Implications of Stem Cells and Cancer Stem Cells for Understanding Fomation and Therapy of Cancer

Most cancers are heterogeneous with respect to proliferation and differentiation. There is increasing evidence suggesting that only a minority of cancer cells, tumorigenic or tumor initiating cells, possess the capacity to proliferate extensively and form new hematopoietic cancer or solid tumors. Tumor initiating cells share characteristics required for normal stem cells. The dysregulation of self-renewal and proliferation of stem cells is a likely requirement for cancer development. This review formulates a model for the origin of cancer stem cells and regulating self-renewal which influences the way we study and treat cancer.     

Interleukin 1�� Sustains the Expression of Inflammatory Factors in Human Pancreatic Cancer Microenvironment by Targeting Cancer-Associated Fibroblasts

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic, with an extensive interaction between the stroma and tumor cells. The aim of this study was to delineate the cross talk between PDAC and cancer-associated fibroblasts (CAFs), with a focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effects of the cross talk between PDAC and CAF cell lines on the creation and sustenance of the inflammatory tumor microenvironment in pancreatic cancer. The coculture of PDAC and CAF cell lines enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGF-A, CCL20, and COX-2. CAFs were superior to tumor cells regarding the production of most inflammatory factors, and tumor cell-associated IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. Furthermore, we found a correlation between IL-1α and CXCL8 expression levels in PDAC tissues and correlation between IL-1α expression and the clinical outcome of the patients. This confirmed an important role for the IL-1 signaling cascade in the creation and sustenance of a tumor favorable microenvironment. Neutralization of the IL-1α signaling efficiently diminished the cross talk-induced production of inflammatory factors. These data suggest that the cross talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one essential factor in the formation of the inflammatory tumor environment, and we propose that neutralization of the IL-1α signaling might be a potential therapy for this cancer.     

Sublethal Irradiation Promotes Migration and Invasiveness of Prostate Cancer PC-3 Cells：Implications for Radiotherapy of Human Prostate Cancer

OBJECTIVE To study the changes in the matrix metalloproteinases-2 and 9 （MMP2, MMP9） induced by ^60Co γ-ray external irradiation of human prostate cancer PC-3 cells. METHODS Human prostate cancer PC-3 cells were irradiated with different doses of ^60Co γ-rays. Cell migration and invasiveness were evaluated and the expression of MMP2, and MMP9 was investigated by RT-PCR, Western blotting and flow cytometry（FCM）. RESULTS Irradiation enchances invasive protential at the doses of 1,3 and 5 Gy,whereas it significantly inhibits cell migration. CONCLUSION The different doses of ^60Co γ-ray external irradiation for prostate cancer may have different effects through the changes of MMP2, and MMP9 expression.     

TGFβ and Hypoxia Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment

Breast cancers frequently metastasize to bone, a site of hypoxia and high concentrations of active TGFβ. Skeletal metastases involve interactions between tumor and bone cells driven by locally secreted proteins, many of     

Preliminary Study on Biological Properties of Adult Human Bone Marrow-derived Mesenchymal Stem Cells

