Stage In Colorectal Cancer Patients Research Articles

Intra‐tumoral tumor infiltrating Lymphocyte‐T CD8+ and chemotherapy response in colorectal cancer: A prospective observational study

Background: The immunotherapy approach to colorectal cancer is becoming one of the key approaches to colorectal cancer treatment. One of the components of immune responses is tumor‐infiltrating lymphocyte CD8+ cells (TILs CD8+). While chemotherapy is one of the main treatments for colorectal cancer, we need to consider immunotherapy for advanced colorectal cancer. Thus, this study is aimed at finding the association between TIL CD8+ expression and chemotherapy response. Methods: This is a prospective cohort study with colorectal cancer patients in the Digestive Surgery division of a tertiary general hospital in West Java, Indonesia. An immunohistochemistry examination was used to evaluate the expression of TIL CD8+. The response evaluation criteria in solid tumors (RECIST) were used for the evaluation of chemotherapy response. Results: There were 53 research subjects included. There were 20 (37.7%) subjects with high expression of TILs CD8+; there were 30 (56.6%) subjects in stage III, followed by stage IV (17.32%) and stage II (6.11%). There were 18 subjects (34%) who showed progressive disease, 17 subjects (32.1%) showed partial response, and 16 subjects (30.2%) with high expression of TILs CD8+ showed partial chemotherapy response. The TILs CD8+ expression showed no significant relationship with age, sex, subtype, grade, or tumor location, but showed a significant relationship with stage and chemotherapy response (P < 0.05). Conclusion: High TILs CD8+ expression show a relationship with better chemotherapy response and a better prognosis based on disease stage in colorectal cancer patients.

The correlation between tenascin C levels and clinical stage in colorectal cancer patients

The correlation between tenascin C levels and clinical stage in colorectal cancer patients

Investigating the Feasibility of Predicting KRAS Status, Tumor Staging, and Extramural Venous Invasion in Colorectal Cancer Using Inter-Platform Magnetic Resonance Imaging Radiomic Features

(1) Background: Colorectal cancer is the third most common type of cancer with a high mortality rate and poor prognosis. The accurate prediction of key genetic mutations, such as the KRAS status, tumor staging, and extramural venous invasion (EMVI), is crucial for guiding personalized treatment decisions and improving patients’ outcomes. MRI radiomics was assessed to predict the KRAS status and tumor staging in colorectal cancer patients across different imaging platforms to improve the personalized treatment decisions and outcomes. (2) Methods: Sixty colorectal cancer patients (35M/25F; avg. age 56.3 ± 12.9 years) were treated at an oncology unit. The MRI scans included T2-weighted (T2W) and diffusion-weighted imaging (DWI) or the apparent diffusion coefficient (ADC). The manual segmentation of colorectal cancer was conducted on the T2W and DWI/ADC images. The cohort was split into training and validation sets, and machine learning was used to build predictive models. (3) Results: The neural network (NN) model achieved 73% accuracy and an AUC of 0.71 during training for predicting the KRAS mutation status, while during testing, it achieved 62.5% accuracy and an AUC of 0.68. In the case of tumor grading, the support vector machine (SVM) model excelled with a training accuracy of 72.93% and an AUC of 0.7, and during testing, it reached an accuracy of 72% and an AUC of 0.69. (4) Conclusions: ML models using radiomics from ADC maps and T2-weighted images are effective for distinguishing KRAS genes, tumor grading, and EMVI in colorectal cancer. Standardized protocols are essential to improve MRI radiomics’ reliability in clinical practice.

CTHRC1 promotes colorectal cancer progression by recruiting tumor-associated macrophages via up-regulation of CCL15.

