Tumor stem cell, or its niche, which plays a primary role in tumorigenesis?

Cancer research over the past decades has focused on neoplastic cells, or a fraction of them, i.e. tumor stem cells, as the ultimate causes of tumorigenesis. However, during recent years, scientists have come to realize that tumorigenesis is not a solo act of neoplastic cells, but rather a cooperative process in which the roles of numerous types of non-neoplastic cells should be recognized. These tumor-residing non-neoplastic cells constitute the so-called tumor-associated stroma, which in certain cases even greatly surpasses the neoplastic cellular compartment that was previously thought of as a sole determiner leading to a seemingly autonomous growth pattern. In this review, we summarize several recent research highlights that have unveiled many previously unappreciated roles for microenvironmental factors, especially during the initiation stage of tumorigenesis. It is becoming increasingly clear that the stroma’s regulatory effects constitute not only an essential force for maintaining tumor growth, but also primary causes initiating tumorigenesis.

Bortezomib in treatment of extramedullary plasmacytoma of the pancreas

BACKGROUND: Extramedullary pancreatic plasmacytoma treated with bortezomib is rarely reported. METHODS: We admitted a 53-year-old woman with an asymptomatic mass above the left clavicle for over three months, then an asymptomatic swelling of the pancreas was found. A biopsy on the mass and a fine needle aspiration of the pancreas were performed. The diagnosis of extramedullary plasmacytoma (EMP) was made. The patient was initially treated with combination chemotherapy consisting of vincristine, doxorubicin and dexamethasone (VAD regimen). She progressed to painless jaundice during the chemotherapy. Then she was treated with bortezomib and hyper-dose dexamethasone. As a result, she had a near complete remission. RESULTS: The data demonstrated that the diagnosis was EMP of the pancreas. The patient responded very well to bortezomib, while failing to respond to the traditional chemotherapy regimen of VAD. CONCLUSION: EMP of the pancreas is rare. This case gives evidence for an excellent response of EMP of the pancreas to bortezomib. (Hepatobiliary Pancreat Dis Int 2009; 8: 329-331)

Local injection of endothelial progenitor cells can improve the hind -limb ischemic vascular disorder of diabetic rats

Objective To study the effect of aUotype endothelial progenitor cells （EPCs） injection on the hind-limb ischemic vascular disorder of diabetic rats. Methods EPCs of diabetic rats were isolated and cultured. Immunofluorescent assays were used to detect the expression of CD34, CD133 and Flk-1. EPCs were injected locally on the ischemic hind-limb area after labeled by DAPI.

Combined intensive preconditioning regimen allo-HSCT with imatinib for treatment of Ph chromosome positive acute lymphocyte leukemia

Objective To evaluate the outcome of combination of intensive preconditioning regimen allo - HSCT with imatinib for treatment of Ph chromosome positive acute lymphocyte leukemia ( ALL) . Methods Between 2009 and 2010,8 patients diagnosed as Ph + ALL received

Support of ex vivo expansion,homing and hematopoiesis reconstitution by differentiation inhibiting culture system in hematopoietic cells from mouse marrow

To explore whether differentiation inhibiting culture system (DICS) supports ex vivo expansion,homing and hematopoiesis reconstitution of hematopoietic cells from mouse marrow.Methods DISC were co-cultured with hemapoietic cells from mouse marrow for 7 days.The total number of cells,CFC and Sca-1+ cells were counted.The expanded cells from male donor were transplanted.To female recipients,the homing percentage of Y-Chromosome from male donor in FISH was measured 24 h after transplantation.The number of RBC,WBC and PLT in peripheral blood was counted 3,6,9,12,15,18,25,32 and 42 days after transplantation.Results The total number of cells,CFC and Sca-1+ cells were significantly increased.The homing of expanded cells was increased,and the number of RBC,WBC and PLT was recovered more quickly.Conclusion Differentiation inhibiting culture system (DICS) can support ex vivo expansion,homing and hematopoiesis reconstitution of hematopoietic cells from mouse marrow,and it is a good expansion system.13 refs,3 figs,1 tab.