目的本研究拟建立成人骨髓间充质干细胞(mesenchymal stem cell,MSCs)体外培养和扩增的方法,探讨其生物学特性,为进一步将其应用于临床奠定理论和实验基础。方法取正常成人骨髓液5 mL,用Percoll分离液(密度1．073g/mL)经密度梯度离心法分离得到单个核细胞,以2×108个细胞／cm2的密度接种于含10％新生牛血清的LG-DMEM培养液。经培养、扩增后,进行倒置相差显微镜观察其形态,MTT法测定生长曲线,流式细胞仪行细胞表面抗原及细胞周期的检测,并在透射电镜下观察其超微结构。MtT法观察MSCs的免疫调节功能,观察MSCs对K562细胞生长的影响。检测MSCs培养上清中HA、IV-C、LN浓度的动态变化。结果培养扩增获取的成人骨髓MSCs形态均一,为梭形或纺锤形的成纤维细胞样外观,生长曲线示其增殖能力强。流式细胞仪检测显示有90％以上的细胞处于G0／G1期,表面标记物中CD4表达阳性,而造血细胞表面标志CD3、CD4、CD7、CD13、CD14、CD15、CD19、CD22、CD33、CD34、CD45和与移植排斥发生密切相关的HLA-DR表达阴性。超微结构显示细胞内有丰富的细胞器。成人骨髓MSCs抑制PHA诱导的异体淋巴细胞增殖转化,其增殖转化抑制率为60．68％(P<0．01)。抑制作用同样存在于培养上清中,其增殖转化抑制率为9．00％(P<0．05)。在有PHA刺激淋巴细胞增殖的情况下,培养上清中增殖转化抑制率达20．91％(P<0．01)。和单独的K562细胞生长曲线相比,与骨髓MSCs共孵育的K562细胞生长缓慢,无明显的指数生长期。由浓度变化曲线图可以看出,随着天数的延长,HA升高较迅速,而IV-C、LN则浓度变化不大。结论所建立的分离和培养方法可获取骨髓粘附细胞中一组独特的细胞群,具有MSCs的生物学特性。初步的生物学特性研究显示其具有免疫调节、抗肿瘤、造血支持等作用,可作为组织工程中的种子细胞。     

The Effect of Curcumin on Proliferation and Apoptosis in LNCaP Prostate Cancer Cells

OBJECTIVE To observe the effect of curcumin on proliferation and apop-tosis in the prostate cancer LNCaP cell line. METHODS The AXSYMTM system luciferase method was used to examine the effect of various concentratious of curcumin on the content of prostate specific antigen (PSA) in prostate cancer LNCaP cells. A pGL3-PSA luciferase expression vector, containing 640 bp DNA of the PSA gene 5' -promoter region was constructed and transfected into the LNCaP cells with lipofectin. By measuring luciferase activity, the effect of 10 μmol/L, 20 μmol/L, 30 and 40 μmol/L curcumin on the promoter was studied. Effects on cell growth and apoptosis were analyzed by microscopy, the MTT colorimetric assay and flow cytometry. Western-blotting was used to measure expression of the androgen receptor (AR) in the LNCaP cells treated with different concentrations of curcumin. RESULTS The results showed that the expression of PSA was inhibited as curcumin reduced the activity of luciferase. Curcumin also caused a sigificant concentration-dependent decrease in AR expession measured by Western -blotting. Cell growth was inhibited and apoptosis was induced. CONCLUSION By inhibiting AR expression, curcumin reduced the function of the PSA promoter and inhibited PSA protein expression. Curcumin decreased the cellular proliferation and induced apoptosis in LNCaP cells in a concention-dependent manner.     

68Ga-PSMA PET/CT Replacing Bone Scan in the Initial Staging of Skeletal Metastasis in Prostate Cancer: A Fait Accompli?

Purpose

⁶⁸Ga ligands targeting prostate-specific membrane antigen (PSMA) are rapidly emerging as a significant step forward in the management of prostate cancer. PSMA is a type II transmembrane protein with high expression in prostate carcinoma cells. We prospectively evaluated the use of ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer and compared the results to those for technetium-99m (^99mTc)-10-metacyloyloxydecyl dihydrogen phosphate (MDP) bone scintigraphy (BS).

