Prostate cancer and metastasis initiating stem cells

Androgen refractory prostate cancer metastasis is a major clinical challenge. Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell. Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis. This review focuses upon current evidence and concepts addressing the identification and properties of normal prostate stem or progenitor cells and their transformed counterparts.     

造血干细胞研究进展

造血干细胞（hematopoietic stem cell,HSC）是成体干细胞研究领域的范式。对造血干细胞自我更新和不对称分裂分子遗传学机制的诠释,将不仅帮助理解成体干细胞“干性”维持的发育遗传学机制,也将对白血病干细胞和其他类型肿瘤干细胞的发育起源及开发针对肿瘤干细胞的靶向治疗模式产生深远的影响。     

Understanding cancer stem cell heterogeneity and plasticity

Heterogeneity is an omnipresent feature of mammalian cells in vitro and in vivo. It has been recently realized that even mouse and human embryonic stem cells under the best culture conditions are heterogeneous containing pluripotent as well as partially committed cells. Somatic stem cells in adult organs are also heterogeneous, containing many subpopulations of self-renewing cells with distinct regenerative capacity. The differentiated progeny of adult stem cells also retain significant developmental plasticity that can be induced by a wide variety of experimental approaches. Like normal stem cells, recent data suggest that cancer stem cells (CSCs) similarly display significant phenotypic and functional heterogeneity, and that the CSC progeny can manifest diverse plasticity. Here, I discuss CSC heterogeneity and plasticity in the context of tumor development and progression, and by comparing with normal stem cell development. Appreciation of cancer cell plasticity entails a revision to the earlier concept that only the tumorigenic subset in the tumor needs to be targeted. By understanding the interrelationship between CSCs and their differentiated progeny, we can hope to develop better therapeutic regimens that can prevent the emergence of tumor cell variants that are able to found a new tumor and distant metastases.     

成体干细胞可塑性的事实、质疑和展望

成体干细胞的可塑性是指存在于成年组织或器官中的不成熟细胞跨胚层分化的一种能力。近年来相关研究很多,有人认为成体干细胞具有可塑性,如造血干细胞可以分化为神经外胚层细胞和内胚层细胞：有人对其持怀疑态度,认为成年造血干细胞发育可塑性证据不足,成体干细胞不能跨胚层分化。由于分离纯化、检测手段等的局限,大多数研究均存在这样或那样的不足和误区,彻底研究清楚还有很长的路要走。     

Cellular immortality in brain tumours: An integration of the cancer stem cell paradigm

Brain tumours are a diverse group of neoplasms that continue to present a formidable challenge in our attempt to achieve curable intervention. Our conceptual framework of human brain cancer has been redrawn in the current decade. There is a gathering acceptance that brain tumour formation is a phenotypic outcome of dysregulated neurogenesis, with tumours viewed as abnormally differentiated neural tissue. In relation, there is accumulating evidence that brain tumours, similar to leukaemia and many solid tumours, are organized as a developmental hierarchy which is maintained by a small fraction of cells endowed with many shared properties of tissue stem cells. Proof that neurogenesis persists throughout adult life, compliments this concept. Although the cancer cell of origin is unclear, the proliferative zones that harbour stem cells in the embryonic, post-natal and adult brain are attractive candidates within which tumour-initiation may ensue. Dysregulated, unlimited proliferation and an ability to bypass senescence are acquired capabilities of cancerous cells. These abilities in part require the establishment of a telomere maintenance mechanism for counteracting the shortening of chromosomal termini. A strategy based upon the synthesis of telomeric repeat sequences by the ribonucleoprotein telomerase, is prevalent in ～ 90% of human tumours studied, including the majority of brain tumours. This review will provide a developmental perspective with respect to normal (neurogenesis) and aberrant (tumourigenesis) cellular turnover, differentiation and function. Within this context our current knowledge of brain tumour telomere/telomerase biology will be discussed with respect to both its developmental and therapeutic relevance to the hierarchical model of brain tumourigenesis presented by the cancer stem cell paradigm.     

Mathematical model for the cancer stem cell hypothesis

Recent research on the origin of brain cancer has implicated a subpopulation of self-renewing brain cancer stem cells for malignant tumour growth. Various genes that regulate self-renewal in normal stem cells are also found in cancer stem cells. This implies that cancers can occur because of mutations in normal stem cells and early progenitor cells. A predictive mathematical model based on the cell compartment method is presented here to pose and validate non-intuitive scenarios proposed through the neural cancer stem cell hypothesis. The growths of abnormal (stem and early progenitor) cells from their normal counterparts are ascribed with separate mutation probabilities. Stem cell mutations are found to be more significant for the development of cancer than a similar mutation in the early progenitor cells. The model also predicts that, as previously hypothesized, repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer.     

