathogenesis.
- Dj Rossi
Rossi DJ, et al. Cell 2008; 132:681-96.
- M Pérez-Caro
Pérez-Caro M, et al. EMBO J 2009; 28:8-20.
- Cj Henry
Henry CJ, et al. Proc Natl Acad Sci USA 2010;
107:21713-8.
- Ch Pui
Pui CH, et al. N Engl J Med 2004; 350:1535-48.
- Pj Linton
- K Dorshkind
Linton PJ, Dorshkind K. Nat Immunol 2004; 5:133-9.
- A Castellanos
Castellanos A, et al. Semin Cancer Biol 2010; 20:93-7.
- M Kim
Kim M, et al. Ann NY Acad Sci 2003; 996:195-2008.
- C Vicente-Dueñas
Vicente-Dueñas C, et al. Aging (Albany NY) 2010;
2:908-13.