Tumor-associated macrophages (TAMs) represent a key factor in the tumor immune microenvironment (TME), exerting significant influence over tumor migration, invasion, immunosuppressive features, and drug resistance. Collagen triple helix repeat containing 1 (CTHRC1), a 30 KDa protein which was secreted during the tissue-repair process, is highly expressed in several malignant tumors, including colorectal cancer (CRC). Previous studies demonstrated that CTHRC1 expression in TAMs was positively correlated to M2 macrophage polarization and liver metastasis, while our discovery suggesting a novel mechanism that CTHRC1 secreted from cancer cell could indirectly interplay with TAMs. In this study, the high expression level of CTHRC1 was evaluated in CRC based on GEO and TCGA databases. Further, CTHRC1 was detected high in all stages of CRC patients by ELISA and was correlated to poor prognosis. Multispectral imaging of IHC demonstrated that M2 macrophage infiltration was increased accompanied with CTHRC1 enrichment, suggesting that CTHRC1 may have chemotactic effect on macrophages. In vitro, CTHRC1 could have chemotactic ability of macrophage in the presence of HT-29 cell line. Cytokine microarray revealed that CTHRC1 could up-regulate the CCL15 level of HT-29, pathway analysis demonstrated that CTHRC1 could regulate CCL15 by controlling the TGFβ activation and Smad phosphorylation level. In vivo, knocking down of CTHRC1 from CT-26 also inhibits tumor formation. In conclusion, CTHRC1 could promote the chemotactic ability of macrophages by up-regulating CCL15 via TGFβ/Smad pathway; additionally, a high level of CTHRC1 could promote macrophage's M2 polarization. This discovery may be related to tumor immune tolerance and tumor immunotherapy resistance in CRC. KEY MESSAGES: CTHRC1 promotes CRC progression by up-regulating CCL15 via TGF-β/Smad pathways to further recruit tumor-associated macrophages. By the means of autocrine or paracrine, CTHRC1 can indeed promote macrophage chemotaxis and enhance the infiltration of macrophages in tumor tissues but in the presence of tumor cells. CAFs were another source of CTHRC1, indicating CTHRC1 can infiltrate tumor islet as well as the stomal and be secreted from both tumor cells and CAFs. This study validated CTHRC1 as a potential immune therapy target CRC.

Comprehensive analysis identifies novel targets of gemcitabine to improve chemotherapy treatment strategies for colorectal cancer.

Gemcitabine (GEM) is a second-line anticancer drug of choice for some colorectal cancer (CRC) patients, and GEM inability to be commonly available in the clinic due to the lack of clarity of the exact action targets. The half maximal inhibitory concentration (IC50) of GEM treatment for 42 CRC cell lines were accessed from the Genomics of Drug sensitivity in Cancer (GDSC) database. High-throughput sequencing data of CRC patients were captured in The Cancer Genome Atlas (TCGA) and Weighted correlation network analysis (WGCNA) was conducted. Pearson correlations were derived for GEM potency-related genes. Differential analysis was conducted in the TCGA cohort to obtain CRC development-related genes (CDRGs), and univariate COX model analysis was performed on CDRGs overlapping with GEM potency-related genes to obtain CDRGs affecting CRC prognosis. Hub genes affecting GEM potency were identified by Spearman correlation. CALB2 and GPX3 were identified as potential targets for GEM treatment of CRC via prognostic analysis, which we also observed to be elevated with elevated clinical stage in CRC patients. The enhanced expression of CALB2 and GPX3 genes identified in the pathway analysis might inhibit the body metabolism as well as activate immune and inflammation related pathways. In addition, we found that CALB2 and GPX3 could also be considered as prognostic biomarkers in pan-cancer. Finally, we found that CALB2 and GPX3 were remarkably associated with the drug sensitivity of MG-132, Dasatinib, Shikonin, Midostaurin, MS-275, and Z-LNle-CHO, which were expected to be the drugs of choice for GEM combination. CALB2 and GPX3 represent prognostic biomarkers for CRC and they might be potential action targets for GEM. Our study offered innovative ideas for GEM administration strategies.

Preoperative prognostic nutritional index associated with anastomotic leakage in colorectal cancer patients after surgery.

Anastomotic leakage (AL) is a severe complication of colorectal cancer (CRC) surgery and is associated with the immune and nutritional status. This study aimed to investigate the role of the prognostic nutritional index (PNI) in AL in CRC patients after surgery. A retrospective case-control study was designed in a single center. The clinicopathological features and preoperative laboratory data of 124 CRC patients and 120 non-cancer patients who underwent surgery were collected and examined. Among the CRC patients, 24 had AL. Nutritional indicators were lower in CRC patients than in non-cancer patients (p < 0.05), but the clinical parameters analysis showed that only metastasis (M) stage, albumin, carcinoembryonic antigen (CEA), CA153, and PNI were associated with AL in CRC after surgery (p < 0.05). Prognostic nutritional index had a moderate predictive value for AL, with an area under the curve (AUC) of 0.625. Using the median value as a cutoff point, a high PNI was associated with a longer survival time in CRC patients (p = 0.033), and AL showed marginal significance (p = 0.048). The nomogram showed that PNI has a better prognostic value than tumor-node-metastasis (TNM) staging in CRC patients who underwent surgery. Prognostic nutritional index is a useful supplement for predicting AL in CRC patients after colorectal surgery. It also helps predict the prognosis of CRC patients.

