scholarly journals 673 (Re-) Solving the biology of colorectal cancer onset and progression to improve treatment and prevention

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A701-A701
Author(s):  
Jessica Roelands ◽  
Manon van der Ploeg ◽  
Hao Dang ◽  
Lukas Hawinkels ◽  
Hans Morreau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Invasive Carcinoma ◽  
Early Stage ◽  
Normal Epithelium ◽  
Spatial Profiling ◽  
Transcriptional Alterations ◽  
Transition Areas ◽  
Different Levels

BackgroundColorectal cancer (CRC) development is accompanied by the gradual accumulation of genetic alterations in epithelial cells of the colon and rectum.1 2 The paradigm of the adenoma-carcinoma sequence was originally centered around cancer cells; however, it is now clear that the tumor microenvironment plays a substantial role in cancer progression and patient outcome.3 In recent years, technologies have evolved rapidly, allowing the multiplexed quantification of gene expression while preserving spatial context.4 Furthermore, some spatial transcriptomic technologies also allow the parallel interrogation of different cell populations in the tumor microenvironment. Here, we performed digital spatial profiling on early-stage CRC samples to elucidate the biological processes that are at the basis of malignant transformation and to identify novel therapeutic targets and (immune) biomarkers.MethodsEndoscopically resected early-stage CRC samples were obtained at Leiden University Medical Center. In total, 144 areas of illumination were interrogated with GeoMx digital spatial profiling using the Cancer Transcriptome Atlas (>1,800 genes). In each of eight samples, nine regions of interest with different levels of cancer progression were selected, including normal epithelium, transition areas, low-, and high-grade dysplasia, and invasive carcinoma (figure 1A). We segmented each region based on cytokeratin and vimentin protein expression (figure 1B). Immunohistochemical detection was performed on these samples and 26 additional samples to validate targets associated with disease progression.ResultsDigital spatial profiling allowed us to dissect transcriptional alterations in epithelial and stromal fractions between different regions from healthy tissue, different degrees of dysplasia, and cancer. Gene expression data revealed a clear separation of profiled areas by histologic category. Interestingly, gene expression features in the stromal compartment provided a better data-driven separation of histologic categories than the epithelial fraction (figure 1C). Substantial changes in immune-related pathways were identified, including differential expression of specific immunomodulators. We validated the expression of several candidate biomarkers/targets that demonstrated consistent alterations from normal tissue to cancer by immunohistochemistry. Several proteins were identified that could clearly discriminate benign from malignant tissue.ConclusionsWe here demonstrated the unique biological insights that are provided by spatial examination of early-stage CRC by digital spatial profiling. We identified specific genes that were altered during CRC tumorigenesis, in epithelial and stromal/immune fractions. Furthermore, our results indicate an essential role for innate immunity in colorectal cancer onset and progression. The genes identified by this approach could potentially serve as novel biomarkers and targets for early interception or prevention of CRC development.AcknowledgementsThis work was supported by the European Research Council (ERC) Starting grant awarded to Dr. Noel F. de Miranda and the Stichting Management Apothekers en de Gezondheidszorg (STIMAG) Research grant awarded to Jessica Roelands.Trial RegistrationN/AReferencesFearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61(5):759–767. doi: 10.1016/0092-8674(90)90186-I.Nowell PC. The clonal evolution of tumor cell populations. Science 1976;194(4260):23–28. doi: 10.1126/science.959840.Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013.Merritt CR, et al. Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat Biotechnol 2020;38(5):586–599. doi: 10.1038/s41587-020-0472-9.Ethics ApprovalThis study was approved by the METC Leiden-Den Haag-Delft (protocol B20.039). Patient samples were anonymised and handled according to the medical ethical guidelines described in the Code of Conduct for Proper Secondary Use of Human Tissue of the Dutch Federation of Biomedical Scientific Societies.Abstract 673 Figure 1Transcriptional alterations in early-stage colorectal cancer. Digital spatial profiling defines transcriptional alterations in early-stage colorectal cancer. (A) Schematic representation of an early-stage CRC sample containing regions with different levels of cancer progression, including normal epithelium, transition areas, low-, and high-grade dysplasia, and invasive carcinoma. (B) Segmentation based immunofluorescent labelling with antibodies directed against PanCK and Vimentin in one of the early-stage CRC samples. Artificial overlay of implemented segmentation is indicated for each ROI, visualizing Vimentin+ (pink) and PanCK+ (orange) segments. Inset: higher magnification of an individual ROI. (C) Dimension reduction of expression of all quantified genes by t-Distributed Stochastic Neighbor Embedding (tSNE). tSNE plots are annotated by segment (left), and histological region (right).

