干细胞、肿瘤干细胞与造血系统肿瘤

随着干细胞研究的不断深入,人们对胚胎干细胞(ES)、造血干细胞等干细胞了解日益加深.发现干细胞与肿瘤细胞有许多共性,如无限增生能力、迁移能力及在某些条件下能相互转化.提出肿瘤起源于干细胞、肿瘤中存在肿瘤干细胞等学说.这些学说的理论依据多来源于对造血系统肿瘤的研究.     

Mast cells,eosinophils and goblet cells in nasal allergy

This work was taken up to assess the mast cell population in nasal allergy both in nasal smear and nasal tissue in correlation with the eosinophils and goblet cells. An attempt had been made to find out the significance of these cells in arriving at a diagnosis of nasal allergy.     

Farnesyl-O-acetylhydroquinone and geranyl-O-acetylhydroquinone suppress the proliferation of murine B16 melanoma cells, human prostate and colon adenocarcinoma cells, human lung carcinoma cells, and human leukemia cells

Farnesyl-O-acetylhydroquinone (IC(50)=2.5 microM/l) suppressed the proliferation of murine B16F10 melanoma cells with a potency much greater than those of farnesol (IC(50)=45 microM/l) and farnesyl anthranilate (IC(50)=46 microM/l), its alcohol, and ester counterparts with proven anti-tumor activities in vivo. Geranyl-O-acetylhydroquinone (IC(50)=5.1 microM/l) also had a much-improved activity compared to geraniol (IC(50)=160 microM/l) and geranyl anthranilate (IC(50)=30 microM/l). The suppression by farnesyl-O-acetylhydroquinone was concentration- and time-dependent and was accompanied by arrest of cell cycle at G1 and G2/M phases as shown by flow cytometry. Farnesyl-O-acetylhydroquinone and lovastatin had additive impact on B16 cell proliferation. Farnesyl-O-acetylhydroquinone also suppressed the proliferations of human cancer cells HL-60, DU145, PC-3, LNCaP, Caco-2, and A549. Our results suggested that farnesyl derivatives, suppressors of tumor 3-hydroxy-3-methylglutaryl coenzyme A reductase activities, have potential as chemopreventive or chemotherapeutic agents.     

Dendritic cells, pulsed with lysate of allogeneic tumor cells, are capable of stimulating MHC-restricted antigen-specific antitumor T cells

A variety of approaches have been used to deliver tumor-associated antigens (TAA) in conjunction with dendritic cells (DC) as cellular adjuvants. DC derived from monocytic precursors have been pulsed with whole tumor antigen using a variety of strategies and have been demonstrated to induce CD4+ and CD8+ antitumor responses. In the present study, monocyte-derived DC have been pulsed with lysate from an allogeneic melanoma cell line, A-375, and used to repeatedly stimulate T cells. The resultant T cells were examined for cytotoxic activity against A-375 targets as well as the HLA A2-positive melanoma cell line DFW. Uptake of FITC-labeled melanoma lysate by DC established that lysate of melanoma cells was efficiently endocytosed. Stimulation with lysate-pulsed DC resulted in strong proliferative responses by T cells, which could be inhibited by antibodies against both MHC class I and class II. T cells stimulated in vitro with lysate-pulsed DC demonstrated potent cytotoxicity against the melanoma targets which were blocked by antibodies against MHC class I. Lysate-pulsed DC also elicited IFN-gamma secretion by T cells as measured in an ELISPOT assay. We have also examined the ability of lysate-pulsed DC to present melanoma-associated antigens to T cells. ELISPOT assays with synthetic peptides of melanoma-associated antigens, such as gp100, mage1, NY-ESO, and MART-1, revealed that lysate-pulsed DC could stimulate T cells in an antigen-specific manner. The results demonstrate that lysate from allogeneic tumor cells may be used as a source of antigens to stimulate tumor-specific T cells in melanoma.     

Isozyme profiles of oval cells, parenchymal cells, and biliary cells isolated by centrifugal elutriation from normal and preneoplastic livers

The fetal liver isozymes aldolase A and pyruvate kinase K increase in livers of adult rats fed a choline deficient-diet containing 0.1% ethionine. Oval cells isolated by centrifugal elutriation from preneoplastic livers of animals receiving the carcinogenic diet contained these fetal forms as well as fetal-adult isozyme hybrids. In contrast, parenchymal cells isolated from the livers of these animals had only aldolase B and pyruvate kinase L, the same isozymes present in parenchymal cells of normal adult rats. Liver homogenates from rats receiving the carcinogenic diet contain lactate dehydrogenase (LDH) 1, LDH 2, and LDH 3 in addition to LDH 4 and LDH 5, which are the forms detected in normal liver homogenates. LDH 1, LDH 2, and LDH 3 are present in oval cells of preneoplastic livers and in biliary epithelial cells of normal livers, but not in parenchymal cells isolated from normal and preneoplastic livers. Cells of biliary epithelium from normal livers also contain aldolase A and pyruvate kinase K, but not the fetal-adult isozymes present in oval cell populations. The results indicate that, in animals receiving this carcinogenic diet, isozyme alterations associated with neoplasia result from the proliferation of a new cell population which contains these enzymes and not from "dedifferentiation" of mature hepatocytes. Furthermore, the data suggest that this new cell population may include a liver stem cell compartment containing cells in transitional states of differentiation.     

