Tumor vessel formation is largely dependent on the recruitment of endothelial cells. Rare in healthy individuals, circulating endothelial cells (CEC) are shed from vessel walls and enter the circulation reflecting endothelial damage or dysfunction. Increased numbers of CEC have been documented in different types of cancer. Recent studies have suggested the role for CEC in tumor angiogenesis, but whose presence could also reflect normal endothelium perturbation in cancer. Originating from the bone marrow rather than from vessel walls, endothelial progenitor cells (EPC) are mobilized following tissue ischemia and may be recruited to complement local angiogenesis supplied by existing endothelium. Recently, studies in mouse models suggest that the circulating fraction of endothelial progenitors (CEP) is involved in tumor angiogenesis but their contribution is less clear in humans. The detection of CEC and CEP is difficult and impeded by the rarity of these cells. They may have important clinical implication as novel biomarkers susceptible to predict more efficiently and rapidly the therapeutic response to anti-angiogenic treatments. However, a methodological consensus would be necessary in order to correctly evaluate the clinical interest of CEC and CEP in patients.

A meta-analysis of recent data from the literature underscores the considerable body of present knowledge concerning prostate carcinogenesis, in part due to the numerous molecular biology tools now at our disposal. As concerns early events, much interest is being paid to modifications in the expression of GSTP1 and NKX3.1 occurring in totipotent stem cell populations. The discovery of fusion genes implicating TMPRSS2 and ERG (and, on rare occasions, other ETS family transcription factors) constitutes a major advance. Under physiological androgenic stimulation, the presence of these fusion genes leads to overexpression of genes involved in cell growth and differentiation. Concomitantly, alterations in numerous signalling pathways (growth factors, Wnt-beta catenine, PI3K/Akt) are responsible for the onset of an aggressive tumor phenotype. Hormono-independence is currently explained by an amplification of, or mutations in, androgenic receptors. These are facilitated by genomic instabilities linked to alterations in proteins which regulate gene expression, such as EZH2, and by the influence of the tumor microenvironment. Disturbances in the interactions between tumor cells and the microenvironment contribute to local extension of the tumor. Changes in the expression of E-cadherin are responsible for modifications in cell adhesion to the extracellular matrix. The expression of metalloproteases and of angiogenic factors favors tumor dissemination. Finally, the bone tropism in prostate metastases is probably linked to osteomimetic properties of prostate tumor cells which are capable of expressing certain proteins involved in bone remodelling, such as Runx-2, BSP (bone sialoprotein) and BMP (bone morphogenetic protein). Numerous studies remain to be carried out in order to correlate the identified genetic profiles and molecular anomalies with tumor prognosis. Nevertheless, the possibility of decrypting these anomalies for use in therapeutic applications is encouraging.

Poor prognosis childhood cancers are mainly metastatic diseases represented by stage IV neuroblastomas developed in children more than one year and metastatic Ewing tumours. These both diseases are chemosensitive but not curable with conventional chemotherapy. In these indications, high-dose chemotherapy with autologous peripheral blood stem cells transplantation is delivered in patients achieving a good partial remission with conventional treatment. The toxicity of these procedures is high but manageable; these approaches have improved the prognosis of these patients.

"Biotherapies" include both biopharmaceuticals and cell and gene therapies. Biopharmaceuticals are macromolecules created by biotechnologies. In the case of monoclonal antibodies, the starting dose to be given to Humans is difficult to select because there may be no relevant animal model. At the time of registration, the knowledge of the mechanism of action of monoclonal antibodies is insufficient and cohort follow up studies are needed. Genetic predisposition and pharmacokinetics are interindividual sources of variability. Some of the adverse drug reactions are predictable but others are unexpected or even paradoxical. Cell and "ex vivo" gene therapies consist in the manipulation of collected cells and their infusion in autologous or allogenic clinical settings. The methodology of the clinical development of drugs cannot be readily applied to these therapies. On the other hand, "in vivo" gene therapy uses vectors or macromolecules which can be considered as biopharmaceuticals.

