iPS细胞:一种肿瘤细胞

诱导多能干细胞(iPS细胞)可以用于定向分化、动物发育、药物筛选和疾病治疗等研究和应用领域,可以避免ES细胞产生的免疫排斥和伦理道德问题.因此,iPS细胞的产生具有里程碑的意义,并迅速成为生物科学领域中的研究热点.然而,iPS细胞并非非常完美,没有任何瑕疵.研究过程中发现iPS细胞存在诱导频率过低、致瘤性、临床应用安全等一系列问题.本文主要综述有关iPS细胞前期研究成果和iPS细胞存在的一些问题以及iPS细胞与肿瘤细胞之间的联系.     

Xenotransplantation becoming reality

To bridge the gap between organ demand and supply, xenotransplantation has long been considered as a realistic option for end-stage organ failure. Early this year this promise became reality for David Bennett Sr., the first patient whose own failing heart was replaced with a xeno-pig heart. To get here has been a rollercoaster ride of physiological hurdles seemingly impossible to overcome, technological breakthroughs and ethical and safety concerns. It started in 1984, with Stephanie Fae Beauclair, also known as baby Fae, receiving a baboon heart, which allowed her to survive for another 30 days. For ethical reasons primate work was soon abandoned in favour of the pig. But increased phylogenetic distance also brought with it an increased immunological incompatibility. It has been the development of ever more sophisticated genetic engineering tools, which brought down the physiological barriers, enabled humanisation of porcine organs and helped addressing safety concerns. This renewed the confidence in xenotransplantation, brought new funding opportunities and resulted finally in the first in human trial.

     

Targeting tumor cells

Several recent scientific and technical developments have made it possible to postulate the use of the 'magic bullet' concept; that is, the identification of specific antigens present on tumor cells that can be targeted either by therapeutic antibodies or by small molecules. The use of monoclonal antibodies in cancer, in particular, has moved beyond the proof-of-concept stage, and many such antibodies are presently being tested in the clinic. Several antibodies have been successfully developed and are now in use against various cancers, and we can expect many more to become available in the next few years. The use and development of these new therapeutics represent significant opportunities but also new challenges.     

Jamaican Creole: In the process of becoming

Questions of attitudes and identity are foregrounded in this discussion of Jamaican Creole [JC] as a language of the diaspora. It is presented as a language that challenges the standardizing impulses of modernity, resisting homogeneity in a variable and multi-layered process of change. The article follows the evolutionary path of the language through Africa and the Caribbean to London and America and shows how its speakers see, use and connect through a vernacular that mirrors and embodies the social forces, experienced. The key sites are Jamaica, largely, and urban London. Through a review of the literature, documentary analysis, interviews and classroom observations this essay examines the ways in which Jamaican Creole could be said to exemplify the diasporic predicament and the ways in which it has managed to gain dominance in a) Caribbean society, b) the wider movement of the Caribbean diaspora.     

Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells

In adult skin, stem cells in the hair follicle bulge cyclically regenerate the follicle, whereas a distinct stem cell population maintains the epidermis. The degree to which all bulge cells have equal regenerative potential is not known. We found that Sonic hedgehog (Shh) from neurons signals to a population of cells in the telogen bulge marked by the Hedgehog response gene Gli1. Gli1-expressing bulge cells function as multipotent stem cells in their native environment and repeatedly regenerate the anagen follicle. Shh-responding perineural bulge cells incorporate into healing skin wounds where, notably, they can change their lineage into epidermal stem cells. The perineural niche (including Shh) is dispensable for follicle contributions to acute wound healing and skin homeostasis, but is necessary to maintain bulge cells capable of becoming epidermal stem cells. Thus, nerves cultivate a microenvironment where Shh creates a molecularly and phenotypically distinct population of hair follicle stem cells.     

Circulating tumor cells: highlight on practical implications

Circulating tumor cells (CTCs) are cells of presumed epithelial origin, whose prognostic and predictive value in metastatic cancer patients has recently been demonstrated. To date, the count of CTCs through the CellSearch? system represents a valid approach for monitoring disease status in patients with metastatic colorectal, breast, and prostate cancer; in these cancer types, a rise in the CTC count at any time during treatment predicts a poor outcome. Nevertheless, the clinical utility of monitoring CTC counts remains controversial, and what to do when CTC counts rise during therapy still remains an unanswered question. In this report, we suggest how to integrate CTC counts with their molecular characterization to better translate biologic information obtained on CTCs into daily clinical practice.     

