M2-Polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma

OBJECTIVES: Tumor-associated macrophages have been implicated in promoting tumor growth, progression and metastasis. However, the activated phenotype (M1 or M2) of tumor-associated macrophages remains unknown in solid tumors. Therefore, this study examined the density and prognostic significance of M2-polarized tumor-associated macrophages in lung adenocarcinoma. METHODS: Tumor specimens from 65 lung adenocarcinoma patients were assessed by ELISA for Th1/Th2 cytokine concentrations. The activated phenotype (M1 or M2) of tumor-associated macrophages was determined utilizing immunofluorescence staining. Additionally, to evaluate lymphangiogenesis, peritumoral lymphatic microvessel density was measured using D2-40. The correlation between tumor-associated macrophage subtype and overall patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. RESULTS: A shift toward Th2 cytokine expression was detected within lung adenocarcinoma microenvironments. Approximately 79.71±16.27% of tumor-associated macrophages were M2 polarized; the remaining 20.35±5.31% were M1 polarized. The infiltration of M2-polarized macrophages was significantly associated with P-TNM staging and lymph node metastasis. The peritumoral lymphatic microvessel density was significantly higher in the high M2-polarized tumor-associated macrophage group than in the low M2-polarized tumor-associated macrophage group. A significant difference in overall patient survival was detected not only between patients with tumors with high and low macrophage counts but also between patients with tumors with high and low counts of M2-polarized macrophages. CONCLUSION: Tumor-associated macrophages in lung adenocarcinoma have an M2-polarized subtype and are associated with poor prognoses, perhaps resulting from accelerated lymphangiogenesis and lymph node metastasis

M2-polarized macrophages promote metastatic behavior of Lewis lung carcinoma cells by inducing vascular endothelial growth factor-C expression

OBJECTIVES: Tumor-associated macrophages that generally exhibit an alternatively activated (M2) phenotype have been linked to tumor progression and metastasis. However, the role of M2-polarized macrophages in the growth and metastasis of lung adenocarcinoma remains enigmatic. The aim of this study was to explore the effect of M2 macrophages on the proliferation and migration of mouse Lewis lung carcinoma cells and tumor-induced lymphangiogenesis. METHODS: Trypan blue staining and the Transwell migration assay were performed to evaluate the effects of activated (M1 or M2) macrophages on the proliferation and migration of Lewis cells. Furthermore, vascular endothelial growth factor-C expression in Lewis cells and nitric oxide secretion from activated macrophages were detected during the co-culture assay. Following treatment with activated macrophages, lymphatic endothelial cells differentiated into capillary-like structures, and the induction of Lewis cell migration was assessed using a twodimensional Matrigel-based assay. RESULTS: In the co-culture Transwell system, the proliferation and migration of Lewis cells were promoted by M2 macrophages. Moreover, the co-culture significantly increased the expression of vascular endothelial growth factor-C by Lewis cells and reduced the secretion of nitric oxide from M2 macrophages, which subsequently led to the capillary morphogenesis of lymphatic endothelial cells. Interestingly, following co-culture with Lewis cells, the function of RAW264.7 cells was polarized toward that of the M2 macrophage phenotype. CONCLUSION: M2-polarized macrophages promoted the metastatic behavior of Lewis cells by inducing vascular endothelial growth factor-C expression. Thus, the interruption of signaling between M2 macrophages and Lewis cells may be considered to be a new therapeutic strategy

Polo-like kinase 1 (Plk1) overexpression enhances ionizing radiation-induced cancer formation in mice

Polo-like kinase 1 (Plk1), a serine/threonine protein kinase normally expressed in mitosis, is frequently up-regulated in multiple types of human tumors regardless of the cell cycle stage. However, the causal relationship between Plk1 up-regulation and tumorigenesis is incompletely investigated. To this end, using a conditional expression system, here we generated Plk1 transgenic mouse lines to examine the role of Plk1 in tumorigenesis. Plk1 overexpression in mouse embryonic fibroblasts prepared from the transgenic mice led to aberrant mitosis followed by aneuploidy and apoptosis. Surprisingly, Plk1 overexpression had no apparent phenotypes in the mice. Given that no malignant tumor formation was observed even after a long period of Plk1 overexpression, we reasoned that additional factors are required for tumorigenesis in Plk1-overexpressing mice. Because Plk1 can directly participate in the regulation of the DNA damage response (DDR) pathway, we challenged Plk1-overexpressing mice with ionizing radiation (IR) and found that Plk1-overexpressing mice are much more sensitive to IR than their wild-type littermates. Analysis of tumor development in the Plk1-overexpressing mice indicated a marked decrease in the time required for tumor emergence after IR. At the molecular level, Plk1 overexpression led to reduced phosphorylation of the serine/threonine kinases ATM and Chk2 and of histone H2AX after IR treatment both in vivo and in vitro Furthermore, RNA-Seq analysis suggested that Plk1 elevation decreases the expression of several DDR genes. We conclude that Plk1 overexpression may contribute to tumor formation by both inducing chromosomal instability and suppressing the DDR pathway