Fascinating and provocative findings have shaken the stem cell field during these past years, which may be exploited in the future in cell replacement therapies. Continuous renewal of blood, skin, and gut cells, has long be attributed to stem cells, but it was more unexpected to identify cells that fulfil the requirements for stem-progenitor cells in many tissues with a slow turnover such as heart, kidney, muscle and brain. However, despite their lack of risk and immunological barrier, adult stem cells are yet of poor therapeutic value in many diseases, because they are available in scarce number, are poorly amplified, and loose potential with ageing, among many obstacles. Thus, the identification in adult, and more recently fetal tissues, of cells with a high proliferative capacity and multi-lineage differentiation potential has been wellcome, although their existence is still a matter of controversy. An alternative would be to activate stem cells in situ, by acting on components of the niche as recently exemplified in the hematopoetic system. Finally, as fiction meets reality, it may become possible to reprogram human adult cells in pluripotent ES cells-like, as recently demonstrated in mice.

Whilst maintaining the principle of a ban on embryo research, the bioethics law of August 6th 2004, updating the first bioethics laws passed in 1994, authorises French research teams to carry out studies and research on embryos or embryonic cells generated as part of an assisted reproduction programme, under special dispensation and for a maximum of five years from the date of publication of the decree of application of this text (Decree n(o) 2006-126, February 6th 2006, JO of 07/02/06). It also permits the importation and exportation of embryonic tissues and cells for such research and the storage of stem cells for scientific purposes. This highly supervised disposition is subject to control by the Biomedicine Agency, which is responsible for delivering and controlling authorisations for embryo research.

Any clinician dreams to obtain the regeneration of the destroyed organ for his patient. In the human being, the regeneration of complex structures is not possible, except the liver and the bone marrow, which can be regenerated because of the presence of adult stem cells in these tissues. The stem cells have two principal properties: they ensure their self-renewal and they have the ability to differentiate into several cellular types. Using specific markers allowing the identification of the stem cells in bone marrow, stem cells were observed in dental pulp tissues. Although the origin, the identification, and the localization of these stem cells of dental pulp remain under consideration, the optimism in research on stem cells permits to believe that the knowledge on dental stem cells will lead to their use in therapeutics.

Mesenchymal stem cells (MSC) are progenitors of osteoblasts, chondrocytes and adipocytes. They are in the bone marrow at the concentration of 1 to 104 at 105 mononucleated cells. There is not specific marker to select them. They can be cultured and differentiated in osteoblats or chondrocytes. They induced osteoformation in autologous bone graft. Therapeutic application includes concentrate of bone marrow or MSC expanded by culture, implanted with or without biomaterials. The implantation of MSC cultured on biomaterial has not been yet published in human. The aim of these technics is to reduce the use of bone graft. The first indications for these technics will be pseudarthrosis and bone defect.

Breast cancer is a major health problem as well as scientifically poorly understood. Our knowledge of breast cancer is however rapidly progressing in several directions. First, genomic studies are establishing a new molecular classification of breast cancers. Molecular subtypes have been identified and are being associated with the histoclinical forms of breast cancers. Second, genetic alterations are discovered and classified, generating new potential therapeutical targets. Third, mammary stem cells have been identified in the normal mammary epithelium. Their altered counterparts have been identified in tumors and are being characterized. These combined studies allow a new integrated cellular and molecular definition of breast cancers and a conceptual basis that will help the management of the disease.

Germ line specification is an early cell fate decision essential for the transmission of totipotency over generations. Two types of germ line stem cells populate the male gonads in mammals. Primordial germ cells (PGCs) are the germ line founders only present during prenatal life. Spermatogonial stem cells (SSCs) appear a few days after birth and divide asymmetrically to give rise to one stem cell and one spermatogonia that initiates differentiation to produce spermatozoa. Germ cell specification and differentiation involve specific environmental stimuli and a sequential order of maturing phases required for gamete function. Spatio-temporal controls similarly dictate the erasure of somatic methylation marks and the subsequent acquisition of sex-specific marks at imprinted genes in gametes. We review here the recent advancements in male germ cell derivation from ES cells and discuss the limits of these in vitro methods in providing a kinetics and a microenvironment suitable for the programming of a proper gametic and parental identity.