Adenoviruses 16 and CV23 Efficiently Transduce Human Low-passage Brain Tumor and Cancer Stem Cells

Most clinical protocols involving adenovirus （Ad） vectors for gene therapy use a vector based on serotype 5 （Ad5）. We believe that this serotype is not suitable for all gene therapy applications and that alternative vectors based on other serotypes should be developed. We have compared the ability of Ad5, Adllp, Ad16p, and a chimpanzee Ad （CV23） to infect human low-passage brain tumor cells as well as primary glioma cells sorted into a CD133（＋） and CD133（-） population. Cancer stem cells have been shown to reside in the CD133（＋） population of cells in human glioma tumors and they are of considerable interest in glioma therapy.[第一段]     

TNFα as a Physiological Regulator of Hematopoietic Progenitor Cells:Increase of Early Hematopoietic Progenitor Cells in TNFR55--/-mice in vivo and Potent Inhibition of Progenitor Cell Proliferation by TNFα in Vitro

Murine lineage marker (Lin)^--Sca-1^ c-kit^ and Lin^-Sca-1^-c-kit^ cens represent the primitive hematopoietic stem cells (HSC)and coommitted hematopoietic progenitor cells(HPC),respectively. The number of Lin^-Sca-1^ c-kit^ HSCs in bone marrow was significantly increased (2.9folds) in tumor necrosis factor(TNF)-receptor-55(TNF-R55)-deficient mice compared with that of wildtype ones without marked change in cellularity of bone marrow.     

TNFα as a Physiological Regulator of Hematopoietic Progenitor Cells:Increase of Early Hematopoietic Progenitor Cells in TNFR55--/-mice in vivo and Potent Inhibition of Progenitor Cell Proliferation by TNFα in Vitro

Murine lineage marker (Lin) ~-Sca-l~ c-kit~ and Lin ~-Sca-l~- c-kit~ cells represent the primitive hematopoietic stem cells (HSC)and coommitted hematopoietic progenitor cells(HPC),respectively. The number of Lin ~-Sca-l~ c-kit ~ HSCs in bone marrow was significantly increased (2.9folds) in tumor necrosis factor(TNF)-receptor-55(TNF-R55)-deficient mice compared with that of wildtype ones without marked change in cellularity of bone marrow. Both in the methylcellulose culture and a single cell proliferation assay,mouse TNFα(mTNFα)inhibited in vitro the proliferation of wild type mouse-derived Lin-Sca-l~ c-kit~ cells stimulated with the combination of multiple growth factors as well as that of Lin ~-Sca-l~- c-kit~ cells stimulated with granulocyte-colony stimulating factor (G-CSF) plus stem cell factor (SCF).Human TNFα(hTNFα),which selectively binds to mouse TNF-R55 but not to mouse TNF-R75, exhibited similar spectrum of inhibitory effects as mTNFα     

Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: ‘Game Over’?

Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

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The Biological Effect of Hepsin on the Proliferation and Invasion of PC-3 Prostate Cancer Cells

OBJECTIVE Recent studies have shown that hepsin, a type of transmembrane serine protease, is highly upregulated in prostate cancer, but, little is known about its role in progression and invasion of this cancer. We constructed a hepsin-expressing plasmid and transfected it into PC-3 cells to investigate the effect of the hepsin gene on the biological behavior of the PC-3 cells. METHODS Plasmid pHepsin-IRES2 was transfected into prostate cancer PC-3 cells using Fugene6, and the cells with stable hepsin expression were screened and selected with Zeocin (600 mg/L). The hepsin mRNA level was measured by real-time PCR and the growth curve of the PC-3-transfected cells assessed using MTT and BrdU assays. A Boyden chamber was used to examine the difference in invasion and metastases between transfected and non-transfected cells. RESULTS The hepsin mRNA level in pHepsin-IRES2 transfected -PC-3 cells was significantly higher than that found in the control PC -3 cells. While the growth curve of the hepsin gene transfected PC -3 cells showed that there was no significant effect on proliferation, the invasive ability of the pHepsin-IRES2 transfected PC-3 cells, as compared with control cells, was significantly increased (P<0.05). CONCLUSION The results suggest that even though hepsin has no effect on the proliferation of prostate cancer PC-3 cells, it does promote cellular invasion and metastasis.Therefore hepsin may have a role in the development of prostate cancer.