The prostaglandine E2 transporting organic anion transporting polypeptide OATP4A1: A potential prognostic marker in colorectal cancer?

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 430-430
Author(s):  
Veronika Buxhofer-Ausch ◽  
Christoph A. Ausch ◽  
Heike Bauer ◽  
Marina Mollik ◽  
Aida Larijani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Marker ◽  
Cell Lines ◽  
Cancer Progression ◽  
Early Stage ◽  
Organic Anion ◽  
Staining Intensity ◽  
Clinical Impact ◽  
Well Differentiated ◽  
Inflammatory Infiltrates

430 Background: Organic anions transporters (OATPs) are important for tumor progression and therapeutic response by regulating cellular levels of hormones, second messenger proteins and drugs. OATP4A1 is a transporter of pro-inflammatory prostaglandin E2 and may contribute to cancer progression. Data on the expression of OATP4A1 and its clinical impact in primary colorectal cancer (CRC) is rare. Our study was designed to proof the overexpression of OATP4A1 in primary CRC. Methods: Frozen samples from 20 unselected CRC patients (pat) and five CRC cell lines were analyzed for OATP4A1 mRNA expression by real time PCR (mean level normalized to the calibrator, MNE). Immunohistochemistry was performed on paraffin- embedded tumor sections from 50 CRC pat., UICC 0-II (25/50 with subsequent relapse). An automatic quantitative image analysis program was applied to quantify OATP4A1 expression. Expression and intensity was correlated with clinical parameters and relapses. Results: Significant (p>0.05) higher levels of OATP4A1 mRNA were observed in 20 cancer samples as compared to adjacent non-cancerous tissue (2.44 vs. 0.46 MNE). The highest expression (9.85 MNE) was observed in a well-differentiated tumor sample. Similar high levels were observed in the COGA1A cell line, expression in the other cell lines ranged between 1.83 and 0.28 MNE. Immunoreactive staining for OATP4A1 was located in the membrane and occasionally in the cytosol of tumor cells, it was exclusively membrane located in the adjacent non-cancerous epithelial cells. The staining intensity was significantly higher in cancer cells compared to non-cancerous areas (1528±326 vs.376±218) while staining of stroma cells was only occasionally detectable. Surprisingly, the highest OATP4A1 levels were observed in immune cells (2839±381 vs.298±56). Data on the clinical impact of OATP4A1 in the early stage CRC pat. will be presented at the meeting. Conclusions: The profound expression of OATP4A1 in CRC cells and in the inflammatory infiltrates supports its implication on cancer progression. Suitability of OATP4A1 as a potential prognostic marker has to be established on a larger patient collective.

Impaired Metabolic Pathways Related to Colorectal Cancer Progression and Therapeutic Implications

2020 ◽  
Author(s):  
Chunyan QIU ◽  
Yue ZHANG ◽  
Longhua CHEN
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Primary Tumor ◽  
Metabolic Pathways ◽  
Expression Patterns ◽  
Tumor Grade ◽  
Functional Enrichment ◽  
Cancer Center ◽  
Gene Expression Patterns

