Vienna Cancer Stem Cell Club (VCSCC): 20 year jubilee and future perspectives.

INTRODUCTION: The Vienna Cancer Stem Cell Club (VCSCC) was launched by a group of scientists in Vienna in 2002. AREAS COVERED: Major aims of the VCSCC are to support research on cancer stem cells (CSC) in hematopoietic malignancies and to translate CSC-related markers and targets into clinical application. A primary focus of research in the VCSCC is the leukemic stem cell (LSC). Between 2013 and 2021, members of the VCSCC established a special research program on myeloproliferative neoplasms and since 2008, members of the VCSCC run the Ludwig Boltzmann Institute for Hematology and Oncology. In all these years, the VCSCC provided a robust intellectual platform for translational hematology and LSC research in Vienna. Furthermore, the VCSCC interacts with several national and international study groups and societies in the field. Representatives of the VCSCC also organized a number of international meetings and conferences on neoplastic stem cells, including LSC, in the past 15 years, and contributed to the definition and classification of CSC/LSC and related pre-malignant and malignant conditions. EXPERT OPINION: The VCSCC will continue to advance the field and to develop LSC-detecting and LSC-eradicating concepts through which diagnosis, prognostication, and therapy of blood cancer patients should improve.

Ludwig Boltzmann Cluster Oncology (LBC ONC): first 10 years and future perspectives.

In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previous Ludwig Boltzmann Institutes working in the field of hematology and cancer research. The general aim of the LBC ONC is to improve treatment of hematopoietic neoplasms by eradicating cancer-initiating and disease-propagating cells, also known as leukemic stem cells (LSC) in the context of leukemia. In a first phase, the LBC ONC characterized the phenotype and molecular aberration profiles of LSC in various malignancies. The LSC phenotypes were established in acute and chronic myeloid leukemia, in acute lymphoblastic leukemia and in chronic lymphocytic leukemia. In addition, the concept of preleukemic (premalignant) neoplastic stem cells (pre-L-NSC) was coined by the LBC ONC and was tested in myelodysplastic syndromes and myeloproliferative neoplasms. Phenotypic characterization of LSC provided a solid basis for their purification and for the characterization of specific target expression profiles. In a second phase, molecular markers and targets were validated. This second phase is ongoing and should result in the development of new diagnostics parameters and novel, more effective, LSC-eradicating, treatment strategies; however, many issues still remain to be solved, such as sub-clonal evolution, LSC niche interactions, immunologic control of LSC, and LSC resistance. In the forthcoming years, the LBC ONC will concentrate on developing LSC-eradicating strategies, with special focus on LSC resistance, precision medicine and translation of LSC-eradicating concepts into clinical application.

Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines.

Statins and bisphosphonates are increasingly recognized as anti-cancer drugs, especially because of their cholesterol-lowering properties. However, these drugs act differently on various types of cancers. Thus, the aim of this study was to compare the effects of statins and bisphosphonates on the metabolism (NADP⁺/NADPH-relation) of highly proliferative tumor cell lines from different origins (PC-3 prostate carcinoma, MDA-MB-231 breast cancer, U-2 OS osteosarcoma) versus cells with a slower proliferation rate like MG-63 osteosarcoma cells. Global gene expression analysis revealed that after 6 days of treatment with pharmacologic doses of the statin simvastatin and of the bisphosphonate ibandronate, simvastatin regulated more than twice as many genes as ibandronate, including many genes associated with cell cycle progression. Upregulation of starvation-markers and a reduction of metabolism and associated NADPH production, an increase in autophagy, and a concomitant downregulation of H3K27 methylation was most significant in the fast-growing cancer cell lines. This study provides possible explanations for clinical observations indicating a higher sensitivity of rapidly proliferating tumors to statins and bisphosphonates.

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate.

Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation viaTet1andTet2and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2,Col1a1,Bglap2,Sp7,Atf4, andAlpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-κB ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of theTet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (∼20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorptionin vivo Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.

Inhibition of the mevalonate pathway affects epigenetic regulation in cancer cells.

