39 research outputs found
RESIDUAL DORMANT CANCER STEM CELL FOCI ARE RESPONSIBLE FOR TUMOR RELAPSE AFTER ANGIOGENIC METRONOMIC THERAPY IN HEPATOCELLULAR CARCINOMA XENOGRAFTS
No full textHepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related death. Current available chemotherapeutic options are not curative due in part to their resistance to conventional therapies.
We have generated orthotopic HCC mouse models in immunodeficient NOD/SCID/IL2rγ null mice by injection of AFP- and/or luciferase-expressing HCC cell lines and primary cells from patients, where tumor growth and spread can be accurately monitored in a non-invasive way. Low dose metronomic administration of cyclophosphamide (LDM-CTX) causes in this model complete regression of the tumor mass with a significant increase in survival (p<0.0001), and reduction in aberrant angiogenesis, IL-6 and TNFα (but not VEGF) levels, hyperproliferation, and alteration of normal liver parenchyma, compared to untreated animals. However, the presence of residual circulating hAFP levels suggested that some tumor cells were still present in livers of treated mice. Immunohistochemistry revealed that those cells had a hAFP+/CD13+/PCNA- phenotype, suggesting that they were dormant cancer stem cells (CSC). Indeed, off-therapy mice developed rapidly tumor growth, which was still sensitive to LDM-CTX therapy. The capacity of developing hepatoshperes in vitro was drastically reduced upon LDM-CTX treatment, which resulted in selection of CD13+ cells, showing that these cells are particularly resistant to therapy. Co-treatment of the CD13-targeting drug bestatin with LDM-CTX resulted in a dramatic reduction in tumor burden.
Therefore, our results demonstrate the therapeutic efficacy of administering LDM-CTX and targeting the residual CD13+ CSC-like population in these novel orthotopic HCC models, and strongly suggests that this therapy could be implemented in clinical trials
Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains
No full textTransplantation of human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) primary cells and cell lines in different strains of immunodeficient mice has led to preclinical models extensively used to investigate acute leukemia stem cells, biology and drug sensitivity. We studied the engraftment kinetics of AML and ALL cell lines and primary cells in 3 strains of NOD.CB17-Prkdc(scid) (NOD/scid, NS)-related mice (NOD.Cg-Prkdc(scid)B2m(tm1Unc)/J, abbreviated NOD/scid/beta2 null, NSB; and NOD.Cg-Prkdc(scid)Il2rg(tm1Wjll)/SzJ, abbreviated NOD/scid/IL-2Rgamma null, NSG). The engraftment of human malignant cells was investigated by means of clinicopathological criteria, flow cytometry, PCR and immunohistochemistry. In NSG mice, we observed a significantly faster development of leukemia-related symptoms and a higher percentage of leukemia cells in the blood, in the marrow and in the spleen. The leukemia-related angiogenic switch (measured as the number of circulating endothelial cells and progenitors) was faster in NSG compared to NS and NSB mice. These models will be instrumental to studies on leukemia-initiating stem cells, leukemia biology, preclinical treatment studies, and to obtain patient-specific preclinical models to design and investigate patient-tailored therapies. (c) 2008 Wiley-Liss, In
Spontaneous Cell Fusion of Acute Leukemia Cells and Macrophages Observed in Cells with Leukemic Potential
No full textCell fusion plays a well-recognized physiological role during development, while its function during progression is still unclear. Here, we show that acute myeloid leukemia (AML) cells spontaneously fused with murine host cells in vivo. AML cells fused in most cases with mouse macrophages. Other targets of AML cell fusion were dendritic and endothelial cells. Cytogenetic and molecular analysis revealed that successive recipients conserved detectable amounts of parental DNA. Moreover, in a mouse AML1-ETO model where female AML1-ETO-leukemic cells, expressing CD45.2, were injected in congenic CD45.1 male mice AML cells, we found hybrid cells expressing both allelic types of CD45 and XXY set of sexual chromosomes. More importantly, the fusion protein AML1-ETO was transferred in the hybrid cells. When sorted hybrid cells were reinjected in a secondary recipient, they gave rise to leukemia with 100% penetrance and similar time of onset of leukemic cells. Our data indicate that in vivo fusion of cancer cells with host cells may be a mechanism of gene transfer for cancer dissemination and suggest that fused cells may be used to identify still unrecognized leukemogenic genes that are conserved in hybrid cells and able to perpetuate leukemia in vivo
