Transcriptomic response of prostate cancer cells to carbon ion and photon irradiation with focus on androgen receptor and TP53 signaling.

Background: Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage.

Modulation of immune checkpoint regulators in interferon γ induced urothelial carcinoma and activated T-lymphocyte cells by cytostatics.

Exploring the regulation of co-inhibitory (PD-1, PD-L1, CTLA-4) and co-stimulatory (CD28) genes by chemotherapeutic drugs is important for combined immune checkpoint blockade (ICB) therapy. ICB interferes with T-cell receptor and major histocompatibility complex (MHC) signaling by antibody drugs directed against the co-inhibitors. Here, we analyzed urothelial (T24) cell line with respect to cytokine signaling by interferon γ (IFNG) and the leukemia lymphocyte (Jurkat) cell line with respect to T-cell activation as mimicked by phorbolester and calcium ionophore (pma/iono).

Increased Density of Growth Differentiation Factor-15+ Immunoreactive M1/M2 Macrophages in Prostate Cancer of Different Gleason Scores Compared with Benign Prostate Hyperplasia.

Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1.

Soluble PD-L1 in blood correlates positively with neutrophil and negatively with lymphocyte mRNA markers and implies adverse sepsis outcome.

Sepsis causes a myriad of immunological reactions that result in life-threatening alterations in the human body. Immunosuppression in sepsis is partly attributed to the programmed death receptor (PD-1) and its associated ligand (PD-L1) via the regulation of lymphocytes and neutrophils. Although the soluble forms of these proteins (i.

Cellular and soluble immune checkpoint signaling forms PD-L1 and PD-1 in renal tumor tissue and in blood.

Immune checkpoint blockade therapy is a treatment option of various metastatic cancer diseases including renal cell carcinoma (RCC). Approved antibody drugs target the co-inhibitory signaling of Programmed Cell Death Ligand-1 (PD-L1) and its receptor Programmed Cell Death-1 (PD-1). The combined evaluation of PD-L1 and PD-1 at the mRNA and protein levels in tumor tissue with differentiation of tumor and immune cells as well as of soluble forms (sPD-L1) and (sPD-1) in blood is of basic interest in assessing biomarker surrogates.

Co-Regulation of Immune Checkpoint PD-L1 with Interferon-Gamma Signaling is Associated with a Survival Benefit in Renal Cell Cancer.

Background: Programmed death ligand (PD-L1)-based immune checkpoint blockade therapy for metastatic renal cell carcinoma (RCC) achieves significant response rates in a subgroup of patients. The relevance of PD-L1 gene regulation for disease outcome is not clear.

Objective: To evaluate PD-L1 expression and its dependence on interferon-γ (IFN-γ) in RCC cell lines and tissues in relation to disease outcome.

Prostate specific membrane antigen (PSMA) in urothelial cell carcinoma (UCC) is associated with tumor grading and staging.

Introduction: Prostate specific membrane antigen (PSMA) has become a target for radionuclide imaging and therapy. Previous studies have shown that the expression of PSMA is not specific to prostate tissue. In this study we examine the expression of PSMA in urothelial cell carcinoma (UCC).

Prostate cancer tissues with positive TMPRSS2-ERG-gene-fusion status may display enhanced nerve density.

Innervation of prostate cancer (CaP) tissue favors tumor progression and metastasis but the regulation of innervation in CaP is unclear. The oncogenic transcription factor ERG is commonly induced by a typical TMPRSS2-ERG (TE) gene fusion in CaP and may affect innervation. Here, we analyzed whether nerve density of CaP tissue is related to TE status or perineural infiltration status of CaP tissue.

Effects of multi and selective targeted tyrosine kinase inhibitors on function and signaling of different bladder cancer cells.

Background: Signaling of receptor tyrosine kinases (RTK) is dysregulated in various malignancies including bladder cancer. RTKs trigger pro-proliferative, anti-apoptotic and metastatic signaling pathways. Here, we assessed the effects of a selective tyrosine kinase inhibitor (TKI) (BGJ398) targeting fibroblast growth factor receptor (FGFR) and a pan-TKI (TKI258) targeting (FGFR), platelet derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) in bladder cancer cells.