The mevalonate pathway provides metabolites for post-translational modifications such as farnesylation, which are critical for the activity of RAS downstream signaling. Subsequently occurring regulatory processes can induce an aberrant stimulation of DNA methyltransferase (DNMT1) as well as changes in histone deacetylases (HDACs) and microRNAs in many cancer cell lines. Inhibitors of the mevalonate pathway are increasingly recognized as anticancer drugs. Extensive evidence indicates an intense cross-talk between signaling pathways, which affect growth, differentiation, and apoptosis either directly or indirectly via epigenetic mechanisms. Herein, we show data obtained by novel transcriptomic and corresponding methylomic or proteomic analyses from cell lines treated with pharmacologic doses of respective inhibitors (i.e., simvastatin, ibandronate). Metabolic pathways and their epigenetic consequences appear to be affected by a changed concentration of NADPH. Moreover, since the mevalonate metabolism is part of a signaling network, including vitamin D metabolism or fatty acid synthesis, the epigenetic activity of associated pathways is also presented. This emphasizes the far-reaching epigenetic impact of metabolic therapies on cancer cells and provides some explanation for clinical observations, which indicate the anticancer activity of statins and bisphosphonates.

The role of epigenetics in the regulation of apoptosis in myelodysplastic syndromes and acute myeloid leukemia.

Disordered stem cell epigenetics and apoptosis-regulating mechanisms contribute essentially to the pathogenesis of myelodysplastic syndromes (MDS) and may trigger disease-progression to secondary acute myeloid leukemia (AML). Expression of apoptosis-mediators FAS (CD95) and DAPK1 the latter being also known for its association with autophagy are upregulated in neoplastic cells in patients with low-risk MDS and epigenetically silenced and downregulated in high-risk MDS and AML as confirmed by a study 50 MDS and 30 AMLs complementing this review. 5-Azacytidine (AZA) and 5-aza-2'deoxycytidine (DAC), promoted FAS and DAPK1 gene demethylation and their (re)expression as well as apoptosis in leukemic cell lines (HL-60, KG1) which can be reversed by siRNA against FAS. Thus, promoter-demethylation of FAS and DAPK1 represents a critical mechanism of drug-induced apoptosis in neoplastic cells in MDS and AML which underscores the clinical implication of epigenetically active therapies.

DMSO is a strong inducer of DNA hydroxymethylation in pre-osteoblastic MC3T3-E1 cells.

Artificial induction of active DNA demethylation appears to be a possible and useful strategy in molecular biology research and therapy development. Dimethyl sulfoxide (DMSO) was shown to cause phenotypic changes in embryonic stem cells altering the genome-wide DNA methylation profiles. Here we report that DMSO increases global and gene-specific DNA hydroxymethylation levels in pre-osteoblastic MC3T3-E1 cells. After 1 day, DMSO increased the expression of genes involved in DNA hydroxymethylation (TET) and nucleotide excision repair (GADD45) and decreased the expression of genes related to DNA methylation (Dnmt1, Dnmt3b, Hells). Already 12 hours after seeding, before first replication, DMSO increased the expression of the pro-apoptotic gene Fas and of the early osteoblastic factor Dlx5, which proved to be Tet1 dependent. At this time an increase of 5-methyl-cytosine hydroxylation (5-hmC) with a concomitant loss of methyl-cytosines on Fas and Dlx5 promoters as well as an increase in global 5-hmC and loss in global DNA methylation was observed. Time course-staining of nuclei suggested euchromatic localization of DMSO induced 5-hmC. As consequence of induced Fas expression, caspase 3/7 and 8 activities were increased indicating apoptosis. After 5 days, the effect of DMSO on promoter- and global methylation as well as on gene expression of Fas and Dlx5 and on caspases activities was reduced or reversed indicating down-regulation of apoptosis. At this time, up regulation of genes important for matrix synthesis suggests that DMSO via hydroxymethylation of the Fas promoter initially stimulates apoptosis in a subpopulation of the heterogeneous MC3T3-E1 cell line, leaving a cell population of extra-cellular matrix producing osteoblasts. 

Determination of surface concentrations of individual molecule-layers used in nanoscale biosensors by in situ ATR-FTIR spectroscopy.

