Biomedical subjects

Thomas Dittmar

Publications and source records attributed to Thomas Dittmar.

8 recordsLinked to original sources

PubMed2006

Carcinogenesis driven by bone marrow-derived stem cells.

The overall mechanism of bone marrow-derived stem cell (BMDC) trans-differentiation seems to be simple: BMDCs trans-differentiate as referred to the blueprint, which is given by the tissue itself. Thereby, the blueprint can be the local tissue micro-environment (defined by the tissue-specific cytokine, chemokine, adhesion molecule pattern, etc.), it can be a single cell (cell fusion), or it can be a combination of both. In fact stem cell trans-differentiation is a complex not yet fully understood process. In between the start- and stop-points of transdifferentiation several gene reprogramming steps have to occur in a sequential step-by-step manner, for which a defined set of instructions is a prerequisite to ensure an accurate transdifferentiation. However, a recent study indicated that the ability of BMDCs - to adopt tissue function by reading its blueprint - seems to be a double-edged sword since BMDCs that have received a faulty blueprint, provided by chronically inflamed tissue, trans-differentiated into a neoplastic phenoytpe. Here, we review the importance of an accurate blueprint for BMDC trans-differentiation and discuss a model showing that BMDCs might contribute to overall tumor development due to recruitment to tumor tissue.

Animals↗

PubMed2006

Visualization of tumor cell extravasation.

In cancer the blood-borne spread of tumor cells leads to the formation of secondary tumors at distant loci, whereby the extravasation of tumor cells is a prerequisite step during hematogenous metastasis. In regard to the fate of endothelial cells located at the site of tumor cell infiltration, tumor cell-endothelial interactions were analyzed using an in vitro real-time model. This model shows the complete sequence of the transmigration process and gave new insights into the complex and dynamic cell-cell and cell-matrix interactions which occur during tumor cell transmigration across the endothelial barrier. An in vitro real-time apoptosis assay permits the distinction between apoptotic cell death from necrotic cell death. This model indicates that transmigration of tumor cell clusters derived from the invasive human bladder carcinoma cell line T24 irreversibly damages the endothelial cells by inducing apoptosis at the site of tumor cell infiltration. It is postulated here that apoptosis induction facilitates the removal of detached endothelial cells, thereby forestalling a local inflammatory response which might be detrimental to extravasating tumor cells.

Cell Communication↗

PubMed2005

The Viscum album extract Iscador P does not cause an autocrine interleukin-6 loop in B-Non-Hodgkin's Lymphoma cell lines.

BACKGROUND: Single cases of clinical observations suggest the efficacy of the Viscum album (VA) extract Iscador P in the treatment of follicular B-Non-Hodgkin's Lymphoma (B-NHL). A previously published study aroused a controversial dispute as it indicated that IL-6 serum levels are elevated following i.v. VA treatment. Increased IL-6 levels have been shown to promote the progression of B-cell neoplasia such as B-NHL. Objective of this study was to investigate whether the VA extract influences the expression of IL-6 and its receptor components in follicular B-NHL cell lines. METHODS: Follicular B-NHL cell lines (WSU-NHL, DoHH-2) were incubated with clinically relevant doses of VA extract for up to 3 days. At specified time points (6, 24, 48, 72 h) samples were taken and the expression of IL-6 and its receptor components were analysed by real-time-RT-PCR, flow cytometry and ELISA. RESULTS: Treatment of follicular B-NHL cell lines with VA extract did not alter the expression level of IL-6 and its' receptor components at any time and with any of the applied VA extract concentrations. CONCLUSIONS: Clinically relevant doses of the VA extract do not trigger an autocrine or paracrine IL-6 loop nor do they initiate IL-6 trans-signalling in follicular B-NHL cell lines.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Role of the beta1-integrin subunit in the adhesion, extravasation and migration of T24 human bladder carcinoma cells.

The abilities of tumor cells to extravasate from the blood vessel system and to migrate through the connective tissue are prerequisites in metastasis formation. Both processes are chiefly mediated by integrins, which mediate both cell-cell and cell-matrix interactions. We investigated the role of integrin subunits in the adhesion, extravasation and migration of the highly invasive human bladder carcinoma cell line T24. Here we show that inhibition of the beta(1)-integrin subunit using the specific beta(1)-integrin blocking antibody 4B4 significantly reduces the adhesion to HUVEC and transmigratory activity of T24 cells. The blockade of the beta(1)-integrin subunit also resulted in a significantly reduced locomotory activity of T24 cells. A detailed cell migration analysis on a single cell level revealed that blockade of the beta(1)-integrin subunit leads to an altered migration pattern of single cells but does not influence migration per se. Migration parameters such as time active, velocity and distance migrated were significantly reduced as compared to untreated control cells. Our observations strongly suggest a central role for the beta(1)-integrin subunit in forming the cell-cell and cell-matrix bonds necessary for adhesion, extravasation and migration.

