Biomedical subjects

Kurt S Zaenker

Publications and source records attributed to Kurt S Zaenker.

At least 19 recordsLinked to original sources

PubMed2006

The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers.

The development of metastases is a decisive step in the course of a cancer disease. The detection of metastases in cancer patients is correlated with a poor prognosis, and over 90% of all deaths from cancer are not due to the primary tumor, which often can be successfully treated, but are due to the metastases. Tumor cell migration, a prerequisite for metastasis development, is not merely genetically determined, but is distinctly regulated by signal substances of the environment including chemokines and neurotransmitters. We have shown previously that the migration of breast, prostate, and colon carcinoma cells is enhanced by the stress-related neurotransmitter norepinephrine in vitro, and that this effect can be inhibited by the beta-blocker propranolol. We now provide for the first time evidence for the in vivo relevance of this neurotransmitter-driven regulation using PC-3 prostate carcinoma cells. The development of lumbar lymph node metastases in athymic BALB/c nude mice increased with the application of norepinephrine via microosmotic pumps, while propranolol inhibited this effect. However, the growth of the primary tumor was not affected by either treatment. Additionally, experiments using human tissue microarrays showed that 70-90 percent of breast, colon, and prostate carcinoma tissues express the relevant beta2-adrenoceptor. Thus, our work contributes to the understanding of the basic cellular mechanisms of metastasis development, and furthermore delivers a rationale for the chemopreventive use of clinically established beta-blockers for the inhibition of metastases.

Adrenergic beta-Antagonists↗

PubMed2006

Neoneurogenesis: tumors may initiate their own innervation by the release of neurotrophic factors in analogy to lymphangiogenesis and neoangiogenesis.

Malignant tumors frequently release angiogenic factors, which lead to the vascularization of the tumor, a process called neoangiogenesis. This neoangiogenesis provides sufficient nourishment of the tumor when it exceeds a certain size. Recently, a similar mechanism has been postulated for the development of new lymph vessels in tumors, termed lymphangiogenesis. Thus, tumors get access to the circulation and lymph drainage like any other growing or regenerating tissue. Furthermore, it has been hypothesized that neoangiogenesis and lymphangiogenesis support metastasis development. Elaborating on this model, we herein present strong arguments for the new theory that tumors initiate their own innervation by the release of neurotrophic factors in analogy to lymphangiogenesis and neoangiogenesis. For this process, we coin the term neoneurogenesis. It is likely that neoneurogenesis further supports the formation of metastases, since the ingrown nerve endings can release neurotransmitters which enhance the metastasis development. Strikingly, the presence of nerve cell markers in tumor tissues has been shown to be a prognostic marker for the course of a cancer disease, and we have recently reported on the metastasis-increasing function of the neurotransmitter norepinephrine in a mouse model.

Animals↗

PubMed2006

Tumor immune escape mechanisms: impact of the neuroendocrine system.

Tumor cells act upon, and react to both their proximate and more distant environment, the mechanisms by which this is achieved being both autocrine and paracrine in nature. This interaction, however, takes place not only between adjacent malignant cells, but also non-malignant cells such as those of the immune system, the latter also partaking in the modeling of the tumor environment. Although tumor cells descend from normal tissue cells and thus bear in classical immunological terms 'self signals', it is evident that the immune system is able to recognize tumor cells as a harassment for the body and in consequence tries to eliminate these cells. On the counterpart, tumor cells acquire various characteristics which allow them to evade this immunological surveillance, and have been collectively coined with the term "tumor escape mechanisms". This review will describe and summarize current understanding of tumor escape strategies, and also more closely elaborate on the modulatory role of the neuroendocrine system in the immune system-tumor cell interaction.

Animals↗

PubMed2006

Phosphatidylinositol 3-kinase in the G protein-coupled receptor-induced chemokinesis and chemotaxis of MDA-MB-468 breast carcinoma cells: a comparison with leukocytes.

