Cellular senescence is the process of the permanent proliferative arrest of cells in response to various inducers. It is accompanied by typical morphological changes, in addition to the secretion of bioactive molecules, including proinflammatory cytokines and chemokines [known as the senescence-associated secretory phenotype (SASP)]. Thus, senescent cells may affect their local environment and induce a so-called 'bystander' senescence through the state of SASP. The phenotypes of senescent cells are determined by the type of agent inducing cellular stress and the cell lineages. To characterise the phenotypes of senescent cancer cells, two murine cell lines were employed in the present study: TC-1 and B16F10 (B16) cells. Two distinct senescence inductors were used: Chemotherapeutic agent docetaxel (DTX) and a combination of immunomodulatory cytokines, including interferon γ (IFNγ) and tumour necrosis factor α (TNFα). It was demonstrated that DTX induced senescence in TC-1 and B16 tumour cell lines, which was demonstrated by growth arrest, positive β-galactosidase staining, increased p21Waf1 (p21) expression and the typical SASP capable of inducing a 'bystander' senescence. By contrast, treatment with a combination of T helper cell 1 cytokines, IFNγ and TNFα, induced proliferation arrest only in B16 cells. Despite the presence of certain characteristic features resembling senescent cells (proliferation arrest, morphological changes and increased p21 expression), these cells were able to form tumours in vivo and started to proliferate upon cytokine withdrawal. In addition, B16 cells were not able to induce a 'bystander' senescence. In summary, the present study described cell line- and treatment-associated differences in the phenotypes of senescent cells that may be relevant in optimization of cancer chemo- and immunotherapy.

• MeSH
• Bystander Effect drug effects   immunology   MeSH
• Docetaxel pharmacology   therapeutic use   MeSH
• Phenotype MeSH
• Interferon-gamma immunology   metabolism   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neoplasms drug therapy   immunology   pathology   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Cellular Senescence drug effects   immunology   MeSH
• Tumor Necrosis Factor-alpha immunology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Docetaxel MeSH
• IFNG protein, mouse MeSH Browser
• Interferon-gamma MeSH
• Antineoplastic Agents MeSH
• Tumor Necrosis Factor-alpha MeSH

Host's physiology is significantly influenced by microbiota colonizing the epithelial surfaces. Complex microbial communities contribute to proper mucosal barrier function, immune response, and prevention of pathogen invasion and have many other crucial functions. The oral cavity and large intestine are distant parts of the digestive tract, both heavily colonized by commensal microbiota. Nevertheless, they feature different proportions of major bacterial and fungal phyla, mostly due to distinct epithelial layers organization and different oxygen levels. A few obligate anaerobic strains inhabiting the oral cavity are involved in the pathogenesis of oral diseases. Interestingly, these microbiota components are also enriched in gut inflammatory and tumor tissue. An altered microbiota composition - dysbiosis - and formation of polymicrobial biofilms seem to play important roles in the development of oral diseases and colorectal cancer. In this review, we describe the differences in composition of commensal microbiota in the oral cavity and large intestine and the mechanisms by which microbiota affect the inflammatory and carcinogenic response of the host.

• Keywords
• Fusobacterium, biofilm, dysbiosis, microbiome, mycobiome, oral diseases, pathobiont,
• Publication type
• Journal Article MeSH
• Review MeSH

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammation-related changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosis in vitro. To provide insights into in vivo effects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement with in vitro experiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC.

• Keywords
• 5-azacytidine, DNA damage, bone marrow plasma, cytokines, inflammation, myelodysplastic syndromes,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Many cancers arise at sites of infection and inflammation. Cellular senescence, a permanent state of cell cycle arrest that provides a barrier against tumorigenesis, is accompanied by elevated proinflammatory cytokines such as IL1, IL6, IL8 and TNFα. Here we demonstrate that media conditioned by cells undergoing any of the three main forms of senescence, i.e. replicative, oncogene- and drug-induced, contain high levels of IL1, IL6, and TGFb capable of inducing reactive oxygen species (ROS)-mediated DNA damage response (DDR). Persistent cytokine signaling and activated DDR evoke senescence in normal bystander cells, accompanied by activation of the JAK/STAT, TGFβ/SMAD and IL1/NFκB signaling pathways. Whereas inhibition of IL6/STAT signaling had no effect on DDR induction in bystander cells, inhibition of either TGFβ/SMAD or IL1/NFκB pathway resulted in decreased ROS production and reduced DDR in bystander cells. Simultaneous inhibition of both TGFβ/SMAD and IL1/NFκB pathways completely suppressed DDR indicating that IL1 and TGFβ cooperate to induce and/or maintain bystander senescence. Furthermore, the observed IL1- and TGFβ-induced expression of NAPDH oxidase Nox4 indicates a mechanistic link between the senescence-associated secretory phenotype (SASP) and DNA damage signaling as a feature shared by development of all major forms of paracrine bystander senescence.