The white adipose tissue used in lipotransfer procedures is a rich reservoir of CD34+ progenitors able to promote cancer progression
No full textPrevious studies have suggested a "catalytic role" in neoplastic angiogenesis and cancer progression for bone marrow-derived endothelial progenitor cells (EPC). However, preclinical and clinical studies have shown that the quantitative role of marrow-derived EPCs in cancer vascularization is extremely variable. We have found that human and murine white adipose tissue (WAT) is a very rich reservoir of CD45-CD34(+) EPCs with endothelial differentiation potential, containing a mean of 263 times more CD45-CD34(+) cells/mL than bone marrow. Compared with marrow-derived CD34(+) cells mobilized in blood by granulocyte colony-stimulating factor, purified WAT-CD34(+) cells expressed similar levels of stemness-related genes, significantly increased levels of angiogenesis-related genes, and increased levels of FAP-alpha, a crucial suppressor of antitumor immunity. In vitro, WAT-CD34(+) cells generated mature endothelial cells and capillary tubes as efficiently as mature mesenchymal cells. The coinjection of human WAT-CD34(+) cells from lipotransfer procedures contributed to tumor vascularization and significantly increased tumor growth and metastases in several orthotopic models of human breast cancer in immunodeficient mice. Endothelial cells derived from human WAT-CD34(+) cells lined the lumen of cancer vessels. These data indicate that CD34(+) WAT cells can promote cancer progression and metastases. Our results highlight the importance of gaining a better understanding of the role of different WAT-derived cells used in lipotransfer for breast reconstruction in patients with breast cancer
Estudio experimental de las características del viento incidente sobre estructuras en caso de terrenos complejos
No full textFil: Wittwer, Adrián Roberto. Universidad Nacional del Nordeste. Facultad de Ingeniería; Argentina.Fil: Loredo Souza, Acir Mércio. Universidade Federal de Rio Grande do Sul; Brasil.Fil: Klaus Oliveira, Mario Gustavo. Universidade Federal de Rio Grande do Sul; Brasil.Fil: Marighetti, Jorge Omar. Universidad Nacional del Nordeste. Facultad de Ingeniería; Argentina.Fil: De Bortoli, Mario Eduardo. Universidad Nacional del Nordeste. Facultad de Ingeniería; Argentina.En el caso de estructuras sensibles a la acción aerodinámica, las características del viento incidente
se ven modificadas por la topografía circundante provocando variaciones de las cargas
aerodinámicas respecto a las que se podrían prever en caso de terrenos planos. Los Reglamentos
de Viento incorporan factores vinculados a las características topográficas que permiten tener en
cuenta estas modificaciones para las situaciones más comunes. En casos más complejos es
necesario realizar simplificaciones que pueden disminuir la confiabilidad en el cálculo, o bien
utilizar el túnel de viento que permite un análisis más adecuado de este tipo de efecto. En este
estudio se presentan los resultados obtenidos en dos estudios experimentales realizados en el túnel
de viento “Jacek P. Gorecki” de la UNNE, utilizando modelos a escala, para terrenos complejos
de características diferentes. Los casos evaluados corresponden a un edificio de gran altura y a un
puente atirantado de dimensiones importantes. Los resultados obtenidos a partir de mediciones de
valores medios y fluctuantes de velocidad de viento son analizados y comparados con datos de
referencia, para su aplicación en términos de la Normativa de Vientos
Investigation of BCRP-inhibitors using QSAR and machine learning methods