Differentiation of transplanted fetal liver stem cell antigen-positive cells into neural cells in mice

To study whether stem cell antigen-positive (Sca-1+) cells from fetal liver can differentiate into neural cells.Methods Sca-1+ cells from male fetal liver were isolated with a magnetic cell sorting kit and transplanted into lethally irradiated female mice (2×103 cells/mouse).The donor cells and their characteristics in recipient brains were identified and detected by FISH and immunohistochemistry double-staining analysis at 2,4,6 months after transplantation.Results There existed many male cells in brains of female recipents,including white and gray matters,forbrain,midbrain,the ependyma of the ventricular system,and the choroid plexus of the lateral ventricle.Immunochemistry revealed that the Y chromosome-positive cells expressed many neural specific markers,including Neu N,TuJ-1,NF-M,GFAP and so on.Statistic analysis showed that ratio of Y chromosome-postitive cells in brain was (4.5±0.5)%,ratio of both Y chromosome and NeuN positive cells (1.2±0.3)%,ratio of both Y chromosome and GFAP postitive cells (1.0±0.2)%.There was no difference between the ratios of Y chromosome-positive cells in brains 2,4,and 6 month after transplantation.Conclusion Sca-1+ cells from fetal liver,the most of which are regarded as hematopoientic stem cells,can differentiate into neural cells and astrocytes in the brains of adult mice and survive more than 6 months.7 refs.

The more, the less： age and chemotherapy load are predictive of poor stem cell mobilization in patients with hematologic malignancies

Background Intensive treatment such as autologous peripheral blood stem cell （PBSC） transplantation is an important therapeutic strategy in many hematologic malignancies.A number of factors have been reported to impact PBSC mobilization,but the predictive factors varied from one study to another.This retrospective study assessed our current mobilization and collection protocols,and explored the factors predictive of PBSC mobilization in patients with hematologic malignancies.Methods Data of 64 consecutive patients with hematologic malignancies （multiple myeloma,n=22; acute leukemia,n=27; lymphoma,n=15） who underwent PBSC mobilization for over 1 year were analyzed.Four patients with response to treatment of near complete remission or better were administered granulocyte colony-stimulating factor （G-CSF） to mobilize PBSCs.Sixty patients received G-CSF followed by chemotherapy mobilizing regimens.Poor mobilization （PM） was defined as when ≤2.0×106 CD34＋ cells/kg body weight were collected within three leukapheresis procedures.Results The incidence of PM at the first mobilization attempt was 19% （12/64）.The PM group was older than the non-PM group （median age,51 vs.40 years; P=0.013）.In univariate analysis,there were no significant differences in gender,diagnosis,and body weight between the PM and non-PM groups.A combination of chemotherapy and G-CSF was more effective than G-CSF alone as a mobilizing regimen （P=0.019）.Grade Ⅲ or Ⅳ hematopoietic toxicity of chemotherapy had no significant effect on the mobilization efficacy.Supportive care and the incidence of febrile neutropenia were not significantly different between the two groups.In multivariate analysis,age （odds ratio （OR）,9.536;P=-0.002） and number of previous chemotherapy courses （OR 3.132; P=0.024） were two independent negative predictive factors for CD34＋ cell yield.PM patients could be managed well by remobilization.Conclusion Older age and a heavy load of previous chemotherapy are the negative risk factors for PBSC mobilization.

