Project description:Blood vessels in cancerIntra-tumoral blood vessels are of supreme importance for tumor growth, metastasis and therapy. Yet, little is known about spatial distribution patterns of these vessels. Most experimental or theoretical tumor models implicitly assume that blood vessels are equally abundant in different parts of the tumor, which has far-reaching implications for chemotherapy and tumor metabolism. In contrast, based on histological observations, we hypothesized that blood vessels follow specific spatial distribution patterns in colorectal cancer tissue. We developed and applied a novel computational approach to identify spatial patterns of angiogenesis in histological whole-slide images of human colorectal cancer.A characteristic spatial pattern of blood vessels in colorectal cancerIn 33 of 34 (97%) colorectal cancer primary tumors blood vessels were significantly aggregated in a sharply limited belt-like zone at the interface of tumor tissue to the intestinal lumen. In contrast, in 11 of 11 (100%) colorectal cancer liver metastases, a similar hypervascularized zone could be found at the boundary to surrounding liver tissue. Also, in an independent validation cohort, we found this vascular belt zone: 22 of 23 (96%) samples of primary tumors and 15 of 16 (94%) samples of liver metastases exhibited the above-mentioned spatial distribution.Summary and implicationsWe report consistent spatial patterns of tumor vascularization that may have far-reaching implications for models of drug distribution, tumor metabolism and tumor growth: luminal hypervascularization in colorectal cancer primary tumors is a previously overlooked feature of cancer tissue. In colorectal cancer liver metastases, we describe a corresponding pattern at the invasive margin. These findings add another puzzle piece to the complex concept of tumor heterogeneity.
Project description:In the absence of a primary crop host, secondary plant hosts may act as a reservoir for fungal plant pathogens of agricultural crops. Secondary hosts may potentially harbor heteroecious biotrophs (e.g., the stripe rust fungus Puccinia striiformis) or other pathogens with broad host ranges. Agricultural grain production tends toward monoculture or a limited number of crop hosts over large regions, and local weeds are a major source of potential secondary hosts. In this study, the fungal phyllospheres of 12 weed species common in the agricultural regions of Western Australia (WA) were compared through high-throughput DNA sequencing. Amplicons of D2 and ITS were sequenced on an Illumina MiSeq system using previously published primers and BLAST outputs analyzed using MEGAN. A heatmap of cumulative presence-absence for fungal taxa was generated, and variance patterns were investigated using principal components analysis (PCA) and canonical correspondence analysis (CCA). We observed the presence of several major international crop pathogens, including basidiomycete rusts of the Puccinia spp., and ascomycete phytopathogens of the Leptosphaeria and Pyrenophora genera. Unrelated to crop production, several endemic pathogen species including those infecting Eucalyptus trees were also observed, which was consistent with local native flora. We also observed that differences in latitude or climate zones appeared to influence the geographic distributions of plant pathogenic species more than the presence of compatible host species, with the exception of Brassicaceae host family. There was an increased proportion of necrotrophic Ascomycete species in warmer and drier regions of central WA, compared to an increased proportion of biotrophic Basidiomycete species in cooler and wetter regions in southern WA.
Project description:BackgroundOver the past years, some members of the family of suppressor of cytokine signalling (SOCS) proteins have emerged as potential tumour suppressors. This study aimed at investigating the clinical significance of SOCS proteins in colorectal carcinoma (CRC).MethodsWe integrated publicly available microarray expression data on CRC in humans, analysed the expression pattern of SOCSs and assessed the predictive power of SOCS2 and SOCS6 for diagnostic purposes by generating receiver operating characteristic curves. Using laser microdissected patient material we assessed SOCS expression on RNA and protein levels as well as their methylation status in an independent CRC patient cohort. Finally, we investigated the prognostic value of SOCS2 and SOCS6.ResultsThe meta-analysis as well as the independent patient cohort analysis reveal a stage-independent downregulation of SOCS2 and SOCS6 and identify both molecules as diagnostic biomarkers for CRC. We demonstrate a different methylation pattern within the SOCS2 promoter between tumour tissue and normal control tissue in 25% of CRC patients. Furthermore, early CRC stage patients with low expression of SOCS2 display significantly shorter disease-free survival.ConclusionsOur data offers evidence that SOCS2 and SOCS6 levels are reduced in CRC and may serve as diagnostic biomarkers for CRC patients.