For the development of nanowire sensors for chemical and medical detection purposes, the optimal functionalization of the surface is a mandatory component. Quantitative ATR-FTIR spectroscopy was used in situ to investigate the step-by-step layer formation of typical functionalization protocols and to determine the respective molecule surface concentrations. BSA, anti-TNF-α and anti-PSA antibodies were bound via 3-(trimethoxy)butylsilyl aldehyde linkers to silicon-oxide surfaces in order to investigate surface functionalization of nanowires. Maximum determined surface concentrations were 7.17 × 10(-13) mol cm(-2) for BSA, 1.7 × 10(-13) mol cm(-2) for anti-TNF-α antibody, 6.1 × 10(-13) mol cm(-2) for anti-PSA antibody, 3.88 × 10(-13) mol cm(-2) for TNF-α and 7.0 × 10(-13) mol cm(-2) for PSA. Furthermore we performed antibody-antigen binding experiments and determined the specific binding ratios. The maximum possible ratio of 2 was obtained at bulk concentrations of the antigen in the µg ml(-1) range for TNF-α and PSA.

5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand.

Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced hematopoietic neoplasms with poor prognosis. In these patients, neoplastic mast cells (MCs) are resistant against various drugs. We examined the effects of 2 demethylating agents, 5-azacytidine and decitabine on growth and survival of neoplastic MCs and the MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both agents induced apoptosis in HMC-1.1 and HMC-1.2 cells. Decitabine, but not 5-azacytidine, also produced a G(2)/M cell-cycle arrest in HMC-1 cells. Drug-induced apoptosis was accompanied by cleavage of caspase-8 and caspase-3 as well as FAS-demethylation and FAS-re-expression in neoplastic MCs. Furthermore, both demethylating agents were found to synergize with the FAS-ligand in inducing apoptosis in neoplastic MCs. Correspondingly, siRNA against FAS was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Neither 5-azacytidine nor decitabine induced substantial apoptosis or growth arrest in normal MCs or normal bone marrow cells. Together, 5-azacytidine and decitabine exert growth-inhibitory and proapoptotic effects in neoplastic MCs. These effects are mediated through "FAS-re-expression" and are augmented by the FAS-ligand. Whether epigenetic drugs produce antineoplastic effects in vivo in patients with ASM and MCL remains to be determined.

Blockade of fatty acid synthase induces ubiquitination and degradation of phosphoinositide-3-kinase signaling proteins in ovarian cancer.

Aberrations within the phosphoinositide-3-kinase (PI3K) pathway occur in greater than 45% of ovarian carcinomas. The PI3K cascade transmits signals from ErbB receptors downstream to S6 and 4EBP1, which are involved in protein biosynthesis. Many ovarian carcinomas reveal hyperactivation of ErbB1 (epidermal growth factor receptor) or ErbB2 (HER2/neu). Unfortunately, the benefit of anti-ErbB drugs is yet rather limited in ovarian carcinomas. Thus, novel targeting strategies are needed for ovarian carcinomas. The lipogenic enzyme fatty acid synthase (FASN) is overexpressed in approximately 80% of ovarian carcinomas. It stimulates cell growth and signifies poor prognosis. FASN inhibition impedes (ErbB) membrane receptor signaling and sensitizes cells against anti-ErbB drugs. Here, we show that the FASN inhibitor C75 and FASN-targeting siRNAs abrogate growth, induce apoptosis, and downregulate phosphorylation/expression of the PI3K effectors AKT, mTOR, p70S6K, S6, and 4EBP1. In contrast, FASN inhibition impairs expression but only weakly affects phosphorylation of ERK1/2 mitogen-activated protein kinases in ovarian carcinoma cells. Cycloheximide-mediated blockade of protein translation reveals that C75- or FASN siRNA-induced shutdown of FASN accelerates decomposition of signaling proteins. This effect is caused by C75- or FASN siRNA-dependent stimulation of ubiquitination followed by lysosomal-autophagosomal proteolysis. In contrast, PI3K inhibitor LY294002 blocks phosphorylation but does not reduce expression/stability of PI3K effectors. Forced expression of hyperactive (HA) AKT1, unlike HA-MEK1, impairs the growth-inhibitory action of C75. We provide first evidence that the anticancer action of FASN inhibitors is at least partially mediated by drug-dependent proteolysis of PI3K effectors. FASN is a promising cancer target, whose inhibition not only abrogates lipogenesis, which is indispensable for cancer growth, but also downregulates oncogenic PI3K signaling.