Carcinoma↗

PubMed2005

3D-extravasation model -- selection of highly motile and metastatic cancer cells.

Extravasation has been described as a rate-limiting step in the process of hematogeneous metastasis formation. Thereby, transendothelial migration of tumor cells consists of a complex series of events involving multiple cell-cell and cell-matrix interactions. 3D-extravasation assays are valuable tools for the identification of genes, which are the key players at switchboards of the intracellular signaling pathways. In consequence, the combination of 3D-modeling and whole genome expression analysis lead to unravel molecular parameters which descripe distinct clinical phenotypes of cancer and therefore, work as prognosticators, predictors of therapy and new therapy targets.

Cell Movement↗

PubMed2004

Differential effects of culture conditions on the migration pattern of stromal cell-derived factor-stimulated hematopoietic stem cells.

Evidence is mounting that hematopoietic stem cells (HSCs) play a critical role in bone marrow regeneration and tissue renewal, for which migration is an obvious prerequisite. Computer-aided analysis and a three-dimensional collagen matrix assay enabled us to analyze single-cell migratory characteristics of stromal cell-derived factor-1 alpha (SDF-1 alpha)-stimulated cord blood-derived HSCs. We defined and resolved specific migratory parameters in spontaneous and SDF-1 alpha-induced migration of these cells. The addition of interleukin 6 to the culture medium led to differential SDF-1 alpha-stimulated migratory response, which comprised a recruitment of nonmoving cells and an increase in speed and frequency of pauses but a decrease in pause duration. We were thus able to decipher the exact parameters that result in an increase in the migration of HSCs and demonstrate that extensive analysis of single-cell behavior is elementary in the study of stem cell migration.

AC133 Antigen↗

PubMed2003

The protein tyrosine phosphatase PTP-BL associates with the midbody and is involved in the regulation of cytokinesis.

PTP-BL is a highly modular protein tyrosine phosphatase of unknown function. It consists of an N-terminal FERM domain, five PDZ domains, and a C-terminally located tyrosine phosphatase domain. Here we show that PTP-BL is involved in the regulation of cytokinesis. We demonstrate localization of endogenous PTP-BL at the centrosomes during inter- and metaphase and at the spindle midzone during anaphase. Finally PTP-BL is concentrated at the midbody in cytokinesis. We show that PTP-BL is targeted to the midbody and centrosome by a specific splicing variant of the N-terminus characterized by an insertion of 182 amino acids. Moreover, we demonstrate that the FERM domain of PTP-BL is associated with the contractile ring and can be cosedimented with filamentous actin, whereas the N-terminus can be cosedimented with microtubules. We demonstrate that elevating the expression level of wild-type PTP-BL or expression of PTP-BL with an inactive tyrosine phosphatase domain leads to defects in cytokinesis and to the generation of multinucleate cells. We suggest that PTP-BL plays a role in the regulation of cytokinesis.

Actins↗

PubMed2002

Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR.

Induction of tumor cell migration is a key step in invasion and metastasis. Here we report that the epidermal growth factor (EGF)-induced cell migration of breast cancer cells is attributed to a transient, rather than a sustained, activation of phospholipase C (PLC)-gamma1 due to c-erbB-2 signaling. EGF stimulation of EGF receptor (EGFR) overexpressing cells resulted in long-term PLC-gamma1 tyrosine phosphorylation and sustained levels of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) producing sinusoidal calcium oscillations. In contrast, c-erbB-2/EGFR expressing cells displayed baseline transient calcium oscillations after EGF treatment due to short-term PLC-gamma1 tyrosine phosphorylation and short-term IP3 and DAG turnover. A third cell line expressing a point-mutated c-erbB-2 receptor that lacks the autophosphorylation Y1248 was generated to investigate whether the different PLC-gamma1 activation was attributed to this structure. Neither PLC-gamma1 tyrosine phosphorylation nor IP3 and DAG turnover and calcium oscillations were observed in this cell line, indicating the modulation of the PLC-g1 activation time course by c-erbB-2 signaling. Induction of cell migration was solely observable in the c-erbB-2-positive cell line as proved by the mode of actin reorganization and a cell migration assay, using a 3D-collagen lattice. In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation.

Calcium↗