Background: Risk of colorectal cancer (CRC) is defined by genetic predisposition and environmental factors that often co-occur and interact, resulting in diversiform biological reactions. The present study attempted to investigate transcriptome alteration and adaptation associated with CRC progression. Methods: The study consisted of patients who presented at Memorial Sloan-Kettering Cancer Center, Guangzhou, China with a colonic neoplasm in 1992-2004. Microarray GSE41258 of the study was acquired from Gene Expression Omnibus and 253 included microarrays were categorized by groups of normal colon, early primary tumor, lymph node metastases primary tumor, advanced primary tumor and distant metastases. Short Time-series Expression Miner (STEM) was applied to discover tumor grade-dependent gene expression patterns. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to explore functional enrichment of differential expression genes (DEGs). Results: Overall, 2870 significant DEGs were screened out on all groups. Six significant grade-dependent gene expression patterns were statistically significant. DEGs in all significant patterns were mainly assembled in GO terms of metastases and deterioration of tumor, epithelial proteins and cytokines, and protein binding and bridging. DEGs in profile 0 down-regulated with higher tumor grade, prominently enriched in KEGG pathways of metabolism. Conclusion: Besides many well-known colorectal cancer-related pathways, DEGs of profiles especially those down-regulated with CRC progression, clustered in various metabolic pathways including starch and sucrose metabolism, fatty acid metabolism, nitrogen metabolism, as well as xenobiotics biotransformation that link to tumorigenesis, demonstrating the impairment of physiological metabolic pathways in the context of tumor progression. These results gave a high potential for therapeutic strategies.

scholarly journals Gene Expression Signatures of a Preclinical Mouse Model during Colorectal Cancer Progression under Low-Dose Metronomic Chemotherapy

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 49
Author(s):  
Hung Ho-Xuan ◽  
Gerhard Lehmann ◽  
Petar Glazar ◽  
Foivos Gypas ◽  
Norbert Eichner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Metronomic Chemotherapy ◽  
Circular Rnas ◽  
Primary Tumors ◽  
Non Coding Rnas ◽  
Chemotherapeutic Treatment ◽  
Colorectal Cancer Progression

Understanding the molecular signatures of colorectal cancer progression under chemotherapeutic treatment will be crucial for the success of future therapy improvements. Here, we used a xenograft-based mouse model to investigate, how whole transcriptome signatures change during metastatic colorectal cancer progression and how such signatures are affected by LDM chemotherapy using RNA sequencing. We characterized mRNAs as well as non-coding RNAs such as microRNAs, long non-coding RNAs and circular RNAs in colorectal-cancer bearing mice with or without LDM chemotherapy. Furthermore, we found that circZNF609 functions as oncogene, since over-expression studies lead to an increased tumor growth while specific knock down results in smaller tumors. Our data represent novel insights into the relevance of non-coding and circRNAs in colorectal cancer and provide a comprehensive resource of gene expression changes in primary tumors and metastases. In addition, we present candidate genes that could be important modulators for successful LDM chemotherapy.

scholarly journals High level of Nm23-H1 gene expression is associated with local colorectal cancer progression not with metastases

1994 ◽  
Vol 70 (5) ◽  
pp. 1025-1030 ◽  
Author(s):  
ZS Zeng ◽  
S Hsu ◽  
ZF Zhang ◽  
AM Cohen ◽  
WE Enker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Colorectal Cancer Progression ◽  
High Level

Gene Expression Signature to Improve Prognosis Prediction of Stage II and III Colorectal Cancer

2011 ◽  
Vol 29 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Ramon Salazar ◽  
Paul Roepman ◽  
Gabriel Capella ◽  
Victor Moreno ◽  
Iris Simon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
High Risk ◽  
Early Stage ◽  
Survival Rates ◽  
Gene Expression Signature ◽  
Stage I ◽  
Stage Ii ◽  
Free Survival ◽  
Risk Of Cancer