Homocysteine suppresses the expression of the collagen cross-linker lysyl oxidase involving IL-6, Fli1, and epigenetic DNA methylation.

Elevated homocysteine (Hcys) serum levels represent a risk factor for several chronic pathologies, including cardiovascular disease, atherosclerosis, and chronic renal failure, and affect bone development, quality, and homeostasis. Hcys influences the formation of a stable bone matrix directly through the inhibition of the collagen cross-linking enzyme lysyl oxidase (Lox) and, as we have shown recently, by repressing its mRNA expression. The aim of this study was to investigate the mechanisms involved in this process. Through evaluation of gene arrays, quantitative RT-PCR, immunoblots, and ELISA, we identified a Hcys-dependent stimulation of interleukin 6 (IL-6) and genes involved in IL-6/Janus kinase 2 (JAK2)-dependent signal transduction pathways in pre-osteoblastic MC3T3-E1 cells. Moreover, up-regulation of genes essential for epigenetic DNA methylation (DNA (cytosine-5)-methyltransferases and helicase lymphoid-specific (Hells) was observed. Further investigations demonstrated that Hcys increased via IL-6/JAK2 the expression of Fli1 (Friend leukemia virus integration 1), a transcription factor, which we found essential for IL-6-dependent Dnmt1 stimulation. CpG methylation analysis of CpG-rich Lox proximal promoter revealed an increased CpG methylation status after treatment of the cells with Hcys indicating an epigenetic origin for Hcys-dependent Lox repression. Inhibition of the IL-6/JAK2 pathway or of CpG methylation reversed the repressive effect of Hcys on Lox expression. In conclusion, we demonstrate that Hcys stimulates IL-6 synthesis in osteoblasts, which is known to affect bone metabolism via osteoclasts. Furthermore, IL-6 stimulation results via JAK2, Fli1, and Dnmt1 in down-regulation of Lox expression by epigenetic CpG methylation revealing a new mechanism negatively affecting bone matrix formation.

Impact of vitamin D metabolism on clinical epigenetics.

The bioactive vitamin D (VD) metabolite, 1,25-dihydroxyvitamin D(3) regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR). Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). Activity of VDR can be modulated epigenetically by histone acetylation. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs). HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elucidate complex epigenetic mechanisms for cancer preventive actions of VD.

Epigenetics and the power of art.

This review presents an epigenetic view on complex factors leading to development and perception of "genius." There is increasing evidence which indicates that artistic creativity is influenced by epigenetic processes that act both as targets and mediators of neurotransmitters as well as steroid hormones. Thus, perception and production of art appear to be closely associated with epigenetic contributions to physical and mental health.

Functional aspects of cytidine-guanosine dinucleotides and their locations in genes.

Originally, the finding of a particular distribution of cytidine-guanosine dinucleotides (CpGs) in genomic DNA was considered to be an interesting structural feature of eukaryotic genome organization. Despite a global depletion of CpGs, genes are frequently associated with CpG clusters called CpG islands (CGIs). CGIs are prevalently unmethylated but often found methylated in pathologic situations. On the other hand, CpGs outside of CGIs are generally methylated and are found mainly in the heterochromatic fraction of the genome. Hypomethylation of those CpGs is associated with genomic instability in malignancy. Additionally, CpG-rich and CpG-poor regions, as well as CpG-shores, are defined. Usually, the methylation status inversely correlates with gene expression. Methylation of CpGs, as well as demethylation and generation of hydroxmethyl-cytosines, is strictly regulated during development and differentiation. This review deals with the relevance of the organizational features of CpGs and their relation to each other.

Cancer patients' perception of information exchange between hospital-based doctors and their general practitioners.