The polarization of tumor cells and leukocytes into a front end and a rear end is a crucial prerequisite for their autonomous, directed movement. Phosphatidylinositol 3-kinase (PI3K) is assumed to play an important role in this polarization process, whereas the results obtained with different cell types and different migration assays widely vary. Thus, we conducted a comparative study on the role of the PI3K in the locomotor activity and directionality of the migration of tumor cells on the example of MDA-MB-468 breast carcinoma cells in comparison with CTLs and neutrophil granulocytes. We used our well-established, collagen-based, three-dimensional migration assay for the investigation of the chemokinesis and chemotaxis of these cells. Our results show that the role of the PI3K in the regulation of migratory activity is distinct between the investigated cell types: the migration of CTLs and MDA-MB-468 cells was impaired by the inhibition of the PI3K with wortmannin, whereas neutrophil granulocytes were only slightly affected. However, neither cell type was impaired in the ability to respond chemotactically to gradients of ligands to G protein-coupled receptors. Thus, the PI3K contributes to the regulation of migratory activity but not to the directionality of migration of MDA-MB-468 breast carcinoma cells. As a further conclusion with regard to cancer treatment, the PI3K is not a suitable target for the inhibition of metastasis formation, because the migration of leukocytes is also affected, which leads to a dysfunction of the immune defense.

Breast Neoplasms↗

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↗

PubMed2006

Infection, inflammation and neoplasia: an interdisciplinary challenge.

During the past two to three decades there has been an exciting revolution in our understanding of the multistage carcinogenic process and of the molecular genetics of cancer. The general principle of multifactor interactions is central to our understanding of cancer causation. The paradigm that persistent infections and chronic inflammation contributes via cytokine- and chemokine-mediated disbalanced immune response to carcinogenesis becomes more and more attractive in cancer research. Besides genetic factors, the epigenetics of impaired cell signaling and signal transduction by proinflammatory cytokines and chemokines are important potentiators of carcinogenesis. The activation of the nuclear factor kappaB, for example, a hallmark of inflammatory responses that is frequently detected in tumors, might constitute a missing link between inflammation and cancer. It will be a challenge for future therapeutic and preventive cancer research to detect potential targets in chronic inflammatory disease which are essential links to promote inflammation-associated cancer.

Animals↗

PubMed2005

Analysis methods of human cell migration.

The autonomous migration of specialized cells is an essential characteristic in both physiological and pathological functions in the adult human organism. Leukocytes, fibroblasts, and stem cells, but also tumor cells, are thus the subject of intense investigation in a broad range of research fields. A wide spectrum of methods have therefore been established to analyze chemokinetic and chemotactic cell migration, ranging from easy-to-handle two-dimensional surface migration assays to highly specialized three-dimensional and intravital analysis methods. It is now manifest that the results obtained with these various migration assays substantially differ. This review therefore gives an overview of the migration assays which are currently in use, describes the methods, and critically enlightens the particular advantages and disadvantages of each method.

Cell Movement↗

PubMed2005

In vitro and in vivo imaging of cell migration: two interdepending methods to unravel metastasis formation.

Metastasis development requires the migratory activity of tumor cells. It is therefore important to understand the molecular mechanisms of this migration in order to prevent metastasis development, which is the pernicious step in most solid tumor diseases. A lot of methods have been invented to investigate tumor cell migration, but not all are equally suited and no method alone is able to deliver a complete picture of tumor cell migration. We herein suggest a combination of three-dimensional in vitro and in vivo methods for the investigation of tumor cell migration and summarize the knowledge, which has been reached so far.

Animals↗

PubMed2005

Neurotransmitters and chemokines regulate tumor cell migration: potential for a new pharmacological approach to inhibit invasion and metastasis development.

