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Polyunsaturated fatty acids (PUFAs) are essential nutrients for the human body, playing crucial roles in reducing blood lipids, anti-inflammatory responses, and anticancer effect. Quinoa is a nutritionally sound food source, rich in PUFAs. This study investigates the role of quinoa polyunsaturated fatty acids (QPAs) on quelling drug resistance in colorectal cancer. The results reveal that QPA downregulates the expression of drug-resistant proteins P-gp, MRP1, and BCRP, thereby enhancing the sensitivity of colorectal cancer drug-resistant cells to the chemotherapy drug. QPA also inhibits the stemness of drug-resistant colorectal cancer cells by reducing the expression of the stemness marker CD44. Consequently, it suppresses the downstream protein SLC7A11 and leads to ferroptosis. Additionally, QPA makes the expression of ferritin lower and increases the concentration of free iron ions within cells, leading to ferroptosis. Overall, QPA has the dual-function reversing drug resistance in colorectal cancer by simultaneously inhibiting stemness and inducing ferroptosis. This study provides a new option for chemotherapy sensitizers and establishes a theoretical foundation for the development and utilization of quinoa.

Aurora kinases (AURKs) are mitotic kinases important for regulating cell cycle progression. Small-molecule inhibitors of AURK have shown promising antitumor effects in multiple cancers; however, the utility of these inhibitors as inducers of cancer cell death has thus far been limited. Here, we examined the role of the Bcl-2 family proteins in AURK inhibition-induced apoptosis in colon cancer cells. We found that alisertib and danusertib, two small-molecule inhibitors of AURK, are inefficient inducers of apoptosis in HCT116 and DLD-1 colon cancer cells, the survival of which requires at least one of the two antiapoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1. We further identified Bcl-xL as a major suppressor of alisertib- or danusertib-induced apoptosis in HCT116 cells. We demonstrate that combination of a Bcl-2 homology (BH)3-mimetic inhibitor (ABT-737), a selective inhibitor of Bcl-xL, Bcl-2, and Bcl-w, with alisertib or danusertib potently induces apoptosis through the Bcl-2 family effector protein Bax. In addition, we identified Bid, Puma, and Noxa, three BH3-only proteins of the Bcl-2 family, as mediators of alisertib-ABT-737-induced apoptosis. We show while Noxa promotes apoptosis by constitutively sequestering Mcl-1, Puma becomes associated with Mcl-1 upon alisertib treatment. On the other hand, we found that alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into truncated Bid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor-induced apoptosis and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Aberrant expression of serine/arginine-rich splicing factor 2 (SRSF2) can lead to tumorigenesis, but its molecular mechanism in colorectal cancer is currently unknown. Herein, we found SRSF2 to be highly expressed in human colorectal cancer (CRC) samples compared with normal tissues. Both in vitro and in vivo, SRSF2 significantly accelerated the proliferation of colon cancer cells. Using RNA-seq, we screened and identified 33 alternative splicing events regulated by SRSF2. Knockdown of SLMAP-L or CETN3-S splice isoform could suppress the growth of colon cancer cells, predicting their role in malignant proliferation of colon cancer cells. Mechanistically, the in vivo crosslinking immunoprecipitation assay demonstrated the direct binding of the RNA recognition motif of SRSF2 protein to SLMAP and CETN3 pre-mRNAs. SRSF2 activated the inclusion of SLMAP alternative exon 24 by binding to constitutive exon 25, while SRSF2 facilitated the exclusion of CETN3 alternative exon 5 by binding to neighboring exon 6. Knockdown of SRSF2, its splicing targets SLMAP-L, or CETN3-S caused colon cancer cells to arrest in G1 phase of the cell cycle. Rescue of SLMAP-L or CETN3-S splice isoform in SRSF2 knockdown colon cancer cells could effectively reverse the inhibition of cell proliferation by SRSF2 knockdown through mediating cell cycle progression. Importantly, the percentage of SLMAP exon 24 inclusion increased and CETN3 exon 5 inclusion decreased in CRC samples compared to paired normal samples. Collectively, our findings identify that SRSF2 dysregulates colorectal carcinoma proliferation at the molecular level of splicing regulation and reveal potential splicing targets in CRC patients., Competing Interests: Conflict of interest All the authors declare that they have no conflicts of interest with the contents of the article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