RATIONALE, AIMS AND OBJECTIVES: The quality of communication between health care professionals is a key issue determining health outcomes in cancer care. This study aims to find out what importance cancer patients in Austria attach to information exchange between hospital-based doctors and their general practitioners (GPs) and how patients perceive this flow of information. METHODS: In this cross-sectional study, cancer patients seeking help at a community-based organization in the voluntary sector (Viennese Cancer League) were polled with a 16-item questionnaire. Contingency tables were evaluated by means of the chi-squared and Mantel-Haenszel test. RESULTS: The mean age of the 252 respondents - 92.6% of those polled (272) - was 51.9 years (SD ± 13.6). 87.5% [female (f): 92.1%, male (m): 80.2%] considered the exchange of information between the hospital-based specialists and their GP 'very important' or 'important'; 12.5% (f: 8.0%, m: 19.8%) 'not so important' or 'not at all important'; 28.1% (f: 26.0%, m: 31.2%) of patients considered the flow of information as 'very good' or 'fairly good', but 50.9% (f: 58.7, m: 40.0%) as 'rather poor' or 'poor'. Some 34.8% of patients thought that their cancer disease was first suspected by a hospital-based specialist; 42.1% thought that it was first suspected by a doctor outside the hospital. Even when patients were counselled elsewhere they gave high importance to the provision of appropriate information to their GP. CONCLUSIONS: Cancer patients in Austria attach high importance to the provision of appropriate information to their GP by hospitals and perceive this exchange of information as insufficient, a finding that could well be prevalent in other European health systems.

[Tumor stem cell research - basis and challenge for diagnosis and therapy]. / Tumor-Stammzellforschung - Basis und Herausforderung für Diagnostik und Therapie.

Biological features of tumor cells relevant to progression, metastasis, and prognosis in cancer patients have been investigated for many years. During the past few years, the concept of tumor stem cells has gained widespread acceptance. The cancer stem cell (CSC) model is based on the observation that continuous growth of tumors depends on a small population of immature neoplastic cells with unlimited proliferative potential. In contrast to these CSC, more mature clonal cells in the same neoplasm undergo apoptosis and die after a variable number of cell divisions. The self-renewal capacity of CSC plays a central role in this scenario and enables permanent tumor cell repopulation in vivo in patients as well as in experimental animals, e.g., immunodeficient mice. Based on the stem cell concept, it is clear that the success of an anti-neoplastic approach depends on efficient targeting and elimination of CSC. An important aspect of CSC is their intrinsic resistance against conventional drugs. Therefore, a major focus in current research is molecular targets and their expression in CSC, with the goal to use targeted drugs for CSC elimination. It is the hope for the future that therapeutic approaches involving CSC-targeting concepts will lead to sustained remission and thus improvement of prognosis in leukemia and cancer patients.

Extra-cellular matrix suppresses expression of the apoptosis mediator Fas by epigenetic DNA methylation.

The extracellular matrix (ECM) of bone consists mainly of collagen type I, which induces osteoblastic differentiation and prevents apoptosis. Fas induces apoptosis in cells improperly adhering to ECM. Recently, it was described that Fas expression is modulated by epigenetic DNA methylation. Mouse MC3T3-E1 pre-osteoblastic cells were cultured either on collagen coated or on uncoated culture dishes for control. mRNA was isolated and gene expression was analyzed by quantitative RT-PCR. Furthermore, we measured global and specific DNA methylation. Compared to controls, cells cultured on collagen-coated dishes increased the expression of Runx2 and OCN indicating differentiation of pre-osteoblastic cells. Additionally, collagen up-regulated cyclin-A2 and down-regulated Fas expression suggesting increased cell multiplication. Furthermore, the expression of Dnmt1 and Hells, key mediators of the DNA-methylation process, was increased. As a consequence, we demonstrate that global DNA methylation and specific methylation of the Fas promoter was higher in MC3T3-E1 cells cultured on collagen when compared to controls. Investigation of signal transduction pathways by mean of inhibitors suggests that focal adhesion kinase, MAP- and Jun-kinases and AP-1 are involved in this process. In summary, we demonstrate that ECM prevents activation of Fas by epigenetic DNA-methylation.

Neoplastic stem cells: current concepts and clinical perspectives.