Synergistic growth inhibition by sorafenib and vitamin K2 in human hepatocellular carcinoma cells

OBJECTIVE: Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in hepatocellular carcinoma, and there is a strong rationale for investigating its use in combination with other agents. Vitamin K2 is nearly non-toxic to humans and has been shown to inhibit the growth of hepatocellular carcinoma. In this study, we evaluated the effects of a combination of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. METHODS: Flow cytometry, 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) and nude mouse xenograft assays were used to examine the effects of sorafenib and vitamin K2 on the growth of hepatocellular carcinoma cells. Western blotting was used to elucidate the possible mechanisms underlying these effects. RESULTS: Assays for 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) revealed a strong synergistic growth-inhibitory effect between sorafenib and vitamin K2. Flow cytometry showed an increase in cell cycle arrest and apoptosis after treatment with a combination of these two drugs at low concentrations. Sorafenib-mediated inhibition of extracellular signal-regulated kinase phosphorylation was promoted by vitamin K2, and downregulation of Mcl-1, which is required for sorafenib-induced apoptosis, was observed after combined treatment. Vitamin K2 also attenuated the downregulation of p21 expression induced by sorafenib, which may represent the mechanism by which vitamin K2 promotes the inhibitory effects of sorafenib on cell proliferation. Moreover, the combination of sorafenib and vitamin K2 significantly inhibited the growth of hepatocellular carcinoma xenografts in nude mice. CONCLUSIONS: Our results determined that combined treatment with sorafenib and vitamin K2 can work synergistically to inhibit the growth of hepatocellular carcinoma cells. This finding raises the possibility that this combined treatment strategy might be promising as a new therapy against hepatocellular carcinoma, especially for patients with poor liver tolerance

O-GlcNAcylation of G6PD Promotes the Pentose Phosphate Pathway and Tumor Growth

The pentose phosphate pathway (PPP) plays a critical role in macromolecule biosynthesis and maintaining cellular redox homoeostasis in rapidly proliferating cells. Upregulation of the PPP has been shown in several types of cancer. However, how the PPP is regulated to confer a selective growth advantage on cancer cells is not well understood. Here we show that glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is dynamically modified with an O-linked b-N-acetylglucosamine sugar in response to hypoxia. Glycosylation activates G6PD activity and increases glucose flux through the PPP, thereby providing precursors for nucleotide and lipid biosynthesis, and reducing equivalents for antioxidant defense. Blocking glycosylation of G6PD reduces cancer cell proliferation in vitro and impairs tumor growth in vivo. Importantly, G6PD glycosylation is increased in human lung cancers. Our findings reveal a mechanistic understanding of how O-glycosylation directly regulates the PPP to confer a selective growth advantage to tumours

Photoflexoelectric effect in halide perovskites

Harvesting environmental energy to generate electricity is a key scientific and technological endeavour of our time. Photovoltaic conversion and electromechanical transduction are two common energy-harvesting mechanisms based on, respectively, semiconducting junctions and piezoelectric insulators. However, the different material families on which these transduction phenomena are based complicate their integration into single devices. Here we demonstrate that halide perovskites, a family of highly efficient photovoltaic materials, display a photoflexoelectric effect whereby, under a combination of illumination and oscillation driven by a piezoelectric actuator, they generate orders of magnitude higher flexoelectricity than in the dark. We also show that photoflexoelectricity is not exclusive to halides but a general property of semiconductors that potentially enables simultaneous electromechanical and photovoltaic transduction and harvesting in unison from multiple energy inputs

Colloidal Metal-Halide Perovskite Nanoplatelets: Thickness-Controlled Synthesis, Properties, and Application in Light-Emitting Diodes.

Colloidal metal-halide perovskite nanocrystals (MHP NCs) are gaining significant attention for a wide range of optoelectronics applications owing to their exciting properties, such as defect tolerance, near-unity photoluminescence quantum yield, and tunable emission across the entire visible wavelength range. Although the optical properties of MHP NCs are easily tunable through their halide composition, they suffer from light-induced halide phase segregation that limits their use in devices. However, MHPs can be synthesized in the form of colloidal nanoplatelets (NPls) with monolayer (ML)-level thickness control, exhibiting strong quantum confinement effects, and thus enabling tunable emission across the entire visible wavelength range by controlling the thickness of bromide or iodide-based lead-halide perovskite NPls. In addition, the NPls exhibit narrow emission peaks, have high exciton binding energies, and a higher fraction of radiative recombination compared to their bulk counterparts, making them ideal candidates for applications in light-emitting diodes (LEDs). This review discusses the state-of-the-art in colloidal MHP NPls: synthetic routes, thickness-controlled synthesis of both organic-inorganic hybrid and all-inorganic MHP NPls, their linear and nonlinear optical properties (including charge-carrier dynamics), and their performance in LEDs. Furthermore, the challenges associated with their thickness-controlled synthesis, environmental and thermal stability, and their application in making efficient LEDs are discussed