Purpose This study aims to develop a robust gene expression classifier that can predict disease relapse in patients with early-stage colorectal cancer (CRC). Patients and Methods Fresh frozen tumor tissue from 188 patients with stage I to IV CRC undergoing surgery was analyzed using Agilent 44K oligonucleotide arrays. Median follow-up time was 65.1 months, and the majority of patients (83.6%) did not receive adjuvant chemotherapy. A nearest mean classifier was developed using a cross-validation procedure to score all genes for their association with 5-year distant metastasis–free survival. Results An optimal set of 18 genes was identified and used to construct a prognostic classifier (ColoPrint). The signature was validated on an independent set of 206 samples from patients with stage I, II, and III CRC. The signature classified 60% of patients as low risk and 40% as high risk. Five-year relapse-free survival rates were 87.6% (95% CI, 81.5% to 93.7%) and 67.2% (95% CI, 55.4% to 79.0%) for low- and high-risk patients, respectively, with a hazard ratio (HR) of 2.5 (95% CI, 1.33 to 4.73; P = .005). In multivariate analysis, the signature remained one of the most significant prognostic factors, with an HR of 2.69 (95% CI, 1.41 to 5.14; P = .003). In patients with stage II CRC, the signature had an HR of 3.34 (P = .017) and was superior to American Society of Clinical Oncology criteria in assessing the risk of cancer recurrence without prescreening for microsatellite instability (MSI). Conclusion ColoPrint significantly improves the prognostic accuracy of pathologic factors and MSI in patients with stage II and III CRC and facilitates the identification of patients with stage II disease who may be safely managed without chemotherapy.

scholarly journals Study of FGF14 gene expression and cancer progression in colorectal cancer tissue samples

2019 ◽  
Vol 29 (3) ◽  
pp. 210-215
Author(s):  
Homayoun Jalali Tafti ◽  
Mehrdad Hashemi ◽  
Khalil Alimohammadzadeh ◽  
◽  
◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Cancer Tissue ◽  
Tissue Samples ◽  
Colorectal Cancer Tissue

MicroRNA regulation of radiation sensitivity in colorectal cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 608-608
Author(s):  
Shushan Rajesh Rana ◽  
Katherine Kelley ◽  
Rebecca Ruhl ◽  
Charles R. Thomas ◽  
Vassiliki Liana Tsikitis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Locally Advanced ◽  
Radiation Sensitivity ◽  
Colorectal Cancers ◽  
Specific Gene ◽  
Mesenchymal Transition

608 Background: Patients with locally advanced colorectal cancer (T3/T4/Node positive) receive neoadjuvant chemoradiation therapy (CRT) and subsequent surgery. While 10-25% of patients have complete response to CRT, the remaining patients undergo extensive tumor excision that leads to quality of life issues. Response to CRT is an independent predictor of overall survival highlighting the importance of improving CRT response rates. Several tumor intrinsic factors govern responses to CRT including specific gene expression programs. Emerging evidence suggests that microRNAs (miRs) modulate gene expression programs in response to radiation. Moreover, miR-processing machinery is frequently mutated in colorectal cancers (TCGA, 2016 provisional). miRs have been implicated in several pathological processes associated with colorectal cancer progression including cancer stemness and epithelial-to-mesenchymal transition (EMT). In this context, we hypothesized that differential expression of miRs regulates colorectal cancer radiation sensitivity and therefore can be used as a biomarker to predict therapeutic responses to radiation. Methods: To investigate the differences in miR profiles between rectal cancer patients that had either a pathological partial response (PR) or no response (NR), we isolated RNA from FFPE biopsies using the miRvana microRNA isolation kit (Life Technologies). We used the Nanostring miR profiling platform and obtained absolute counts for > 700 human miRs of which ~500 miRs were expressed above detection limits (cut-off of 20 counts after normalization to the top-100 miRs). We performed in vitro gain and loss of studies with miR transfections in human CRC cell lines with RNAimax reagent and used a luminescence-based assay for proliferation (Cell titer glo, Promega). We performed surviving fraction assays by seeding cells on 6 well plate and counting colonies stained with Methylene Blue. Results: We identified seventeen miRs that were differentially expressed. Among the most upregulated in this group, miR-451a, inhibited proliferation and colony formation in 2D and 3D assays in the presence of radiation. Conclusions: Our data suggests miRs may alter cell survival pathways and affect tumor radiosensitivity.

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