The Immune Checkpoint Molecule CD200 Is Associated with Tumor Grading and Metastasis in Bladder Cancer.

Background: We examined the expression of CD200, a ligand of immune tolerance, in transitional cell carcinoma of the human bladder (TCC).

Materials And Methods: CD200 was analyzed by immunohistochemistry (IHC) in 90 patients with suspected TCC lesions of the bladder. Expression of CD200 was exemplarily validated by quantitative reverse transcription polymerase chain reaction and western blot analysis.

In cancer cell lines inhibition of SCF/c-Kit pathway leads to radiosensitization only when SCF is strongly over-expressed.

Background And Purpose: The SCF/c-Kit pathway is often overexpressed in human tumors leading to an enhanced tumorigenesis, proliferation and migration. It was now tested for NSCLC and prostate cancer cells growing in 2D and 3D whether the inhibition of this pathway can be used to achieve a significant radiosensitization and whether a respective biomarker may be identified.

Material And Methods: Experiments were performed with different cancer cell lines (NSCLC: H23, H520, H226, H1975 and PrCa: DU145) growing either under 2D or 3D conditions.

Cancer cell motility is affected through 3D cell culturing and SCF/c-Kit pathway but not by X-irradiation.

Background And Purpose: Success of radiotherapy is often limited by therapy resistance and metastasis resulting from cancer cell motility. It was tested in vitro whether this cancer cell motility is affected by growth condition, active SCF/c-Kit pathway or X-irradiation.

Materials And Methods: Cell motility was measured with BioCoat™ Matrigel™ invasion chamber using four different cancer cell lines (NSCLC: H23, H520, H226 and PrCa: DU145).

Assessing blood platelets as RNA biomarker source for prostate cancer.

Context: Blood platelets may offer as RNA biomarker source for cancer as recently described for an oncogenic transcript in glioma patients and for PCA3 in prostate cancer (PCa) patients.

Objective: Here, we elaborated on this aspect for PCa.

Materials And Methods: PCA3 and other PCa-associated RNA markers were measured in platelets of PCa patients (cases) and healthy subjects (controls) in comparison to PCa cell lines by relative quantitative RT-PCR.

Expression of the anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) in human clear cell renal cell carcinoma.

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is a cytokine-activated transcription factor controlling inflammation, cell proliferation, survival, and differentiation in normal tissue as well as in tumor growth. One of its most important negative regulators is the suppressor of cytokine signaling 3 (SOCS3). Here, we analyzed SOCS3 and other tumor-associated local immune regulators in human clear cell renal cell carcinoma (ccRCC).

TLR4- and TLR9-dependent effects on cytokines, cell viability, and invasion in human bladder cancer cells.

Objectives: Adjuvant immunotherapy of bladder cancer by instillation of bacillus Calmette-Guérin (BCG) is highly recommended within certain groups of non-muscle-invasive stages but only partially effective. Toll-like receptors (TLRs) TLR4 and TLR9 likely mediate BCG effects by triggering innate systemic immune cell responses. In addition, TLR4 and TLR9 expressed in bladder cancer cells may contribute to the outcome of BCG treatment.

Changes in prostaglandin E2 in patients with idiopathic overactive bladder syndrome after botulinum toxin type A treatment: is there a clinical benefit?

Background: The causality of overactive bladder syndrome (OAB) is still not fully understood. Several studies indicate a significant increase of prostaglandin E2 (PGE2) in patients with OAB. However, in order to clarify whether these compounds can help to objectify the clinical diagnosis, further studies are needed.

Carbon ion radiotherapy of human lung cancer attenuates HIF-1 signaling and acts with considerably enhanced therapeutic efficiency.

Carbon ion irradiation is an emerging therapeutic option for various tumor entities. Radiation resistance of solid tumors toward photon irradiation is caused by attenuation of DNA damage in less oxygenated tumor areas and by increased hypoxia-inducible factor (HIF)-1 signaling. Carbon ion irradiation acts independently of oxygen; however, the role of HIF-1 is unclear.

Epithelial mesenchymal transition status is associated with anti-cancer responses towards receptor tyrosine-kinase inhibition by dovitinib in human bladder cancer cells.