• MeSH
• Cell Line MeSH
• Bystander Effect drug effects   MeSH
• Etoposide pharmacology   MeSH
• Genes, ras * MeSH
• Interleukin-1 metabolism   MeSH
• Interleukin-6 metabolism   MeSH
• Janus Kinases metabolism   MeSH
• Culture Media, Conditioned metabolism   MeSH
• Humans MeSH
• NADPH Oxidase 4 MeSH
• NADPH Oxidases metabolism   MeSH
• NF-kappa B metabolism   MeSH
• Oxidative Stress drug effects   MeSH
• Paracrine Communication drug effects   MeSH
• DNA Damage * MeSH
• Cell Proliferation * MeSH
• Smad Proteins metabolism   MeSH
• RNA Interference MeSH
• Signal Transduction drug effects   MeSH
• Cellular Senescence drug effects   MeSH
• Transfection MeSH
• Transforming Growth Factor beta metabolism   MeSH
• STAT Transcription Factors metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Etoposide MeSH
• IL6 protein, human MeSH Browser
• Interleukin-1 MeSH
• Interleukin-6 MeSH
• Janus Kinases MeSH
• Culture Media, Conditioned MeSH
• NADPH Oxidase 4 MeSH
• NADPH Oxidases MeSH
• NF-kappa B MeSH
• NOX4 protein, human MeSH Browser
• Smad Proteins MeSH
• Transforming Growth Factor beta MeSH
• STAT Transcription Factors MeSH

Tumor suppressor PML is induced under viral and genotoxic stresses by interferons and JAK-STAT signaling. However, the mechanism responsible for its cell type-specific regulation under non-stimulated conditions is poorly understood. To analyze the variation of PML expression, we utilized three human cell types, BJ fibroblasts and HeLa and U2OS cell lines, each with a distinct PML expression pattern. Analysis of JAK-STAT signaling in the three cell lines revealed differences in levels of activated STAT3 but not STAT1 correlating with PML mRNA and protein levels. RNAi-mediated knockdown of STAT3 decreased PML expression; both STAT3 level/activity and PML expression relied on IL6 secreted into culture media. We mapped the IL6-responsive sequence to an ISRE(-595/-628) element of the PML promoter. The PI3K/Akt/NFκB branch of IL6 signaling showed also cell-type dependence, being highest in BJ, intermediate in HeLa, and lowest in U2OS cells and correlated with IL6 secretion. RNAi-mediated knockdown of NEMO (NF-κ-B essential modulator), a key component of NFκB activation, suppressed NFκB targets LMP2 and IRF1 together with STAT3 and PML. Combined knockdown of STAT3 and NEMO did not further promote PML suppression, and it can be bypassed by exogenous IL6, indicating the NF-κB pathway acts upstream of JAK-STAT3 through induction of IL6. Our results indicate that the cell type-specific activity of IL6 signaling pathways governs PML expression under unperturbed growth conditions. As IL6 is induced in response to various viral and genotoxic stresses, this cytokine may regulate autocrine/paracrine induction of PML under these pathophysiological states as part of tissue adaptation to local stress.

• MeSH
• Leukemia, Promyelocytic, Acute metabolism   pathology   MeSH
• Chromatin Immunoprecipitation MeSH
• DNA Primers MeSH
• Fluorescent Antibody Technique, Indirect MeSH
• HeLa Cells MeSH
• Interleukin-6 metabolism   MeSH
• Nuclear Proteins metabolism   MeSH
• Janus Kinases metabolism   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Humans MeSH
• Tumor Suppressor Proteins metabolism   MeSH
• Promyelocytic Leukemia Protein MeSH
• Base Sequence MeSH
• Signal Transduction * MeSH
• STAT Transcription Factors metabolism   MeSH
• Transcription Factors metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• DNA Primers MeSH
• Interleukin-6 MeSH
• Nuclear Proteins MeSH
• Janus Kinases MeSH
• Tumor Suppressor Proteins MeSH
• PML protein, human MeSH Browser
• Promyelocytic Leukemia Protein MeSH
• STAT Transcription Factors MeSH
• Transcription Factors MeSH