Increased vaccination efficiency with apoptotic cells by silica-induced, dendritic-like cells

We have demonstrated previously the ability of apoptotic cells to prime a functional immune response using an i.p. vaccination protocol with apoptotic cells and interleukin 2, before injecting a lethal dose of tumor cells into syngeneic rats. This protocol resulted in a survival rate of 33%. To elucidate the nature and the activity of the phagocytes involved in the clearance of apoptotic cells in vivo, we modulated the peritoneal cavity environment by administrating either thioglycollate or silica i.p. before injecting the apoptotic cells. Our results showed that thioglycollate abrogated vaccination efficiency, because none of the rats survived under these conditions. In fact, thioglycollate treatment induced a massive recruitment and activation of inflammatory macrophages that efficiently engulfed apoptotic cells, bypassing induction of specific immune responses. In contrast, silica treatment enhanced the vaccination efficiency of apoptotic cells plus interleukin 2 up to 66%. We distinguished a population of dendrite-like cells among the cells derived from the silica-treated peritoneal cavity both by their phenotype (MHC II(+)/CD80(+)/CD86(+)) and by their ability to induce the proliferation of allogeneic T cells in a mixed leukocyte reaction. Our results demonstrate the different roles of macrophages and dendritic-like cells in the physiological clearance of dead tumor cells and their implication in the design of immunomodulating vaccines.     

Phosphatidylserine-dependent phagocytosis of apoptotic glioma cells by normal human microglia, astrocytes, and glioma cells

Apoptotic cells display signals that trigger phagocytic removal by macrophages or neighboring cells. To better understand the signals triggering phagocytosis of apoptotic glioma cells, and to identify the cells that might be involved in the phagocytic process, U-251 MG glioma cells were made apoptotic by etoposide (25 microg/ml) treatment and were incubated with normal human astrocytes (NHA), glioma cells, or microglia. Extent of phagocytosis was assessed by an in vitro phagocytosis assay. After 3 h of incubation with apoptotic cells, phagocytes tested were washed to remove nonengulfed cells, then fixed, stained, and counted to determine phagocytosis index (PI). NHA, glioma cells, and microglia all phagocytosed apoptotic, but not nonapoptotic, glioma cells. Microglia, however, had a PI approximately 4-fold higher than did either NHA or glioma cells. Binding of phosphatidylserine (PS) on apoptotic glioma cell membranes by annexin-V inhibited phagocytosis by 90% in both microglia and NHA. The activity of an enzyme (scramblase) that moves PS from the inner cell membrane to the outer cell membrane was also increased in apoptotic glioma cells. These results suggest that a variety of cells present in and near gliomas in vivo can remove glioma cells in a PS-dependent scramblase-mediated fashion. Manipulation of scramblase and/or PS exposure in glioma cells may therefore be a means of triggering phagocytic removal of glioma cells.     

Erufosine,an alkylphosphocholine,with differential toxicity to human cancer cells and bone marrow cells

Purpose  

To investigate the activity and myeloprotective properties of erufosine, a novel alkylphosphocholine (APC), on human malignant cells and normal bone marrow cells.     

Platelets,circulating tumor cells,and the circulome

Platelets are cytoplasmic fragments generated by megakaryocytes in the bone marrow and do not possess a nucleus. They contribute to the “Circulome” consisting of all circulating cells, factors and macromolecules such as cfDNA. Their primary function is to recognize vascular lesions and initiate thrombus formation that ceases bleeding. This distinctive characteristic of platelets also contributes to cancer and its progression. The ability of platelets to recognize and interact with other cells and neighboring platelets enables them to interact with tumor cells in the circulation. Receptor recognition and factor mediated crosstalk between tumor cells and platelets stimulate platelet activation, release of factors, and aggregation that promotes tumor cell survival and cancer progression. This review describes platelet: (i) contributions to the “Circulome” (ii) their importance as diagnostic tools in predicting cancer risk and (iii) therapies targeting platelet activation in inhibiting tumor progression and metastasis.     

CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells

Human brain tumor stem cells have been enriched using antibodies against the surface protein CD133. An antibody recognizing CD133 also served to isolate normal neural stem cells from fetal human brain, suggesting a possible lineage relationship between normal neural and brain tumor stem cells. Whether CD133-positive brain tumor stem cells can be derived from CD133-positive neural stem or progenitor cells still requires direct experimental evidence, and an important step toward such investigations is the identification and characterization of normal CD133-presenting cells in neurogenic regions of the embryonic and adult brain. Here, we present evidence that CD133 is a marker for embryonic neural stem cells, an intermediate radial glial/ependymal cell type in the early postnatal stage, and for ependymal cells in the adult brain, but not for neurogenic astrocytes in the adult subventricular zone. Our findings suggest two principal possibilities for the origin of brain tumor stem cells: a derivation from CD133-expressing cells, which are normally not present in the adult brain (embryonic neural stem cells and an early postnatal intermediate radial glial/ependymal cell type), or from CD133-positive ependymal cells in the adult brain, which are, however, generally regarded as postmitotic. Alternatively, brain tumor stem cells could be derived from proliferative but CD133-negative neurogenic astrocytes in the adult brain. In the latter case, brain tumor development would involve the production of CD133.