A broad range of experimental and clinical evidence has highlighted the central role of chronic infl ammation in promoting tumor development. However, the molecular mechanisms converting a transient infl ammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice defi cient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining infl ammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinfl ammatory mediators, maintenance of immune cell infi ltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic infl ammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infi ltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an infl ammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic infl ammation and cancer.
Purpose: Glioblastoma spheroid cultures are enriched in tumor stem-like cells and therefore may be more representative of the respective primary tumors than conventional monolayer cultures. We exploited the glioma spheroid culture model to find novel tumor-relevant genes. Experimental Design: We carried out array-based comparative genomic hybridization of spheroid cultures derived from 20 glioblastomas. Microarray-based gene expression analysis was applied to determine genes with differential expression compared with normal brain tissue and to nonneoplastic brain spheroids in glioma spheroid cultures. The protein expression levels of three candidates were determined by immunohistochemistry on tissue microarrays and correlated with clinical outcome. Functional analysis of PDPN was done. Results: Genomic changes in spheroid cultures closely resembled those detected in primary tumors of the corresponding patients. In contrast, genomic changes in serumgrown monolayer cultures established from the same patients did not match well with the respective primary tumors. Microarray-based gene expression analysis of glioblastoma spheroid cultures identified a set of novel candidate genes being upregulated or downregulated relative to normal brain. Quantitative real-time PCR analyses of 8 selected candidate genes in 20 clinical glioblastoma samples validated the microarray findings. Immunohistochemistry on tissue microarrays revealed that expression of AJAP1, EMP3, and PDPN was significantly associated with overall survival of astrocytic glioma patients. Invasive capacity and RhoA activity were decreased in PDPN-silenced spheroids. Conclusion: We identified a set of novel candidate genes that likely play a role in glioblastoma pathogenesis and implicate AJAP1, EMP3, and PDPN as molecular markers associated with the clinical outcome of glioma patients. (Clin Cancer Res 2009;15(21):6541-50) Glioblastoma is the most common and most malignant primary brain tumor and has one of the worst survival rates among all human cancers. Despite aggressive multimodal treatment, the median survival time after diagnosis has improved only marginally and is still <1 year in population-based studies (1). A better understanding of the complex molecular and cellular mechanisms leading to glioblastoma is an important prerequisite to
The NF-E2-related factor 2 (Nrf2) transcription factor is a potent inducer of cytoprotective genes, which encode--among others--enzymes that detoxify reactive oxygen species (ROS). As we demonstrated a crucial role of Nrf2 in the prevention of skin carcinogenesis, it is of interest to identify Nrf2-activating factors in keratinocytes. For this purpose, keratinocytes from mice transgenic for an Nrf2-responsive reporter gene were analyzed. Electrophilic compounds activated the reporter in keratinocytes, and induced nuclear translocation of Nrf2 and the expression of known Nrf2 target genes. This is biologically relevant, as we show that Nrf2-mediated gene expression protects keratinocytes from the toxicity of these substances. By contrast, hydrogen peroxide, glucose oxidase, UVA, and UVB irradiation had no effect, although these treatments strongly increased the levels of intracellular ROS. To verify these results in vivo, transgenic reporter mice with and without functional Nrf2 alleles were topically treated with electrophilic chemicals or irradiated with UVB. Electrophiles but not UVB activated the reporter in an Nrf2-dependent manner. These results provide the basis for the identification of novel Nrf2 activators in keratinocytes with therapeutic potential for skin tumor prevention.
Cells treated with low doses of linoleic acid hydroperoxide (LoaOOH) exhibit a cell-cycle delay that may provide a mechanism to overcome oxidative stress. Strains sensitive to LoaOOH from the genome-wide deletion collection were screened to identify deletants in which the cell-cycle delay phenotype was reduced. Forty-seven deletants were identified that were unable to mount the normal delay response, implicating the product of the deleted gene in the oxidant-mediated cell-cycle delay of the wild-type. Of these genes, SWI6 was of particular interest due to its role in cell-cycle progression through Start. The swi6 deletant strain was delayed on entry into the cell cycle in the absence of an oxidant, and oxidant addition caused no further delay. Transforming the swi6 deletant with SWI6 on a plasmid restored the G1 arrest in response to LoaOOH, indicating that Swi6p is involved in oxidant sensing leading to cell division delay. Micro-array studies identified genes whose expression in response to LoaOOH depended on SWI6. The screening identified 77 genes that were upregulated in the wild-type strain and concurrently downregulated in the swi6 deletant treated with LoaOOH. These data show that functions such as heat shock response, and glucose transport are involved in the response.
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