Project description:Distant metastasis is the major cause of mortality in colorectal cancer (CRC). We performed a systemic, comprehensive discovery for expression patterns of metastasis-specific microRNAs (miRNAs) by directly comparing primary CRCs (pCRCs) and matched liver metastases (LMs) and evaluated the feasibility of their clinical application as metastasis-specific biomarkers. CRC metastasis-specific miRNA profiles were generated by analyzing nine pairs of pCRC and LM tissues, followed by quantitative validation in an independent cohort of 58 pairs of matched pCRC and LM tissues. We evaluated associations between miRNA expression and patient survival and ability to predict metastasis in another 84 patients with CRC. Subsequently, associations were quantitatively validated in 175 CRC tissues and 169 serum samples. Kaplan-Meier, Cox regression, and logistic regression analyses were used. All statistical tests were two-sided. Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM (P < .001; FDR < .5). Four miRNAs downregulated in LM (let-7i, miR-10b, miR-221, and miR-320a) and one upregulated miR (miR-885-5p) were quantitatively validated in pCRC (P < .0001). Low let-7i expression in pCRC tissue predicted worsened prognosis (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 1.0 to 24.4, P = .0479) as well as distant metastasis (odds ratio [OR] = 5.5, 95% CI = 1.1 to 26.8, P = .0334). High miR-10b expression in pCRC tissue independently predicted distant metastasis (OR = 4.9, 95% CI = 1.2 to 19.7, P = .0248). High serum miR-885-5p expression independently predicted prognosis (HR = 2.9, 95% CI = 1.1 to 7.5, P = .0323), LN metastasis (OR = 3.0, 95% CI = 1.3 to 7.2, P = .0116), and distant metastasis (OR = 3.1, 95% CI = 1.0 to 10.0, P = .0456), whereas tissue miR-885-5p expression did not. Expression patterns of miRNAs were confirmed by in situ hybridization. We discovered a metastasis-specific miRNA signature in pCRCs and discovered novel tissue- and serum-based CRC metastasis-specific miRNA biomarkers through intensive validation. These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC.
Project description:The CDw75 epitope is an α(2,6) sialylated antigen overexpressed in colorectal cancer (CRC), where its expression correlates with the progression of the disease. The CDw75 epitope is located mainly in N-glycoproteins, whose identity remains unknown. The aim of the present study was to identify proteins with the CDw75 epitope as a strategy to deepen the understanding of molecular pathogenesis of CRC and to identify novel biomarkers for this disease. For this purpose, a two-dimensional electrophoresis approach was employed. Protein spots in the gels were matched to the corresponding CDw75 positive spots in the immunoblotted polyvinylidene difluoride membranes, and further identification of the protein species was performed by mass spectrometry. Additionally, one-dimensional western blotting experiments were performed to verify the expression of these candidate proteins in the colorectal tissue and their coincidence in molecular mass with the CDw75-positive bands. The findings of the present study indicate that haptoglobin and the keratins 8 (K8) and 18 (K18) are proteins with the CDw75 epitope in the colorectal tissue from CRC patients and also suggest novel functions and cellular locations for these proteins in the colorectal tissue and in relation to CRC.
Project description:The atmospheres of the four giant planets of our Solar System share a common and well-observed characteristic: they each display patterns of planetary banding, with regions of different temperatures, composition, aerosol properties and dynamics separated by strong meridional and vertical gradients in the zonal (i.e., east-west) winds. Remote sensing observations, from both visiting spacecraft and Earth-based astronomical facilities, have revealed the significant variation in environmental conditions from one band to the next. On Jupiter, the reflective white bands of low temperatures, elevated aerosol opacities, and enhancements of quasi-conserved chemical tracers are referred to as 'zones.' Conversely, the darker bands of warmer temperatures, depleted aerosols, and reductions of chemical tracers are known as 'belts.' On Saturn, we define cyclonic belts and anticyclonic zones via their temperature and wind characteristics, although their relation to Saturn's albedo is not as clear as on Jupiter. On distant Uranus and Neptune, the exact relationships between the banded albedo contrasts and the environmental properties is a topic of active study. This review is an attempt to reconcile the observed properties of belts and zones with (i) the meridional overturning inferred from the convergence of eddy angular momentum into the eastward zonal jets at the cloud level on Jupiter and Saturn and the prevalence of moist convective activity in belts; and (ii) the opposing meridional motions inferred from the upper tropospheric temperature structure, which implies decay and dissipation of the zonal jets with altitude above the clouds. These two scenarios suggest meridional circulations in opposing directions, the former suggesting upwelling in belts, the latter suggesting upwelling in zones. Numerical simulations successfully reproduce the former, whereas there is a wealth of observational evidence in support of the latter. This presents an unresolved paradox for our current understanding of the banded structure of giant planet atmospheres, that could be addressed via a multi-tiered vertical structure of "stacked circulation cells," with a natural transition from zonal jet pumping to dissipation as we move from the convectively-unstable mid-troposphere into the stably-stratified upper troposphere.