Association between immunoscore with lymphovascular invasion and clinical staging in colorectal cancer

Background: Despite the immunoscore benefit function as a prognostic tool in colorectal cancer, no study reports its reason. This study tried to identify the relationship between the immunoscore and the incidence of lymphovascular invasion and clinical stage in colorectal cancer patients as a mechanism for immunoscore to predict the outcome of colorectal cancer. Methods: This is correlational with a cross-sectional study that analyzed medical record data and laboratory results. Immunoscore was collected from an independent private laboratory, and other data (gender, age, diagnosis, tumor location, lymphovascular invasion) were from medical records from the Private Hospital colorectal cancers registry. Data collection was carried out from October to December 2022. We performed data analysis with the Chi-Square statistical test with a significant p-value&lt;0.05. Results: The results showed that the majority of subjects had tumor locations in the rectosigmoid (25%) and advanced stages (65%) with lymphovascular invasion findings (80%). Chi-Square statistical test shows the result of p = 0.025 and p = 0.64, respectively, lymphovascular invasion and clinical staging. Conclusion: This study shows that the immunoscore has a dependent relationship with the incidence of lymphovascular invasion and an independent relationship with the clinical stage of TNM in colorectal cancer patients. The application and use of immunoscore are beneficial for clinicians to give suggestions and understanding to patients about their choice of therapy also outcome for the patient.

Coinfection of HPVs Is Associated with Advanced Stage in Colorectal Cancer Patients from Qatar

High-risk human papillomaviruses (HPVs) are considered risk factors in the origin of several human malignancies, such as breast, cervical, head and neck, as well as colorectal cancers. However, there are no data reported on the HPV status in colorectal cancer in the State of Qatar. Therefore, we herein examined the presence of high-risk HPVs (16, 18, 31, 33, 35, 45, 51, 52, and 59), using polymerase chain reaction (PCR) in a cohort of 100 Qatari colorectal cancer patients, and their association with tumor phenotype. We found that high-risk HPV types 16, 18, 31, 35, 45, 51, 52, and 59 were present in 4, 36, 14, 5, 14, 6, 41, and 17% of our samples, respectively. Overall, 69 (69%) of the 100 samples were HPV positive; among these, 34/100 (34%) were positive for single HPV subtypes, while 35/100 (35%) of the samples were positive for two or more HPV subtypes. No significant association was noted between the presence of HPV and tumor grade, stage, or location. However, the presence of coinfection of HPV subtypes strongly correlated with advanced stage (stage 3 and 4) colorectal cancer, indicating that the copresence of more than one HPV subtype can significantly worsen the prognosis of colorectal cancer. The results from this study imply that coinfection with high-risk HPV subtypes is associated with the development of colorectal cancer in the Qatari population.

Intelligent diagnosis value of preoperative T staging of colorectal cancer based on MR medical imaging.

Colorectal cancer is a common malignant tumor in clinic. With the change of people's diet, living environment and living habits, the incidence of colorectal cancer has risen sharply in recent years, which poses a great threat to people's health and quality of life. This paper aims to investigate the pathogenesis of colorectal cancer and improve the efficiency of clinical diagnosis and treatment. This paper firstly introduces MR Medical imaging technology and related theories of colorectal cancer through literature survey, and then applies MR technology to preoperative T staging of colorectal cancer. 150 patients with colorectal cancer admitted to our hospital every month from January 2019 to January 2020 were used as research objects to carry out the application experiment of MR Medical imaging in the intelligent diagnosis of preoperative T staging of colorectal cancer, and to explore the diagnostic sensitivity, specificity and histopathological T staging diagnosis coincidence rate of MR Staging. The final study results showed that there was no statistical significance in the general data of stage T1-2, T3 and T4 patients (p > 0.05); for patients with preoperative T stage of colorectal cancer, the overall diagnosis coincidence rate of MR Was 89.73%, indicating that it was highly consistent with pathological T stage; compared with MR Staging, the overall diagnosis coincidence rate of CT for preoperative T staging of colorectal cancer patients was 86.73%, which was basically consistent with the diagnosis of pathological T staging. At the same time, three different dictionary learning depth techniques are proposed in this study to solve the shortcomings of long MR Scanning time and slow imaging speed. Through performance testing and comparison, it is found that the structural similarity of MR Image reconstructed by depth dictionary method based on convolutional neural network is up to 99.67%, higher than that of analytic dictionary and synthetic dictionary, which proves that it has the best optimization effect on MR Technology. The study indicated the importance of MR Medical imaging in preoperative T staging diagnosis of colorectal cancer and the necessity of its popularization.