Stem cell: balancing aging and cancer

Stem cells are defined by their self-renewing capacity and the ability to differentiate into one or more cell types. Stem cells can be divided, depending on their origin, into embryonic or adult. Embryonic stem cells derive from early stage embryos and can give rise to cells from all three germ layers. Adult stem cells, first identified in hematopoietic tissue, reside in a variety of adult tissues. Under normal physiologic conditions, adult stem cells are capable of differentiating into the limited cell types that comprise the particular tissue or organ. Adult stem cells are responsible for tissue renewal and exhaustion of their replicative capacity may contribute to tissue aging. Loss of unlimited proliferative capacity in some of the adult stem cells and/or their progenitors may have involved the evolutionary trade-off: senescence prevents cancer but may promote aging. Embryonic stem cells exhibit unlimited self-renewal capacity due to the expression of telomerase. Although they possess some cancer cell characteristics, embryonic stem cells exhibit a remarkable resistance to genomic instability and malignant transformation. Understanding the tumor suppressive mechanisms employed by embryonic stem cells may contribute to the development of novel cancer treatments and safe cell-based therapies for age-related diseases.     

The stem state: mesenchymal plasticity as a paradigm

The mesenchyme is a remarkably plastic tissue in the embryo. Recent studies have led to the discovery of mesenchymal cells in the adult organism that can differentiate in vitro into unexpected directions, beyond the well-known ability of the mesenchyme to give rise to mesodermal derivatives. These studies highlighted the plastic nature of the mesenchyme, also beyond the embryonic developmental stage. This review discusses the possible functions of the mesenchyme in the adult and the reason for the maintenance of plasticity throughout mammalian life. The properties of the mesenchymal cells clearly exemplify the stem state concept; cells, whether early or late in the differentiation cascade, may assume a stem state that entails high plasticity.     

The therapeutic implications of plasticity of the cancer stem cell phenotype

The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer.     

Animal models that elucidate basic principles of the developmental origins of adult diseases

Human epidemiological and animal laboratory studies show that suboptimal environments in the womb and during early neonatal life alter development and predispose the individual to lifelong health problems. The concept of the developmental origins of adult diseases has become well accepted because of the compelling animal studies that have precisely defined the outcomes of specific exposures such as nutrient restriction, overfeeding during pregnancy, maternal stress, and exogenously administered glucocorticoids. This review focuses on the use of animal models to evaluate exposures, mechanisms, and outcomes involved in developmental programming of hypertension, diabetes, obesity, and altered pituitary-adrenal function in offspring in later life. Ten principles of developmental programming are described as fundamental, regardless of the exposure during development and the physiological system involved in the altered outcome. The 10 principles are discussed in the context of the physiological systems involved and the animal model studies that have been conducted to evaluate exposures, mechanisms, and outcomes. For example, the fetus responds to challenges such as hypoxia and nutrient restriction in ways that help to ensure its survival, but this "developmental plasticity" may have long-term consequences that may not be beneficial in adult life. To understand developmental programming, which represents the interaction of nature and nurture, it is necessary to integrate whole animal systems physiology, in vitro cellular biology, and genomic and proteomic approaches, and to use animal models that are carefully characterized and appropriate for the questions under study. Animal models play an important role in this evaluation because they permit combined in vivo and in vitro study at different critical time windows during the exposure and the ensuing developmental responses.     

Our perception of developmental plasticity: esse est percipi (to be is to be perceived)?

The continuing interest in the biology of stem cells is enhanced by new discoveries surrounding developmental plasticity of both embryonic and adult stem cells. Adoptive transfer of concepts and definitions from the hematopoietic system to other tissue stem cells suggests inclusion of characteristics such as ability to self-renew and differentiate to functionally reconstitute a tissue/organ of origin. How adequate and accurate are these definitions? Within the great unknown of how these cells function, modulate their gene expression patterns and respond to extrinsic signals, it is apparent that there are numerous levels of stemness. We may envision a scale of developmental flexibility. At one end of the scale are positioned the embryonic stem cells, and at the other end are positioned partially-differentiated, differentiation restricted (committed) tissue/organ stem cells. There is evidence that some stem cells in the adult are pluripotent, thus positioned close to the embryonic end of the stem scale. It is uncertain yet to what extent stem cells can move back and forth along the stem scale.     

p53: The barrier to cancer stem cell formation

The role of p53 as the “guardian of the genome” in differentiated somatic cells, triggering various biological processes, is well established. Recent studies in the stem cell field have highlighted a profound role of p53 in stem cell biology as well. These studies, combined with basic data obtained 20 years ago, provide insight into how p53 governs the quantity and quality of various stem cells, ensuring a sufficient repertoire of normal stem cells to enable proper development, tissue regeneration and a cancer free life. In this review we address the role of p53 in genomically stable embryonic stem cells, a unique predisposed cancer stem cell model and adult stem cells, its role in the generation of induced pluripotent stem cells, as well as its role as the barrier to cancer stem cell formation.     

Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies

Early experience has a particularly great effect on most organisms. Normal development may be disrupted by early environmental influences; individuals that survive have to cope with the damaging consequences. Additionally, the responses required to cope with environmental challenges in early life may have long-term effects on the adult organism. A further set of processes, those of developmental plasticity, may induce a phenotype that is adapted to the adult environment predicted by the conditions of early life. A mismatch between prediction and subsequent reality can cause severe health problems in those human societies where economic circumstances and nutrition are rapidly improving. Understanding the underlying mechanisms of plasticity is, therefore, clinically important. However, to conduct research in this area, developmental plasticity must be disentangled from disruption and the adverse long-term effects of coping. The paper reviews these concepts and explores ways in which such distinctions may be made in practice.     

The stem cells of early embryos

Cells resident in an organism that possess the dual capacity for self-renewal and differentiation into a spectrum of subtypes are referred to as stem cells. In the past decade, basic research performed on stem cells has shed light on the molecular pathways operating in vivo which can be harnessed in vitro for the establishment of cell lines mirroring the stem cells in the organism. The attractiveness of stem cells as in vitro models of organotypic differentiation and their potential application in a clinical context holds great promise and is only beginning to be exploited. Stem cells can be broadly grouped into two categories based on their origin from either the embryonic or the adult. Only the early embryo possesses truly pluripotent cells that can give rise to all the cell types present in the embryo proper and adult. The adult, on the other hand, possesses specialized, tissue- or organ-specific stem cell types, which can give rise to the differentiated cell types of that specific organ and have in some instances been shown to transdifferentiate. However, no stem cell obtained from an adult organism has yet been shown to exhibit developmental potential matching the breadth of that of stem cells obtained from embryos. This review focuses on the different types of stem cells that are resident in early stage mammalian embryos, detailing their derivation and propagation in addition to highlighting their developmental potential and opportunities for future applications.     

Neurotrophin signaling in oocyte survival and developmental competence: a paradigm for cellular toti-potency

While not fulfilling the criterion of a "stem cell" in being capable of self-renewal, mature and fertilized oocytes are the original "toti-potent" cells, whose capacity for expansion and differentiation can only be approximated by stem cells of embryonic or adult origin in vitro. As such, the mechanisms by which oocytes acquire and manifest competence to support embryo development is of fundamental interest to efforts to control and re-specify somatic cell fate and toti-potency. This is underscored by the unparalleled capacity of oocyte cytoplasm to successfully re-specify the genetic program of animal development following cell nuclear replacement (i.e., cloning). Thus, the knowledge gained by understanding the acquisition of oocyte developmental competence could ultimately facilitate the creation of adult stem cells in vitro from terminally differentiated cells, ex ovo. In this paper, we review the concept of oocyte developmental competence, and focus on our own research and that of others implicating a role for neurotrophins in this process, and that of oocyte cell survival. Lastly we propose a role for neurotrophin signalling in embryo stem cell survival.     

Microenvironmental regulation of cancer stem cell phenotypes

Cancer is a complex set of diseases, driven by genomic instability overlaid with epigenetic modifications. Two prevailing concepts, the stochastic theory and the hierarchical theory, are traditionally used to understand tumor progression. These seemingly contradictory theories can be reconciled with the concept of cellular plasticity, such that certain genetic mutations enable epigenetic alterations in cell fate. A growing body of evidence suggests that cancer cells co-opt embryonic stem cell-associated regulatory networks in order to sustain tumor cell plasticity concomitant with growth and progression. The expression of these stem cell associated factors is regulated by dynamic niches, characterized by cellderived proteins as well as biophysical features such low oxygen tensions. In this review we describe specific embryo-associated proteins such as NODAL, NOTCH, and canonical WNT, which cooperate to maintain stem cell phenotypes in cancer. We also illustrate how biophysical factors, in particular oxygen, can orchestrate plasticity by modulating the expression of stem cell-associated proteins. As the microenvironment is known to play a key role in cellular regulation, it is essential to understand its role in cancer progression in order to improve and create new therapies.