The migration of tumor cells is a prerequisite for tumor cell invasion and metastasis development, which accounts for over 90% of cancer mortality. Therefore a major focus of current tumor biological research is the study of those factors that regulate tumor cell migration. Those chemokines and neurotransmitters that bind to G-protein coupled receptors (also known as serpentine receptors) are the most prominent of these factors. Neurotransmitters have been identified that have not only a stimulatory (e.g. norepinephrine) effect, but an inhibitory effect (e.g. GABA) as well. This is an especially fortuitous development, because many known agonists and antagonists of neurotransmitter receptors are currently being successfully used in the treatment of other pathological conditions (e.g. beta-blockers in the treatment of cardiovascular diseases). Likewise, chemokine receptor antagonists, which are under development for the treatment of HIV or rheumatoid arthritis, may be effective tools for the inhibition of chemokine-driven tumor cell migration as well. A further approach to inhibit tumor cell migration arises from the investigation of the relevant signal transduction pathways. The PKC alpha, for example, is a key enzyme in the regulation of tumor cell migration, but not of leukocyte migration. It thus offers a selective target opportunity for specific pharmacological agents to interfere with tumor cell migration. In this review we therefore summarize the current findings on those serpentine receptors involved in the neurotransmitter- and chemokine-regulated tumor cell migration, on the underlying signal transduction pathways, and on the opportunities to inhibit tumor cell migration and ultimately metastasis development with pharmaceutical agents.

Cell Movement↗

PubMed2004

Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs.

The active migration of tumor cells, a crucial requirement for metastasis development and cancer progression, is regulated by signal substances including neurotransmitters. We investigated the migration of tumor cells within a three-dimensional collagen matrix using time-lapse videomicroscopy and computer-assisted analysis of the migration path. Tumor cell migration is induced by norepinephrine, dopamine and substance P. We show that this induced migration, using MDA-MB-468 breast and PC-3 prostate carcinoma cells, can be inhibited by using specific, clinically established receptor antagonists to the beta2-adrenoceptor, the D2 receptor, or the neurokinin-1 receptor, respectively. All of the investigated neurotransmitters significantly activated the cyclic adenosine-monophosphate response element binding protein (CREB). Furthermore, microarray analysis revealed changes of gene expression toward a highly motile tumor cell type, including an upregulation of the alpha2 integrin, which is an essential adhesion receptor for collagen in migration. The gene for the tumor suppressor gelsolin was downregulated. These 2 critical alterations were confirmed on the protein level by flow-cytometry and immunoblotting, respectively. Neurotransmitters thus induce a metastatogenic tumor cell type by directly regulating gene expression and increased migratory activity, which can be prevented by established neurotransmitter antagonists.

Breast Neoplasms↗

PubMed2004

Tumor cell locomotion: differential dynamics of spontaneous and induced migration in a 3D collagen matrix.

Although great strides have recently been made in elucidating the factors initiating tumor cell migration and the relevant cellular pathways involved, the constituent components of migratory dynamics for individual tumor cell motion have still not been resolved. Utilizing a three-dimensional (3D) collagen assay and computer-assisted, continuous single cell tracking, we investigated the basic parameters for both the spontaneous and norepinephrine-induced migration of highly metastatic MBA-MB-468 breast, PC-3 prostate, and SW 480 colon carcinoma cells. We show that tumor cells do not migrate with uniform migrational structure and speed as previously thought, but rather, the induction of locomotion elicits significant increases in speed, break frequency, and total cell displacement, but decreases in break length and no change in the recruitment of nonlocomotory cells. We furthermore illustrate the corresponding morphological changes of induced tumor cell migration with emphasis on motion in a collagen matrix. These results demonstrate the complexity of tumor cell migration, and the compulsion for incorporating not only knowledge of intracellular pathways, but also fundamental parameters of migratory behavior into any expansive theory of tumor cell migration and metastasis formation. We furthermore establish the analytical methodology of investigating both the stimulation and potential pharmaceutical inhibition of tumor cell migration.