Anti-silencing function 1B knockdown suppresses the malignant phenotype of colorectal cancer by inactivating the phosphatidylinositol 3-kinase/AKT pathway.

Mounting studies have highlighted the pivotal influence of anti-silencing function 1B (ASF1B) on the malignancy of cancers. To explore the influence and mechanism of ASF1B in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA expression of ASF1B. Immunohistochemical staining was performed to detect protein expression of ASF1B and Ki67 in tumor tissues. Western blot analysis was used to determine levels of ASF1B and proliferation/epithelial mesenchymal transition (EMT)/stemness-related proteins. In addition, the proliferation of CRC cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2'-Deoxyuridine assays. The migration and invasion of CRC cells were evaluated using transwell assays. Stemness of CRC cells was tested using the sphere formation assay. To construct a xenograft tumor model, HCT116 cells were introduced into mouse flanks via subcutaneous injection. ASF1B expression was markedly increased in CRC tissues and cells, and it was inversely correlated with overall survival of CRC patients and was positively associated with the tumor node metastasis (TNM) stage of CRC patients. Silencing of ASF1B suppressed proliferation, migration, invasion, stemness and EMT of CRC cells as well as tumorigenesis of xenograft mice. Furthermore, protein levels of P-phosphatidylinositol 3-kinase (p-PI3K) and p-AKT were decreased after silencing of ASF1B in CRC cells. The inhibitory effects of ASF1B knockdown on cell proliferation, stemness and EMT were partly abolished by PI3K activator in CRC cells. Silencing of ASF1B inactivated the PI3K/AKT pathway to suppress CRC malignancy in vitro.

Abstract B013: Activin’s influence on the tumor microenvironment in colon cancer

Abstract Background and aims: Activin A (activin) is a key molecule that regulates cell specific and context dependent signaling in tumor growth and metastasis as well as local and systemic inflammatory responses. Understanding the link between tumor-promotive and inflammatory effects may provide a novel opportunity for targeted therapy in colorectal cancer (CRC). We have previously shown that activin signaling promotes epithelial to mesenchymal transition, tumor migration, and that serum activin correlates with advanced stage in CRC patients. Recently, activin has been implicated in enhancing CD4+ to CD8+ communications to promote cytotoxic elimination of tumor cells. We now hypothesize that activin exerts cell-specific effects in the tumor microenvironment (TME) to both promote anti-tumoral activity of immune cells and pro-metastatic behavior of tumor cells in a context-dependent manner. Methods: Western blot and transwell migration assays with and without activin were performed in human epithelial colon cancer cells with varying expression levels of ACVR2 and in human colonic fibroblasts. The influence of the canonical Smad4 pathway was elucidated in a Ts4-Cre;Apcflox;Smad4flox mouse model for CRC. We analyzed a TMA of 1055 stage II and III CRC patients from the QUASAR2 cohort to correlate activin and CD4+ expression with outcome. The TMAs were also analyzed via Digital Spatial Profiling (DSP, NanoString) to determine the immune cell heterogeneity and cell signaling patterns within the tumor microenvironment relative to activin. Results: The non-canonical pAkt pathway is activated in ACVR2-restored but not ACVR2-mutated HCT116+chr2 colon cancer cells, which leads to tumor cell migration in a PI3K-dependent manner. In vivo, ablation of downstream canonical SMAD signaling is associated with elevated activin, alpha-SMA and pAkt and increases in tissue dysplasia, intestinal stromal disorganization, and animal mortality. While there are direct pro-metastatic effects of activin on tumor cells, activin expression in the TME of stage II or III CRC patients is associated with elevated CD4 and survival benefit (High activin/high CD4: 1.665 hazard ratio, 95% Cl of ratio 1.379 to 2.010). DSP analysis confirmed co-localization of activin with immune cells in the TME which influences cell signaling patterns found in these regions. Conclusion: In colon cancer cells, activin leads to preferential prometastatic PI3K/Akt pathway activation. Within the TME, high levels of activin in the presence of CD4+ T-cells is associated with better outcomes in CRC patients. This work lays the foundation to further study context-dependent activin signaling as an adjunct or target in CRC. Citation Format: Mark B. Wiley, Jessica Bauer, Kunaal Mehrotra, David N. Church, Rachel S. Kerr, David J. Kerr, Paul Grippo, Barbara Jung. Activin’s influence on the tumor microenvironment in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B013.