Bispecific antibody and its clinical applications in cancer

Bispecific antibody (BsAb) usually consists of two different antigen-binding arms, by which it is capable of simultaneously binding to target cells and effector cells, and can directly mediate the killing of target cells by retargeting and activating effector cells. The development of BsAb research goes through three main stages: chemical cross-linking of murine-derived monoclonal antibody, hybrid hy-bridomas and engineered BsAb. Among them, engineered BsAb has more formats than the other two, such as diabody, ScdHLX, ScZip, ScCH3, ScFab and BsIgG, etc. Compared with former murine-derived BsAbs, engineered BsAb has lower immunogenicity and stronger penetrating capacity, and currently, some of them appear suitable for clinical application in yields and qualities. Up to now, several phase I and phase II clinical studies of BsAb, for instance, some (Fab’)2 and Diabodies, have been performed. Among those BsAbs, anti-CD3/anti-tumor BsAbs is most common, they not only can activate T cell and induce CD3AK

Anti-human leukocyte antigens and anti-major histocompatibility complex class I-related chain A antibody expression in kidney transplantation during a four-year follow-up

Background Humoral immunity is an important factor for long-term survival of renal allograft. Here we performed a four-year follow-up to explore the clinical significance of monitoring anti-human leukocyte antigens （HLA） and anti-major histocompatibility complex class I-related chain A （MICA） antibody expression after kidney transplantation. Methods We obtained serial serum samples from 84 kidney transplant patients over a four-year period. All patients were followed up at least 6 months after transplantation and had at least two follow-up points. Anti-HLA and anti-MICA antibody titres and serum creatinine （SCr） levels were evaluated at each follow-up. Patients were divided into 4 groups： HLA（＋） MICA（-）, HLA（-）MICA（＋）, HLA（＋）MICA（＋） and HLA（-）MICA（-）. The impact of post-transplant antibody level on kidney allograft function was evaluated. Results Antibodies were detected in 38.1% （32/84） of the renal allograft recipients. HLA, MICA and HLA＋MICA expression was observed in 18.89%, 14.44% and 5.93% of the recipients respectively. The most frequent anti-HLA and anti-MICA specific antibodies identified were All, A24, A29, A32, A33, A80; B7, B13, B37; DR17, DR12, DR18, DR52, DR53, DR1, DR4, DR9, DR51; DQ7, DQ4, DQ8, DQ2, DQ9, DQ5, DQ6 and MICA02, MICA18, MICA19, MICA07, MICA27. As the time after transplantation elapsed, more recipients developed de novo antibody expression. Total 11.91% （10/84） of the recipients had de novo antibody expression during the follow up. The average level of SCr and the percentage of recipients with abnormal allograft function were significantly higher in recipients with anti-HLA and/or anti- MICA antibody expression than those without. The appearance of anti-HLA and anti-MICA antibody expression always preceded the increase in SCr value. Conclusions Anti-HLA and anti-MICA antibody expression has predictive value for early and late allograft dysfunction. The presence of donor specific antibody is detrimental to graft function and graft survival.

Hyper-CVAD chemotherapy or autologous stem cell transplantation in patients with peripheral T cell lymphomas： a single centre report

Background Peripheral T-cell lymphoma （PTCL） is generally characterized by poor prognosis after conventional chemotherapy. The place for high-dose chemotherapy and autologous stem cell transplantation （ASCT） in these patients is still not clear. In this study, we presented the outcomes of PTCL patients followed these treatments in our centre. Methods We retrospectively analyzed the outcomes of 39 patients with PTCL received the two treatments between 1999 and 2010. Results The 3-year overall survival （OS） of 61.9% and 3-year progression free survival （PFS） of 35.7% were observed in the 39 patient. Twenty-one patients received Hyper-CVAD chemotherapy with 3-year OS of 46.2% and 3-year PFS of 27.9%. Eighteen patients received ASCT with 3-year OS of 70.3% and 3-year PFS of 44.2%. Further analysis revealed that patients with elevated lactate dehydrogenase, at least 2 international prognostic index （IPI） points, and extranodal involvement had a poorer outcome compared with the control group. Conclusion These findings might suggest that Hyper-CVAD chemotherapy and ASCT could offer a durable survival benefit for patients with aggressive PTCL.