No full textBCRP is the second member of the subfamily G of the ABC transporters. BCRP is involved in several physiological functions, including protection of the human body from xenobiotics. The overexpression of this membrane protein in certain tumor cell lines leads to cross-resistance against various chemotherapeutic drugs. In this work, the inhibitory activity of several compounds against BCRP and P-gp were assayed using a Hoechst 33342 assay for BCRP and a Calcein AM assay for P-gp. Furthermore, the potency of the studied compounds has been rationalized using a classical QSAR approach. Finally, three machine learning algorithms (Self-Organizing Maps, Support Vector Machine and k-Nearest Neighbors) were used, in order to generate a global model useful to predict if small ligands could be (or not) BCRP-inhibitors
Complementary populations of human adipose CD34+ progenitor cells promote growth, angiogenesis, and metastasis of breast cancer
No full textObesity is associated with an increased frequency, morbidity, and mortality of several types of neoplastic diseases, including postmenopausal breast cancer.Wefound that human adipose tissue contains two populations of progenitors with cooperative roles in breast cancer. CD45CD34þCD31þCD13CCRL2þ endothelial cells can generate mature endothelial cells and capillaries. Their cancer-promoting effect in the breast was limited in the absence of CD45CD34þCD31CD13þCD140bþ mesenchymal progenitors/adipose stromal cells (ASC), which generated pericytes and were more efficient than endothelial cells in promoting local tumor growth. Both endothelial cells and ASCs induced epithelial-to-mesenchymal transition (EMT) gene expression in luminal breast cancer cells. Endothelial cells (but not ASCs) migrated to lymph nodes and to contralateral nascent breast cancer lesions where they generated new vessels. In vitro and in vivo, endothelial cells were more efficient than ASCs in promoting tumor migration and in inducing metastases. Granulocyte colony-stimulating factor (G-CSF) effectively mobilized endothelial cells (but not ASCs), and the addition of chemotherapy and/or of CXCR4
inhibitors did not increase endothelial cell or ASC blood mobilization. Our findings suggest that adipose tissue progenitor cells cooperate in driving progression and metastatic spread of breast cancer
Evidence of distinct tumour-propagating cell populations with different properties in primary human hepatocellular carcinoma.
No full textIncreasing evidence that a number of malignancies are characterised by tumour cell heterogeneity has recently been published, but there is still a lack of data concerning liver cancers. The aim of this study was to investigate and characterise tumour-propagating cell (TPC) compartments within human hepatocellular carcinoma (HCC).After long-term culture, we identified three morphologically different tumour cell populations in a single HCC specimen, and extensively characterised them by means of flow cytometry, fluorescence microscopy, karyotyping and microarray analyses, single cell cloning, and xenotransplantation in NOD/SCID/IL2Rγ/⁻ mice.The primary cell populations (hcc-1, -2 and -3) and two clones generated by means of limiting dilutions from hcc-1 (clone-1/7 and -1/8) differently expressed a number of tumour-associated stem cell markers, including EpCAM, CD49f, CD44, CD133, CD56, Thy-1, ALDH and CK19, and also showed different doubling times, drug resistance and tumorigenic potential. Moreover, we found that ALDH expression, in combination with CD44 or Thy-1 negativity or CD56 positivity identified subpopulations with a higher clonogenic potential within hcc-1, hcc-2 and hcc-3 primary cell populations, respectively. Karyotyping revealed the clonal evolution of the cell populations and clones within the primary tumour. Importantly, the primary tumour cell population with the greatest tumorigenic potential and drug resistance showed more chromosomal alterations than the others and contained clones with epithelial and mesenchymal features.Individual HCCs can harbor different self-renewing tumorigenic cell types expressing a variety of morphological and phenotypical markers, karyotypic evolution and different gene expression profiles. This suggests that the models of hepatic carcinogenesis should take into account TPC heterogeneity due to intratumour clonal evolution
Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34- cell population with intrinsic resistance to imatinib.
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