Overexpression of Eag1 potassium channels in clinical tumours

BACKGROUND: Certain types of potassium channels (known as Eag1, KCNH1, Kv10.1) are associated with the production of tumours in patients and in animals. We have now studied the expression pattern of the Eag1 channel in a large range of normal and tumour tissues from different collections utilising molecular biological and immunohistochemical techniques. RESULTS: The use of reverse transcription real-time PCR and specifically generated monoclonal anti-Eag1 antibodies showed that expression of the channel is normally limited to specific areas of the brain and to restricted cell populations throughout the body. Tumour samples, however, showed a significant overexpression of the channel with high frequency (up to 80% depending on the tissue source) regardless of the detection method (staining with either one of the antibodies, or detection of Eag1 RNA). CONCLUSION: Inhibition of Eag1 expression in tumour cell lines reduced cell proliferation. Eag1 may therefore represent a promising target for the tailored treatment of human tumours. Furthermore, as normal cells expressing Eag1 are either protected by the blood-brain barrier or represent the terminal stage of normal differentiation, Eag1 based therapies could produce only minor side effects

Is CCL2 an Important Mediator of Mast Cell–Tumor Cell Interactions in Oral Squamous Cell Carcinoma?

In this study, we aimed to evaluate the influence of interactions between mast cells (MCs) and oral squamous cell carcinoma (OSCC) tumor cells on tumor proliferation and invasion rates and identify soluble factors mediating this crosstalk. To this end, MC/OSCC interactions were characterized using the human MC cell line LUVA and the human OSCC cell line PCI-13. The influence of an MC-conditioned (MCM) medium and MC/OSCC co-cultures on the proliferative and invasive properties of the tumor cells was investigated, and the most interesting soluble factors were identified by multiplex ELISA analysis. LUVA/PCI-13 co-cultures increased tumor cell proliferation significantly (p = 0.0164). MCM reduced PCI-13 cell invasion significantly (p = 0.0010). CC chemokine ligand 2 (CCL2) secretion could be detected in PCI-13 monocultures and be significantly (p = 0.0161) increased by LUVA/PCI-13 co-cultures. In summary, the MC/OSCC interaction influences tumor cell characteristics, and CCL2 could be identified as a possible mediator

Macrophage-tumor cell interactions regulate the function of nitric oxide

Tumor cell-macrophage interactions change as the tumor progresses, and the generation of nitric oxide (NO) by the inducible nitric oxide synthase (iNOS) plays a major role in this interplay. In early stages, macrophages employ their killing mechanisms, particularly the generation of high concentrations of NO and its derivative reactive nitrogen species (RNS) to initiate tumor cell apoptosis and destroy emerging transformed cells. If the tumor escapes the immune system and grows, macrophages that infiltrate it are reprogramed in situ by the tumor microenvironment. Low oxygen tensions (hypoxia) and immunosuppressive cytokines inhibit iNOS activity and lead to production of low amounts of NO/RNS, which are pro-angiogenic and support tumor growth and metastasis by inducing growth factors (e.g., VEGF) and matrix metalloproteinases (MMPs). We review here the different roles of NO/RNS in tumor progression and inhibition, and the mechanisms that regulate iNOS expression and NO production, highlighting the role of different subtypes of macrophages and the microenvironment. We finally claim that some tumor cells may become resistant to macrophage-induced death by increasing their expression of microRNA-146a (miR-146a), which leads to inhibition of iNOS translation. This implies that some cooperation between tumor cells and macrophages is required to induce tumor cell death, and that tumor cells may control their fate. Thus, in order to induce susceptibility of tumors cells to macrophage-induced death, we suggest a new therapeutic approach that couples manipulation of miR-146a levels in tumors with macrophage therapy, which relies on ex vivo stimulation of macrophages and their re introduction to tumors