Abstract 987: Proteomics identifies differences in the biological phenotype of tumor deposits and lymph node metastases in colorectal cancer

Abstract Background: Distant metastatic disease remains the main cause of colorectal cancer (CRC) mortality, but our knowledge on how cancer cells travel from the primary tumor to a secondary site is limited. Lymph node metastases (LNM) play a central role in the staging of CRC patients since they are currently viewed as the gateway to distant metastases. However, in recent years additional forms of locoregional spread with varying prognostic impact have been identified, with tumor deposits (TD) having significantly more impact than LNM. The biological explanation for the difference in prognostic impact between LNM and TD is lacking, while this is essential for a more comprehensive understanding of the role of these biomarkers CRC spread. Therefore, in this study, shotgun proteomics were used to compare the biological phenotype of TD and LNM. Methods: From 12 CRC patients, one TD and one LNM were included for paired protein analyses. Proteins were isolated from formalin-fixed paraffin-embedded tissue after which a filter aided sample preparation method was performed. Then, the samples were analyzed by liquid-chromatography tandem mass-spectrometry, and after data handling and filtering, 5578 differentially expressed proteins were used for downstream analyses. Differences in expression were visualized using heatmaps and volcano plots, and enrichment analyses as well as gene set enrichment was performed. All analyses were performed using R version 4.1.2. Results: Among the main findings was that the proteins ASPN, MRC2, SPON1, MXRA5, BGN, LUM, and PLOD2 were overexpressed in TD. These proteins play a role in stimulating pro-tumorigenic processes such as migration, invasion, and epithelial to mesenchymal transition. For the enrichment analyses all proteins with a Fold change of less than -1 and more than 1 were included. Enrichment analyses using the KEGG pathways showed more immune activity in the LNM, with upregulated B-cell and T-cell signaling (p&amp;lt;0.001), while TD showed more interaction with the extracellular matrix in the form of proteoglycans, focal adhesion, and ECM-receptor interaction (p&amp;lt;0.01). In addition, when hallmarks from the Molecular Signatures Database (MSigDB) were used for the enrichment analyses, TD showed the hallmark of epithelial mesenchymal transition (p &amp;lt;0.005). Conclusions: This study shows that TD have a more aggressive and invasive phenotype compared to LNM on protein level. TD had a higher expression of proteins that promote pro-tumorigenic processes and a more extensive interaction with the extracellular matrix. Furthermore, the hallmark of epithelial mesenchymal transition is enriched in TD compared to LNM. These findings form a possible explanation for the strong prognostic impact of TD, and give insight into the heterogeneity of different modes of locoregional spread in CRC. Citation Format: Nelleke P. Brouwer, Loth Webbink, Shannon Van Lent-Van Vliet, Pascal W. Jansen, Femke Simmer, Daniele V. Tauriello, Michiel Vermeulen, Iris D. Nagtegaal. Proteomics identifies differences in the biological phenotype of tumor deposits and lymph node metastases in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 987.

Circ_0006174 promotes the malignancy of colorectal cancer cell via the miR‑1205/CCBE1/Wnt pathway.