Neoplastic stem cells have initially been characterized in myeloid leukemias where NOD/SCID mouse-repopulating progenitors supposedly reside within a CD34+/Lin- subset of the malignant clone. These progenitors are considered to be self-renewing cells responsible for the in vivo long-term growth of neoplastic cells in leukemic patients. Therefore, these cells represent an attractive target of therapy. In some lymphoid leukemias, NOD/SCID mouse-repopulating cells were also reported to reside within the CD34+/Lin- subfraction of the clone. More recently, several attempts have been made to transfer the cancer stem cell concept to solid tumors and other non-hematopoietic neoplasms. In several of these tumors, the cell surface antigens AC133 (CD133) and CD44 are considered to indicate the potential of a cell to initiate permanent tumor formation in vivo. However, several questions concerning the phenotype, self-renewal capacity, stroma-dependence, and other properties of cancer- or leukemia-initiating cells remain to be solved. The current article provides a summary of our current knowledge on neoplastic (cancer) stem cells, with special emphasis on clinical implications and therapeutic options as well as a discussion about conceptual and technical limitations.

Osteocalcin attenuates T3- and increases vitamin D3-induced expression of MMP-13 in mouse osteoblasts.

Osteocalcin (OCN), the most abundant non-collagenous protein of the bone matrix, whose function is not fully understood, was recently suggested to act as endocrine factor regulating energy metabolism. Besides OCN, osteoblasts also express MMP-13, a matrix metallo-proteinase important for bone development and remodeling. Although differentially, both genes are regulated by 1,25-dihydroxy vitamin D3 (1,25D3) and T3, important hormones for bone metabolism. In mouse osteoblasts with a distinct differentiation status, T3 increases the expression of both proteins. By contrast, 1,25D3 stimulates the expression of MMP-13 but inhibits the expression of OCN in these cells. In humans, however, 1,25D3 upregulates both genes while T3 inhibits the OCN expression. Using northern blot hybridization we studied gene expression in the mouse osteoblastic cell line MC3T3-E1. We show that MMP-13 expression was strongly increased by T3 when the stimulation of OCN was low and, inversely, that the MMP-13 increase was low when T3 strongly stimulated the OCN expression. These findings suggest an interrelationship between OCN and MMP-13 expression. In fact, we observed that externally added OCN attenuated the T3 induced MMP-13 expression dose dependently and, furthermore, increased the 1,25D3 stimulated MMP-13 expression. Using a protein kinase A inhibitor we were able to show that this inhibitor mimics the effect of OCN suggesting a PKA dependent pathway to be involved in this regulatory process. We therefore hypothesize that OCN is a modulator of the hormonally regulated MMP-13 expression.

Breaking bad news to cancer patients: survey and analysis.

PURPOSE: To find out how patients perceived the disclosure of news about their cancer as regards the physician counselling and how they perceived the flow of information between hospital-based and family physicians. METHODS: 272 cancer patients were polled with a 16-item questionnaire. RESULTS: 252 cancer patients, 92.6% of those asked, completed the questionnaire. 37.7% (f:35.4%, m:41.8%) stated that the fact that they had cancer was presented to them 'very empathically' or 'empathically'. 62.3% (f:64.7%, m:58.3%) stated that it was presented to them 'not so empathically' or ' not at all empathically'. When patients had been counselled by family physicians they were more likely to state that it had been done 'very empathically' or 'empathically', in contrast to when they had been counselled by hospital-oncologists or self-employed specialists (81.8% vs. 41.2% vs. 41.2%; p=0.001). Significantly more patients thought that they had been given adequate opportunity to ask the questions they considered important when counselled by a family physician (81.8%) as compared to counselling by a hospital-oncologist (43.5%; p=0.002) or a self-employed specialist (44.3%; p=0.001). 56.8% preferred to discuss the suggested cancer therapies with an oncologist. 87.5% of patients considered the exchange of information between the hospital-based specialists and their family physician 'very important' or 'important'; more than half of all patients stated that this exchange of information was 'rather poor' or 'poor'. CONCLUSIONS: Oncologists should involve family physicians in disclosing bad news to patients. There are considerable deficiencies regarding information-exchange in cancer care in Austria.