Our fascination for stem cells originates from their ability to divide asymmetrically in order to self-renew and produce daughter cells which can differentiate and replenish tissues. Stem cells could thus represent an unlimited source of differentiated cells that could be used to repair malformed, damaged or ageing tissues. Understanding how their behaviour is regulated is then of paramount medical interest. Specific microenvironments surrounding the stem cells, termed "niches", were proposed to play a major role in the balance between self-renewal and differentiation. However, it is only recently, in the case of the stem cells producing the germline (GSGs) in Drosophila, that the cells and signals creating a niche were identified for the first time. Here, we review how this niche has been defined at the cellular and functional levels in vivo, thanks to the powerful genetic tools available in Drosophila. Such studies have revealed adhesive interactions, cell-cycle modifications and intercellular signals that control the GSC behavior. Extracellular signals from the niche activate the BMP or JAK-STAT pathways in the GSCs and are necessary for their maintenance. Strikingly, both signaling pathways are also sufficient to convert differentiated germ cells into functional GSCs, demonstrating in vivo that a niche has the capacity to regenerate stem cells from differentiated cells. Rapid progresses have further identified direct links between these signaling pathways and the transcriptional regulation of the GSCs, providing a simple paradigm for stem cells regulation. Many of these features and signals are conserved in stem cells niches from Drosophila to mammals. We can thus hope that research on the GSCs in Drosophila will benefit therapeutic approaches to human degenerative diseases.

Cardiac cell therapy has been initially designed to regenerate the infarcted myocardium through its repopulation by new cells able to restore function of scar areas. Six years after the first human application of this novel approach, it is timely appropriate to review the results of the first randomised trials in the three major indications, i.e., acute myocardial infarction, heart failure, and refractory angina. It should be recognized that the results are mixed, with benefits ranging from absent to transient and, at most, marginal. However, lessons drawn from this first wave of clinical series and the experimental data that have been concomitantly collected are multiple and highly informative. They indicate that adult stem cells, whether muscular or bone marrow-derived, fail to generate new cardiomyocytes. They suggest that the potential benefits of cardiac cell therapy are thus mediated by alternate mechanisms such as limitation of left ventricular remodelling or paracrine activation of signalling pathways involved in angiogenesis. They highlight the fact that the therapeutic benefits of grafted cells will not be fully exploited until issues of cell transfer and postengraftment survival have not been adequately addressed. These observations thus allow us to better fine-tune upcoming research, which should specifically concentrate on the development of cells featuring a true regeneration potential. In this setting, the greatest promises are currently held by embryonic stem cells.

Cell therapy was born in 1968 with the first allogeneic transplantation of hematopoietic stem cells for two immune deficiency disorders: the Wiskott-Aldrich syndrome and the Severe Combined ImmunoDeficiency (SCID). From this pioneering experience, thousands of patients affected with inherited or acquired diseases of the hematopoietic system have benefited from this therapeutic approach. Unfortunately, immunologic obstacles, represented by the compatibility in the major histocompatibility HLA system, still dictate today important limitations for a larger therapeutic utilization of hematopoietic stem cells (HSC). In this review, we have summarized the difficulties and the scientific advances leading us to improve the clinical results; the therapeutic research's track for primary immunodeficiencies is also discussed.

Stem cell biology is one of the most exciting subjects in life science nowadays. The major point in stem cell biology is the extraordinary capacity of these cells to self-renew and to give rise to different cell types. Nevertheless, major issues remain to be cleared and very few diseases can actually be cured based on stem cell therapy. Adult stem cells remain difficult to locate, isolate and amplify in a homogeneous fashion and, thus, limit their therapeutic application in clinical trial. Embryonic stem cells could represent a new hope in stem cell therapy but in addition to the scientific difficulties, over ethical and judiciary issues should be addressed. In order to cure routinely patients, controlled conditions for stem cell isolation, amplification, differentiation, and administration must be defined and effective tissue integration have to be established. In this review we will discuss these different aspects of stem cell biology.

Although the treatment of multiple sclerosis has made significant strides in the last decade, successful translation from laboratory to clinical medicine of neuronal repair remains a therapeutic challenge. Nevertheless, advances in the biology of stem and precursor cells, particularly in relation to myelin damage, make this a realistic proposition during the next decade. Replacing lost myelin (remyelination) is currently thought to be an important clinical objective because of the role it might play in slowing or preventing axonal degeneration. Stem/precursor cell-based strategies for enhancing remyelination can be divided into those in which cell are transplanted into a patients (exogenous or cell therapies) and those in which the patients own stem/precursor cells are mobilised to more efficiently engage in healing areas of demyelination (endogenous or pharmacological therapies). While the two approaches tend to be regarded separately they are not mutually exclusive. This article focuses on the endogenous approach and reviews the nature and nomenclature of the stem and precursor cells present within the adult CNS that engage in remyelination and that are therefore potential targets for pharmacological manipulation.