The regulation of angiogenesis by tissue cell-macrophage interactions

Angiogenesis is the physiological process where new blood vessels grow from existing ones, in order to replenish tissues suffering from inadequate blood supply. Perhaps the most studied angiogenic process occurs in solid tumors whose growing mass and expanding cells create a constant demand for additional supply of oxygen and nutrients for survival. However, other physiological and clinical conditions, such as wound healing, ischemic events, autoimmune and age-related diseases also involve angiogenesis. Angiogenesis is a well-structured process that begins when oxygen and nutrients are depleted, leading to the release of chemokines and growth factors that attract immune cells, particularly macrophages and endothelial cells to the site. Macrophages that are recruited to the site, as well as tissue cells and endothelial cells, secrete pro-angiogenic mediators that affect endothelial cells and promote angiogenesis. These mediators include growth factors such as vascular endothelial cell growth factor (VEGF), matrix metalloproteinases (MMPs), as well as low levels of mediators that are usually seen as pro-inflammatory but are pro-angiogenic when secreted in low levels (e.g. nitric oxide (NO) and TNFa). Thus, macrophages play a major role in angiogenesis. Macrophages exhibit high plasticity and are capable of shifting between different activation modes and functions according to their changing microenvironment. Small differences in the composition of activating factors (e.g. TLR ligands such as LPS, anti-inflammatory cytokines, ECM molecules) in the microenvironment may differently activate macrophages to yield classically activated macrophages (or M1 macrophages) that can kill pathogen and tumor cells, alternatively activated macrophages (or M2 macrophages) that secrete antiinflammatory cytokines, resolution macrophages (rM?) that are involved in the resolution of inflammation, or regulatory macrophages (e.g. Myeloid-Derived Suppressor Cells - MDSCs) that control the function of other immune cells. In fact, macrophages may be activated in a spectrum of subsets that may differently contribute to angiogenesis, and in particular non-classically activated macrophages such as tumor-associated macrophages (TAMs) and Tie2-expressing monocytes (TEMs) can secrete high amounts of pro-angiogenic factors (e.g. VEGF, MMPs) or low levels of pro-inflammatory mediators (e.g. NO or TNFa) resulting in pro-angiogenic effects. Although the importance of macrophages as major contributors and regulators of the angiogenic process is well documented, less is known about the interactions between macrophages and other cell types (e.g. tumor cells, normal epithelial cells, endothelial cells) that regulate angiogenesis. We still have only limited understanding which proteins or complexes mediate these interactions and whether they require cell-cell contact (e.g. through integrins) or soluble factors (e.g. the EGF-CSF-1 loop), which signaling pathways are triggered in each of the two corresponding cell types, and how this leads to secretion of pro- or antiangiogenic factors in the microenvironment. The regulation of such interactions and through them of angiogenesis, whether through post-translational modifications of proteins or via the involvement of microRNA, is still unclear. The goal of this Research Topic is to highlight these interactions and their regulation in the context of both physiological and pathological conditions

Is CCL2 an Important Mediator of Mast Cell–Tumor Cell Interactions in Oral Squamous Cell Carcinoma?

In this study, we aimed to evaluate the influence of interactions between mast cells (MCs) and oral squamous cell carcinoma (OSCC) tumor cells on tumor proliferation and invasion rates and identify soluble factors mediating this crosstalk. To this end, MC/OSCC interactions were characterized using the human MC cell line LUVA and the human OSCC cell line PCI-13. The influence of an MC-conditioned (MCM) medium and MC/OSCC co-cultures on the proliferative and invasive properties of the tumor cells was investigated, and the most interesting soluble factors were identified by multiplex ELISA analysis. LUVA/PCI-13 co-cultures increased tumor cell proliferation significantly (p = 0.0164). MCM reduced PCI-13 cell invasion significantly (p = 0.0010). CC chemokine ligand 2 (CCL2) secretion could be detected in PCI-13 monocultures and be significantly (p = 0.0161) increased by LUVA/PCI-13 co-cultures. In summary, the MC/OSCC interaction influences tumor cell characteristics, and CCL2 could be identified as a possible mediator.Open-Access-Publikationsfonds 202