Biological Assay↗

PubMed2004

Anandamide is an endogenous inhibitor for the migration of tumor cells and T lymphocytes.

Cell migration is of paramount importance in physiological processes such as immune surveillance, but also in the pathological processes of tumor cell migration and metastasis development. The factors that regulate this tumor cell migration, most prominently neurotransmitters, have thus been the focus of intense investigation. While the majority of neurotransmitters have a stimulatory effect on cell migration, we herein report the inhibitory effect of the endogenous substance anandamide on both tumor cell and lymphocyte migration. Using a collagen-based three-dimensional migration assay and time-lapse videomicroscopy, we have observed that the anandamide-mediated signals for CD8+ T lymphocytes and SW 480 colon carcinoma cells are each mediated by distinct cannabinoid receptors (CB-Rs). Using the specific agonist docosatetraenoylethanolamide (DEA), we have observed that the norepinephrine-induced migration of colon carcinoma cells is inhibited by the CB1-R. The SDF-1-induced migration of CD8+ T lymphocytes was, however, inhibited via the CB2-R, as shown by using the specific agonist JWH 133. Therefore, specific inhibition of tumor cell migration via CB1-R engagement might be a selective tool to prevent metastasis formation without depreciatory effects on the immune system of cancer patients.

Adrenergic alpha-Agonists↗

PubMed2004

Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters.

Cancer starts as a localised disease, which, if detected early, can often be treated successfully by removal of the primary tumour. A pernicious progression is the invasion of tumour cells into surrounding tissues, resulting in development of distant metastases. Because active migration of tumour cells is a prerequisite for tumour-cell invasion and metastasis, a pressing goal in tumour biology has been the elucidation of factors regulating the migratory activity of these cells. The most prominent regulatory factors are ligands to serpentine receptors-eg, chemokines and neurotransmitters. Many types of neurotransmitter receptors are expressed on tumour cells, supporting the theory that psychosocial factors are involved in the progression of cancer. Understanding how such receptors regulate migration and the availability of specific receptor antagonists could open up new avenues for chemoprevention of tumour-cell migration and metastatic development.

Cell Movement↗

PubMed2004

Inhibition of cell migration via G protein-coupled receptors to opioid peptides and angiotensin.

Neurotransmitters are stimulatory as well as inhibitory regulators of cell migration. Angiotensin is such an inhibitory regulator of the SDF-1-induced migration of cytotoxic T lymphocytes, as we have investigated by time-lapse videomicroscopy and computer-assisted cell tracking. For angiotensin II, the most effective form of angiotensin for the inhibition of migration, two G protein-coupled receptors are known, which both downregulate the activity of the adenylyl cyclase via activation of inhibitory G proteins. This downregulation of the enzymatic activity is a key signaling event for the inhibition of T lymphocyte and tumor cell migration, while stimulatory neurotransmitters--for example, norepinephrine--cause an activation of the adenylyl cyclase. Similar to angiotensin, the SDF-1-induced migration of cytotoxic T lymphocytes was inhibited by DAMGO, a specific agonist for the mu-opioid receptor, which is coupled to inhibitory G proteins, too. More interestingly, DAMGO downregulated the met-enkephalin-induced migration of MDA-MB-468 breast carcinoma cells. Met-enkephalin binds to the delta-opioid receptor and, with lower affinity, to the mu-opioid receptor. Since the delta-opioid receptor also activates inhibitory G proteins, the promigratory effect of met-enkephalin is caused by an intracellular signaling distinct from the engagement of each opioid receptor alone. In summary, the dual control of the adenylyl cyclase functions as an integrator of stimulatory and inhibitory signals for T lymphocyte and tumor cell migration, which are delivered by neurotransmitters and other signal substances that bind to G protein-coupled receptors.

Angiotensins↗

PubMed2004

Immunotherapy of melanoma targeting human high molecular weight melanoma-associated antigen: potential role of nonimmunological mechanisms.