Project description:Although the effects of vascular endothelial growth factor (VEGF) on angiogenesis and vascular function are well known, the effects of VEGF on tumor cell function remain to be elucidated. We studied phenotypic changes in human colorectal cancer (CRC) cells with homozygous deletion of VEGF alleles to determine the potential direct role of VEGF on tumor cell function. Loss of VEGF expression led to significantly decreased cell growth and increased spontaneous apoptosis in CRC cells (P<0.01). Loss of VEGF also increased the in vitro sensitivity of cells to the cytotoxic effects of the chemotherapeutic drug 5-fluorouracil, as shown by increased apoptosis (P<0.05). These effects were mediated via upregulation of the proapoptotic mediators caspase-3, cleaved PARP and Bax and downregulation of the pro-survival mediator survivin. Our findings suggest a novel and distinct function of VEGF in mediating autocrine/intracrine CRC cell survival.
Project description:Enhancers are often mutated and dysregulated in various diseases such as cancer. By integrating the function annotation of the mammalian genome (FANTOM) enhancers expression profiles and RNA-seq data from The Cancer Genome Atlas (TCGA) of 13 cancers and their corresponding para-cancerous tissues, we systematically identified a total of 4702 significantly differentially expressed (DE) enhancers. Furthermore, a total of 1036 DE genes regulated by DE enhancers were identified. It was found that in these 13 cancers, most (61.13%) enhancers were ubiquitously expressed, whereas DE enhancers were more likely to be tissue-specific expressed, and the DE genes regulated by DE enhancers were significantly enriched in cancer-related pathways. Finally, it was manifested that 74 single nucleotide polymorphisms (SNPs) were located in 37 DE enhancers, and these SNPs affected the gain and loss of functional transcription factor binding sites of 758 transcription factors, which were shown to be highly correlated with tumorigenesis and development.
Project description:Objective To identify differences between the composition, abundance, and biological function of the intestinal microbiome of patients with and without lymph-vascular invasion (LVI) colorectal cancer (CRC) and to construct predictive labels to support accurate assessment of LVI in CRC. Method 134 CRC patients were included, which were divided into two groups according to the presence or absence of LVI, and their intestinal microbiomes were sequenced by 16SrRNA and analyzed for differences. The transcriptome sequencing data of 9 CRC patients were transformed into immune cells abundance matrix by CIBERSORT algorithm, and the correlation among LVI-associated differential intestinal microbiomes, immune cells, immune-related genes and LVI-associated differential GO items and KEGG pathways were analyzed. A random forest (RF) and eXtreme Gradient Boosting (XGB) model were constructed to predict the LVI of CRC patients based on the differential microbiome. Result There was no significant difference in α-diversity and β-diversity of intestinal microbiome between CRC patients with and without LVI (P > 0.05). Linear discriminant analysis Effect Size (LEfSe) analysis showed 34 intestinal microbiomes enriched in CRC patients of the LVI group and 5 intestinal microbiomes were significantly enriched in CRC patients of the non-lymph-vascular invasion (NLVI) group. The RF and XGB prediction models constructed with the top 15% of the LVI-associated differential intestinal microbiomes ranked by feature significance had good efficacy. Conclusions There are 39 intestinal flora with significantly different species abundance between the LVI and NLVI groups. g:Alistipes.s:Alistipes_indistinctus is closely associated with colorectal cancer vascular invasion. LVI-associated differential intestinal flora may be involved in regulating the infiltration of immune cells in CRC and influencing the expression of immune-related genes. LVI-associated differential intestinal flora may influence the process of vascular invasion in CRC through a number of potential biological functions. RF prediction models and XGB prediction models constructed based on microbial markers of gut flora can be used to predict CRC-LVI conditions.