Recombinant sTRAIL induces cell death of tumor cell lines as well as primary cancer cells

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a new member of TNF family. It was reported that TRAIL could induce apoptosis of tumor cells but not normal cells in tissue culture system. To further study the biological activity and potential clinical significance, a recombinant soluble TRAIL (rsTRAIL) has been expressed stably in E. coli after transformation of pET28b vector containing the extracellular domain of TRAIL. The yield of rsTRAIL is approximately as high as 60% of whole bacterial proteins. The rsTRAIL, purified by Ni^+ -agarose affinity chromatography, could remarkably trigger apoptosis at the concentrations of 0.1—1 μg/mL in all 7 tumor cell lines tested in vitro. However, this killing activity has not been observed in mouse fibroblast cell line (NIH3T3) as normal control. Further investigation shows that the rsTRAIL could also kill primary tumor cells isolated freshly from patients with cardiac cancer, breast cancer and malignant thymoma, while the normal human

Cancer Cell：我国科学家有望开发出治疗急性髓性白血病的新疗法

近日，刊登在国际杂志Cancer Cell上的一项研究报告中，来自上海交通大学医学院等机构的研究人员通过研究发现了治疗急性髓性白血病（AML）的新型治疗靶点和新型疗法，急性髓性白血病是一种血液骨髓癌症，通常需要及时且积极的疗法对这种癌症进行治疗。

Receptor role of membrane bound macrophage colony-stimulating factor

According to the definition of cytokine, the direction of signaling should be from cytokine to receptor. The counter receptor was presented. Membrane bound macrophage colony-stimulating factor (m-M-CSF) and its receptor (M-CSF-R) were shown in human leukemic cell line J6-1 as autojuxtacrine mechanism. Soluble M-CSF receptor (sM-CSF-R), which was isolated from J6-1 cells membrane, was added into J6-1 cell culture. It was observed inhibition of J6-1 cell proliferation, decreasing of mitosis index and ratio of multinuclear cells, enlargement of cell diameter and volume, down regulation of numerous surface antigens. Dramatic change of intracellular pH was shown between several min to 20 min after treatment of sM-CSF-R. It suggested that some information was transmitted via m-M-CSF from sM-CSF-R. This counter signaling was not influenced by saccharification of m-M-CSF.

Signal transduction pathways mediated by colony stimulating factor-1 receptor

Colony-stimulating factor-1 (CSF-1), which is necessary for cell proliferation and differentiation, regulates both immediate and delayed early responses throughout G1 phase. The binding of CSF-1 to its receptor (CSF-1R) triggers phosphorylation of the receptor and its intrinsic tyrosine kinase. The activated receptor binds directly to cytoplasmic effector proteins, which induce multiple-signal transduction pathways. CSF-1 can induce the c-myc gene expression via Ras and Ets-related proteins. The expression of c-fos/jun family genes is also targeted following the activation of Ras. CSF-1R activates STAT1 and STAT3 to participate in signaling, but JAKs do not appear to contribute to signaling by CSF-1R. CSF-1R activates PI3-kinase, and PI3-kinase can interact with downstream proteins by the MAPKK-related pathway independent of Ras/Raf. PC-PLC can enforce signaling in response to CSF-1. Furthermore, the turnover and dephosphorylation by the phosphatase SHPTP1 of CSF-1R are the major mechanism in the negative regulation of signaling by CSF-1R.

Z-ajoene induces tumor cells to die by apoptosis

To unravel the pharmacological actions of garlic, a simple thiocompound, zajoene, was purified from the fresh cloves. Three tumor cell lines were subjected to treatment with zajoene at different concentrations in vitro and the morphological changes, DNA content of the cells and chromosome DNA fragmentation were observed by light microscopy, flow cytometry and agarose gel electrophoresis respectively. It was found that zajoene induced cell death by apoptosis in human HL60 promyelocytic leukemia cells, MGc803 gastric mucoid adenocarcinoma cells and Molt4 T lymphocyte leukemia cells. Western blot assay showed that z ajoene inhibited protooncogene bcl2 expression in the three different kinds of tumor cells, suggesting that zajoene may be a potential agent for tumor chemotherapy.