Circular RNAs (circRNAs) are novel RNA transcripts that participate in cancer development. Nonetheless, in colorectal cancer (CRC), the information ~circRNA expression and function is largely unknown. The present study aimed to investigate the expression, function and underlying mechanism of circ_0006174 in CRC. Reverse transcription-quantitative PCR analysis was performed to detect circ_0006174, miR-1205 and calcium-binding epidermal growth factor domain-containing protein 1 (CCBE1) expression levels in CRC tissues and cell lines. Circ_0006174 knockdown CRC cell models were established. CCK-8, TUNEL and Transwell methods were utilized to explore the function of circ_0006174 on the malignant phenotype of CRC cells. Moreover, a xenograft nude mouse model was constructed to verify the effects of circ_0006174 on lung metastasis in vivo. Dual-luciferase reporter gene assay was adopted to prove the association between circ_0006174 and miR-1205, miR-1205 and CCBE1. Gene set enrichment analysis was performed using the LinkedOmics database. Western blotting was performed to evaluate the expression of CCBE1, Ki67 and Wnt pathway-related proteins (c-Myc and cyclin D1) in CRC cell lines. Circ_0006174 showed a notable upregulation in CRC tissues and cell lines and its overexpression was linked to larger tumor diameter and advanced T stage of CRC patients. Circ_0006174 knockdown significantly suppressed cell growth and metastatic potential and promoted cell apoptosis in vitro. Circ_0006174 knockdown accelerated the lung metastasis in vivo. Mechanistically, circ_0006174 could decoy miR-1205 to up-modulate CCBE1 expression and Wnt pathway-related proteins (c-Myc and cyclin D1). Circ_0006174 is an oncogenic circRNA, which participates in the promotion of CRC progression by regulating the miR-1205/CCBE1/Wnt pathway.

Diagnosis of Nonperitonealized Colorectal Cancer with Computerized Tomography Image Features under Deep Learning.

This study aimed to explore the value of abdominal computerized tomography (CT) three-dimensional reconstruction using the dense residual single-axis super-resolution algorithm in the diagnosis of nonperitonealized colorectal cancer (CC). 103 patients with nonperitonealized CC (the lesion was located in the ascending colon or descending colon) were taken as the research subjects. The imagological tumor (T) staging, the extramural depth (EMD) of the cancer tissues, and the extramural vascular invasion (EMVI) grading were analyzed. A dense residual single-axis super-resolution network model was also constructed for enhancing CT images. It was found that the CT images processed using the algorithm were clear, and the peak signal-to-noise ratio (PSNR) and structural similarity (SSIM) were 33.828 dB and 0.856, respectively. In the imagological T staging of CC patients, there were 17 cases in the T3 stage and 68 cases in the T4 stage. With the EMD increasing, the preoperative carcinoembryonic antigen (CEA) highly increased, and the difference was statistically significant (P < 0.05). The postoperative hospital stays of patients were also different with different grades of EMVI. The hospital stay of grade 1 patients (19.45 days) was much longer than that of grade 2 patients (13.19 days), grade 3 patients (15.36 days), and grade 4 patients (14.36 days); the differences were of statistical significance (P < 0.05). It was suggested that CT images under the deep learning algorithm had a high clinical value in the evaluation of T staging, EMD, and EMVI for the diagnosis of CC.

Reduced serum high-density lipoprotein cholesterol levels and aberrantly expressed cholesterol metabolism genes in colorectal cancer.

BACKGROUNDColorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract. Lipid metabolism, as an important part of material and energy circulation, is well known to play a crucial role in CRC.AIMTo explore the relationship between serum lipids and CRC development and identify aberrantly expressed cholesterol metabolism genes in CRC.METHODSWe retrospectively collected 843 patients who had confirmed CRC and received surgical resection from 2013 to 2015 at the Cancer Hospital of the Chinese Academy of Medical Sciences as our research subjects. The levels of serum total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C and clinical features were collected and statistically analyzed by SPSS. Then, we used the data from Oncomine to screen the differentially expressed genes (DEGs) of the cholesterol metabolism pathway in CRC and used Gene Expression Profiling Interactive Analysis to confirm the candidate DEGs. PrognoScan was used to analyze the prognostic value of the DEGs, and Search Tool for the Retrieval of Interacting Genes was used to construct the protein–protein interaction network of DEGs.RESULTSThe serum HDL-C level in CRC patients was significantly correlated with tumor size, and patients whose tumor size was more than 5 cm had a lower serum HDL-C level (1.18 ± 0.41 mmol/L vs 1.25 ± 0.35 mmol/L, P < 0.01) than their counterparts. In addition, TC/HDL (4.19 ± 1.33 vs 3.93 ± 1.26, P < 0.01) and LDL-C/HDL-C (2.83 ± 1.10 vs 2.61 ± 0.96, P < 0.01) were higher in patients with larger tumors. The levels of HDL-C (P < 0.05), TC/HDL-C (P < 0.01) and LDL-C/HDL-C (P < 0.05) varied in different stages of CRC patients, and the differences were significant. We screened 14 differentially expressed genes (DEGs) of the cholesterol metabolism pathway in CRC and confirmed that lipoprotein receptor-related protein 8 (LRP8), PCSK9, low-density lipoprotein receptor (LDLR), MBTPS2 and FDXR are upregulated, while ABCA1 and OSBPL1A are downregulated in cancer tissue. Higher expression of LDLR (HR = 3.12, 95%CI: 1.77-5.49, P < 0.001), ABCA1 (HR = 1.66, 95%CI: 1.11-2.48, P = 0.012) and OSBPL1A (HR = 1.38, 95%CI: 1.01-1.89, P = 0.041) all yielded significantly poorer DFS outcomes. Higher expression of FDXR (HR = 0.7, 95%CI: 0.47-1.05, P = 0.002) was correlated with longer DFS. LDLR, ABCA1, OSBPL1A and FDXR were involved in many important cellular function pathways.CONCLUSIONSerum HDL-C levels are associated with tumor size and stage in CRC patients. LRP8, PCSK9, LDLR, MBTPS2 and FDXR are upregulated, while ABCA1 and OSBPL1A are downregulated in CRC. Among them, LDLR, ABCA1, OSBPL1A and FDXR were valuable prognostic factors of DFS and were involved in important cellular function pathways.