Utilizing circulating tumor cells: challenges and pitfalls

Circulating tumor cells (CTC) detected in the blood of cancer patients could be used for risk-stratification, molecular subclassification and as an intermediate end-point in therapeutic efficacy studies. Most studies to date have focused on enumeration of CTC in advanced cancer patients but further development of CTC evaluation technologies could allow expansion into early disease, monitoring of treatment response, and selection of patients for targeted therapies based on a CTC derived signature. This review discusses the challenges faced in achieving these goals, including the potential absence of CTC in patients with no blood-borne metastases, CTC intra-patient molecular heterogeneity, ex vivo loss of CTC viability, and the biological differences between CTC and metastatic tissue.     

Conjunction of tumor cells with lymphocytes: implications for tumor invasion and metastasis

Our previous studies have led to a novel hypothesis that tumor metastasis is triggered by aberrant lymphocyte infiltration that disrupts intercellular junctions and surface adhesion molecules and causes dissociation of tumor cells from the primary tumor core, allowing lymphocytes to conjoin with dissociated tumor cells and physically 'drag' them to different tissue sites. Our hypothesis is supported by morphological and immunohistochemical data from multiple types of human cancer. This hypothesis challenges the traditional belief that the physical conjunction between tumor cells and lymphocytes would lead to degeneration of the tumor cells. To validate our hypothesis, H&E and immunostained sections were examined under high magnification to identify potential signs of degeneration-related changes. Our study revealed that >60% of isolated tumor cells overlying focal capsule disruptions, or within the stroma and vascular structures, were physically conjoined with lymphocytes to form tumor cell-lymphocyte chimeras (TLCs). Approximately 90% of the tumor cell partners of TLCs were morphologically indistinguishable from their counterparts within the tumor core. In addition, one third of the tumor cells of TLCs expressed high levels of cell proliferation specific proteins, or were undergoing mitosis. Our study also revealed that a subset of dilated lymphatic ducts or blood vessels at the site of focal capsule disruptions harbored variable numbers of tumor cells, and the wall of these structures was in direct physical continuity with the myoepithelial cell layer. Our study suggests that the onset of tumor metastasis may occur in two forms: (1) lymphocyte-mediated shuttling that allows lymphocytes to physically 'drag' tumor cells to different sites, and (2) tumor progenitor-mediated angiogenesis that allows tumor cells to directly enter the vascular structures.     

Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor cells with their host cells: essential basis to define tumor malignancy

Status of tumor progression (either remaining in situ, or becoming invasive/metastatic) may be defined largely by subtle interactions ('cross-talk') in a microenvironment formed by interfacing tumor cell and host cell membrane domains (termed 'glycosynapses') involved in glycosylation-dependent cell adhesion and signaling. Functional roles of tumor-associated gangliosides, organized in glycosynapses of three types of tumor cell lines, are discussed. Gangliosides function as adhesion receptors or as 'sensors' that can be stimulated by antibodies, with consequent activation of signal transducers leading to enhanced motility and invasiveness.     

Interactions of tumor cells with dendritic cells: balancing immunity and tolerance

Dendritic cells (DCs) are antigen-presenting cells specialized to initiate and maintain immunity and tolerance. DCs initiate immune responses in a manner that depends on signals they receive from pathogens, surrounding cells and their products. Most tumors are infiltrated by DCs. Thus, interactions between DCs and dying tumor cells may determine the balance between immunity and tolerance to tumor cells. In addition, DCs also display non-immunologic effects on tumors and the tumor microenvironment. Therefore, improved understanding of the cross talk between tumor cells and DCs may suggest new approaches to improve cancer therapy.     

Kinetochore function: the complications of becoming attached.

Kinetochores are specialized protein complexes assembled on centromeric DNA that connect to spindle microtubules and mediate proper chromosome segregation during cell division. Recent results have implicated specific kinetochore proteins in microtubule attachment.     

CT hybridomas: tumor cells capable of lysing virally infected target cells

By fusing primed murine lymphocytes with a syngeneic T cell lymphoma, we have been able to select for H-2-restricted, virus-specific cytotoxic T cell hybridomas (CTH). These T cell hybrids, which replicate in ordinary tissue culture medium or in ascites, are capable of lysing virally infected target cells, and their activity is facilitated by the presence of lectins in the assay medium. Unlike cells mediating lectin nonspecific lysis, these hybridomas are H-2 restricted and specific for single viral proteins. The ability to maintain these cells in culture for over 18 mo and to pass them in vivo without loss of activity or specificity indicates that they will provide sufficient material for the analysis of surface proteins and genetic information required for the recognition and lysis of virally infected cells by killer T cells.