Induction of humoral anti-human high molecular weight melanoma-associated antigen (anti-HMW-MAA) immunity following active specific immunotherapy is associated with a statistically significant prolongation of survival in patients with melanoma. This association does not appear to be mediated by immunological mechanisms because anti-HMW-MAA antibodies are poor mediators of complement- and cell-mediated cytotoxicity of melanoma cells. Therefore, we have been investigating nonimmunological mechanisms by which anti-HMW-MAA antibodies (Abs) affect the biology of melanoma cells. We have demonstrated that anti-HMW-MAA mAbs interfere with the interaction of HMW-MAA with extracellular matrix (ECM) components, a process known to be crucial in the early phase of melanoma metastasis. Furthermore, anti-HMW-MAA mAbs appear to block the series of signal transduction events triggered by the interaction of HMW-MAA with ECM. They include the activation of the family of Rho GTPases, p130cas, and focal adhesion kinase (FAK). These findings parallel the inhibition of the rat homologue of HMW-MAA NG2 function by anti-NG2 antibodies. Taken together, all these results provide a mechanistic explanation not only for the therapeutic effect of anti-HMW-MAA antibodies in the treatment of melanoma, but also for the function of HMW-MAA in the biology of melanoma cells. This information is expected to serve as a useful background to design effective HMW-MAA-targeted immunotherapy in patients with melanoma.

Animals↗

PubMed2003

Boswellic acid acetate induces differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells.

The aim of the study was to investigate the antitumor and/or preventive effect of BC-4, an isomeric compound isolated from the plant Boswellia carteri Birdw. containing alpha- and beta-boswellic acid acetate in 1:1, MW 498.3. We used the MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) assay to study the growth inhibition activity of BC-4. Tumor cells migration within a three-dimensional collagen matrix was recorded by time-lapse videomicroscopy and computer-assisted cell tracking. Topoisomerase II was isolated from mouse melanoma B16F10 cells and its activity was determined by its ability to cut plasmid pBR322 DNA. The secretion and activity of matrix metalloproteinases (MMPs) from human fibrosarcoma HT-1080 cells were determined by gelatin zymography. BC-4 was a cytostatic compound and could induce the differentiation of B16F10 mouse melanoma cells, blocked the cell population in G1 phase and inhibited topoisomerase II activity. The G1 phase population of B16F10 cells was increased from 57.4 to 87.7%, while S phase population was reduced from 33.3 to 5.9% after treatment with BC-4 at 25 microM concentration for 48 h. BC-4 also inhibited the migration activity of B16F10. BC-4 could induce apoptosis of HT-1080 cells, as proved by acridine orange fluorescence staining, Wright-Giemsa staining, electromicroscopy, DNA fragmentation and flow cytometry. BC-4 inhibited the secretion of MMPs from HT-1080 cells, too. In conclusion, if it turns out that BC-4 is a well tolerated substance, exhibiting no significant toxicity or side effects, being evaluated currently in China, BC-4 is a good candidate for the prevention of primary tumor, invasion and metastasis.

Animals↗

PubMed2002

The neurotransmitter gamma-aminobutyric acid is an inhibitory regulator for the migration of SW 480 colon carcinoma cells.

Gamma-aminobutyric acid (GABA) is the inhibitory neurotransmitter in the brain, also playing a role in diseases like epilepsy. We now show that this inhibitory neurotransmitter can also reduce migratory activity in SW 480 colon carcinoma cells. GABA reduced the norepinephrine-induced migratory activity of these cells within a three-dimensional collagen matrix to spontaneous migration levels, as was analyzed by time-lapse videomicroscopy. This inhibitory effect of GABA was mediated by the serpentine receptor GABA(B) and was intracellularly transduced by a decrease of the cyclic AMP concentration. Cancer cell migration is thus regulated by neurobiological signals, opening new possibilities for pharmacological agonists in cancer therapy.

Bucladesine↗