Evaluation of combined detection of multigene mutation and SDC2/SFRP2 methylation in stool specimens for colorectal cancer early diagnosis

Molecular diagnostics of colorectal cancer (CRC) can be used as an auxiliary approach for patients recommended for colonoscopy, providing more CRC supplemental diagnosis options. This study investigated whether combined detection of KRAS/BRAF/APC mutation and SDC2/SFRP2 methylation can serve as auxiliary diagnostics in clinical management. KRAS/BRAF/APC mutation and SDC2/SFRP2 methylation in stool samples from healthy donors, patients with CRC, advanced adenoma (AA), non-advanced adenoma (NAA), or other gastroenterological diseases were evaluated using quantitative PCR (qPCR) or methylation-specific quantitative PCR (MSP). Test accuracy was determined by evaluating the tests' sensitivity, specificity, positive/negative predictive value (PPV/NPV), or positive/negative likelihood ratio (PLR/NLR). The combined fecal KRAS/BRAF/APC mutation and SFRP2/SDC2 methylation detection test achieved a sensitivity of 88.57% with a PPV of 93.64% and a PLR of 7.10 for CRC patients. In comparison, the corresponding parameters for multigene mutation were 46.67%, 92.59%, and 36.26 and 83.81%, 93.94%, and 7.47, for DNA methylation, separately. The sensitivity of the combined test, gene mutation test, and DNA methylation test approach was 75%, 28.26%, and 72.83%. Furthermore, the specificity of this approach in the NAA group was 79.49%. Meanwhile, the overall diagnostic specificity for the combined test in NAA, healthy control, and interference groups was 88.42%. In addition, the sensitivity of the combined detection method increased with the disease stage in CRC patients and elevated along with the lesion size (≥ 1cm) in AA patients. Combined detection of fecal KRAS/BRAF/APC mutation and SFRP2/SDC2 methylation has potential application value for the auxiliary diagnosis of CRC and AA.

Extracellular Matrix Protein 1 Regulates Colorectal Cancer Cell Proliferative, Migratory, Invasive and Epithelial-Mesenchymal Transition Activities Through the PI3K/AKT/GSK3β/Snail Signaling Axis

In prior reports, extracellular matrix protein 1 (ECM1) upregulation has been reported in colorectal cancer (CRC) patient tumor tissues, and has been suggested to be related to the metastatic progression of CRC, although the underlying mechanisms have yet to be clarified. In this study, we found that ECM1 was overexpressed in both CRC tissues and cell lines. Upregulation of ECM1 was correlated with tumor size, lymph node status and TNM stage in CRC patients. Knocking down ECM1 suppressed CRC cell growth, migration and invasion, in addition to reducing the expression of Vimentin and increasing E-cadherin expression. The overexpression of ECM1, in contrast, yielded the opposite phenotypic outcomes while also promoting the expression of p-AKT, p-GSK3β, and Snail, which were downregulated when ECM1 was knocked down. Treatment with LY294002 and 740 Y-P reversed the impact upregulation and downregulation of ECM1 on CRC cell metastasis and associated EMT induction. In vivo analyses confirmed that ECM1 overexpression was able to enhance EMT induction and CRC tumor progression. In conclusion, ECM1 influences CRC development and progression in an oncogenic manner, and regulates CRC metastasis and EMT processes via the PI3K/AKT/GSK3β/Snail signaling axis.