Background: Dovitinib (TKI-258) is a receptor tyrosine kinase (RTK) inhibitor targeting fibroblast growth factor receptor (FGFR) and further related RTKs. TKI-258 is under investigation as anticancer drug for the treatment of various cancers including bladder cancer with aberrant RTK signaling. Here, we analyzed the responses of ten human bladder cancer cell lines towards TKI-258 treatment in relation to the epithelial mesenchymal transition (EMT) status of the cells.

Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF.

Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Pathophysiological role of phosphodiesterase 4 (PDE4) with possible therapeutic prospects in lung cancer was investigated.

Comparison of the effects of carbon ion and photon irradiation on the angiogenic response in human lung adenocarcinoma cells.

Purpose: Radiotherapy resistance is a commonly encountered problem in cancer treatment. In this regard, stabilization of endothelial cells and release of angiogenic factors by cancer cells contribute to this problem. In this study, we used human lung adenocarcinoma (A549) cells to compare the effects of carbon ion and X-ray irradiation on the cells' angiogenic response.

EphA2 blockade enhances the anti-endothelial effect of radiation and inhibits irradiated tumor cell-induced migration of endothelial cells.

Background: EphA2 tyrosine kinase plays an important role in tumor angiogenesis, but whether targeting this pathway can affect response to ionizing radiation (IR) remains unknown.

Methods: We investigated, using a soluble EphA2-Fc chimera, whether EphA2 inhibition could sensitize A549 and MCF-7 tumor cells, as well as human umbilical vein endothelial cells (HUVEC) and dermal microvascular endothelial cells (HDMEC), to IR.

Results: EphA2-Fc resulted in a greater response of endothelial cells (EC) to IR than either treatment alone.

TIAR and TIA-1 mRNA-binding proteins co-aggregate under conditions of rapid oxygen decline and extreme hypoxia and suppress the HIF-1α pathway.

T-cell intracellular antigen (TIA)-1 and TIA-1-related protein (TIAR) are mRNA-binding proteins that can aggregate within granules under specific stress conditions. In this study, we analyzed TIAR/TIA-1 aggregation under different hypoxic conditions, and studied the effects on the hypoxia-inducible factor (HIF)-1α in different cancer cell lines. Under acute and pronounced hypoxic conditions TIAR/TIA-1 co-aggregated to granules and positive co-staining with eIF3η marker suggested these to represent stress granules.

Irradiation-dependent effects on tumor perfusion and endogenous and exogenous hypoxia markers in an A549 xenograft model.

Purpose: Hypoxia is a major determinant of tumor radiosensitivity, and microenvironmental changes in response to ionizing radiation (IR) are often heterogenous. We analyzed IR-dependent changes in hypoxia and perfusion in A549 human lung adenocarcinoma xenografts.

Materials And Methods: Immunohistological analysis of two exogenously added chemical hypoxic markers, pimonidazole and CCI-103F, and of the endogenous marker Glut-1 was performed time dependently after IR.

HIF-1 alpha signaling is augmented during intermittent hypoxia by induction of the Nrf2 pathway in NOX1-expressing adenocarcinoma A549 cells.

Fluctuations in cellular oxygenation causing intermittent hypoxia and oxidative stress affect the regulation of hypoxia-inducible factor (HIF-1) and the nuclear factor erythroid 2-related factor 2 (Nrf2). HIF-1 is primarily induced in hypoxia, whereas Nrf2 is induced in response to oxidative stress. Whereas HIF-1 regulates the expression of genes important for the adaptation of cells to hypoxia, Nrf2 induces antioxidative enzymes such as thioredoxin 1 (Trx1), exerting a cytoprotective role.

Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model.

Different routes for the in vivo administration of synthetic siRNA complexes targeting lung tumors were compared, and siRNA complexes were administered for the inhibition of hypoxia-inducible factor (HIF-1alpha and HIF-2alpha). Intravenous jugular vein injection of siRNA proved to be the most effective means of targeting lung tumor tissue in the Lewis lung carcinoma (LLC1) model. In comparison, intraperitoneal injection of siRNA was not suitable for targeting of lung tumor and intratracheal administration of siRNA exclusively targeted macrophages.