The Effect of the COVID-19 Pandemic on the Clinical and Pathological Stages of Colorectal Cancer Patients

The Effect of the COVID-19 Pandemic on the Clinical and Pathological Stages of Colorectal Cancer Patients

SCG2 is a Prognostic Biomarker Associated With Immune Infiltration and Macrophage Polarization in Colorectal Cancer.

Colorectal cancer (CRC) is the second most lethal malignancy around the world. Limited efficacy of immunotherapy creates an urgent need for development of novel treatment targets. Secretogranin II (SCG2) is a member of the chromogranin family of acidic secretory proteins, has a role in tumor microenvironment (TME) of lung adenocarcinoma and bladder cancer. Besides, SCG2 is a stroma-related gene in CRC, its potential function in regulating tumor immune infiltration of CRC needs to be fully elucidated. In this study, we used western blot, real-time PCR, immunofluorescence and public databases to evaluate SCG2 expression levels and distribution. Survival analysis and functional enrichment analysis were performed. We examined TME and tumor infiltrating immune cells using ESTIMATE and CIBERSORT algorithm. The results showed that SCG2 expression was significantly decreased in CRC tumor tissues, and differentially distributed between tumor and adjacent normal tissues. SCG2 was an independent prognostic predictor in CRC. High expression of SCG2 correlated with poor survival and advanced clinical stage in CRC patients. SCG2 might regulate multiple tumor- and immune-related pathways in CRC, influence tumor immunity by regulating infiltration of immune cells and macrophage polarization in CRC.

Serum DJ-1 Is a Biomarker of Colorectal Cancer and DJ-1 Activates Mitophagy to Promote Colorectal Cancer Progression.

Simple SummaryColorectal cancer is common cancer, and currently used serum markers for detecting colorectal cancer lack excellent diagnostic accuracy. In the present study, we collected matched tumor and adjacent normal tissues and serum from patients and cancer cells to demonstrate the clinical value of DJ-1 in colorectal cancer and the role of DJ-1-induced mitophagy in colorectal cancer progression. Our data indicate that DJ-1 might be clinically valuable as serum and tissue biomarkers for predicting the TNM (tumor-node-metastasis) stage in colorectal cancer patients. Besides, DJ-1 knockdown enhanced intracellular reactive oxygen species generation and damaged mitochondrial accumulation and mitophagy inhibition in metastatic colorectal adenocarcinoma cells. Since DJ-1-induced mitophagy promotes tumor progression, DJ-1 inhibition is a potential therapeutic strategy for colorectal cancer treatment.Colorectal cancer is the second most common cancer and the third cancer-associated death in Taiwan. Currently used serum markers for detecting colorectal cancer lack excellent diagnostic accuracy, which results in colorectal cancer being often recognized too late for successful therapy. Mitophagy is the selective autophagic degradation of damaged or excessive mitochondria. DJ-1 is an antioxidant protein that attenuates oxidative stress and maintains mitochondrial quality through activating mitophagy. Mitophagy activation contributes to anti-cancer drug resistance. However, the role of DJ-1-induced mitophagy in colorectal cancer progression remains unclear. In the present study, we collected matched tumor and adjacent normal tissues and serum from patients and cancer cells to demonstrate the clinical value and physiological function of DJ-1 in colorectal cancer. We found that DJ-1 increased in tumor tissues and serum; it was positively correlated with TNM (tumor-node-metastasis) stages of colorectal cancer patients. Through stable knockdown DJ-1 expression in metastatic colorectal adenocarcinoma cells SW620, DJ-1 knockdown inhibited cancer cell survival, migration, and colony formation. In SW620 cells, DJ-1 knockdown induced an incomplete autophagic response that did not affect ATP production; DJ-1 knockdown enhanced intracellular reactive oxygen species generation and damaged mitochondrial accumulation and mitophagy inhibition. It suggests that DJ-1 knockdown inhibits mitophagy that causes metastatic colorectal adenocarcinoma cells to be unable to remove damaged mitochondria and further enhance cancer cell apoptosis. Our data indicate that DJ-1 might be clinically valuable as serum and tissue biomarkers for predicting the TNM stage in colorectal cancer patients. Since DJ-1-induced mitophagy promotes tumor progression, DJ-1 inhibition is a potential therapeutic strategy for colorectal cancer treatment.