miR‑1291 exerts an anti‑tumor effect in a subset of human carcinomas, including pancreatic cancer. However, its role in colorectal cancer (CRC) is largely unknown. In the present study, the expression and effect of miR‑1291 in CRC cells was investigated. It was identified that miR‑1291 significantly suppressed the proliferation, invasion, cell mobility and colony formation of CRC cells. Additionally, miR‑1291 induced cell apoptosis. A luciferase reporter assay revealed that miR‑1291 directly bound the 3'‑untranslated region sequence of doublecortin‑like kinase 1 (DCLK1). miR‑1291 also suppressed DCLK1 mRNA and protein expression in HCT116 cells that expressed DCLK1. Furthermore, miR‑1291 suppressed cancer stem cell markers BMI1 and CD133, and inhibited sphere formation. The inhibitory effects on sphere formation, invasion and mobility in HCT116 cells were also explored and verified using DCLK1 siRNAs. Furthermore, miR‑1291 induced CDK inhibitors p21 WAF1/CIP1 and p27 KIP1 in three CRC cell lines, and the overexpression of DCLK1 in HCT116 cells led to a decrease of p21 WAF1/CIP1 and p27 KIP1 . Intravenous administration of miR‑1291 loaded on the super carbonate apatite delivery system significantly inhibited tumor growth in the DLD‑1 xenograft mouse model. Additionally, the resultant tumors exhibited significant upregulation of the p21 WAF1/CIP1 and p27 KIP1 protein with treatment of miR‑1291. Taken together, the results indicated that miR‑1291 served an anti‑tumor effect by modulating multiple functions, including cancer stemness and cell cycle regulation. The current data suggested that miR‑1291 may be a promising nucleic acid medicine against CRC.

Colon adenocarcinoma (COAD) is the most common type of gastrointestinal cancer and is still the third leading cause of cancer-related mortality worldwide. Accurate screening tools for early diagnosis and prediction of prognosis and precision treatment strategies are urgently required to accommodate the unmet medical needs of COAD management. We herein aimed to explore the significance of the microRNA (miR)-216a/growth differentiation factor 15 ( GDF15 ) axis in terms of clinical value, tumor immunity, and potential mechanisms in COAD by using multi-omic analysis. The gene expression levels of miR-216a and GDF15 showed an increase in the COAD group compared to those of the normal group. The expression of miR-216a presented a negative correlation with GDF15 in COAD tumor tissue. The use of an in vitro luciferase reporter assay and bioinformatic prediction revealed that miR-216a-3p acted toward translational inhibition on GDF15 by targeting its 3'untranslated region (UTR) site. High miR-216a expression was associated with decreased overall survival (OS), while the high expression of GDF15 was associated with increased OS. Enriched type 1 T-helper (Th1), enriched regulatory T (Treg), enriched eosinophils, and decreased nature killer T-cells (NKTs) in COAD tumor tissue may play counteracting factors on the tumor-regulatory effects of miR-216a and GDF15 . In addition, high GDF15 expression had associations with suppressed immunoinhibitory genes and negative correlations with the infiltration of macrophages and endothelial cells. The enrichment analysis revealed that GDF15 and its co-expression network may be implicated in mitochondrial organization, apoptosis signaling, and endoplasmic reticulum (ER) stress response. The Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) analysis identified that Gemcitabine acted as a precision treatment for COAD when GDF15 expression was low. This study supports the miR-216a/ GDF15 axis as a diagnostic/prognostic panel for COAD, identifies Th1, Treg, eosinophils, and NKTs as counteracting factors, indicates potential relationships underlying immunomodulation, mitochondrial organization, apoptotic signaling, and ER stress and unveil Gemcitabine as a potential drug for the development of treatment strategy when combined with targeting GDF15 .

Background: A new strategy, particularly a novel combination, for immunotherapy in microsatellite stable metastatic colorectal cancer (mCRC) treatment needs to be formulated. Studies on the interferon-γ (IFN-γ)/ Janus kinase (JAK)/ signal transducer and activator of transcription (STAT)1 pathway provide new directions in this regard., Methods: Our study applies three colon cancer cell lines, including microsatellite stable (MSS) cell lines, which are SW480 and SW620, and microsatellite instability-high (MSI-H) cell line, which is DLD-1. We compared the expressions of immune surface markers on colon cancer cells in response to IFN-γ. We elucidated these mechanisms, which involved the upregulation of immune surface markers. Furthermore, we examined real-world clinical samples using the PerkinElmer Opal multiplex system and NanoString analysis., Results: We established that the baseline expression of major histocompatibility complex (MHC) class I alleles and programmed death-ligand 1 (PD-L1) were generally low in cell line models. The immune surface markers were significantly increased after IFN-γ stimulation on SW480 but were notably unresponsive on the SW620 cell line. We discovered that STAT1 and phosphorylated STAT1 (pSTAT1) were downregulated in the SW620 cell line. We verified that the STAT1/pSTAT1 could be restored through the application of proteasome inhibitors, especially bortezomib. The expression of MHC class I as downstream signals of STAT1 was also up-regulated by proteasome inhibitors. The similar results were reproduced in DLD-1 cell line, which was also initially unresponsive to IFN-γ. In real-world samples of patients with mCRC, we found that higher STAT1 expression in tumor cells was strongly indicative of a highly immunogenic microenvironment, with significantly higher expression levels of MHC class I and PD-L1, not only on tumor cells but also on non-tumor cells. Furthermore, tumor infiltrating lymphocytes (TILs) were increased in the positive-STAT1 group. Through NanoString analysis, we confirmed that the mRNA expressions of IFN-γ, human leukocyte antigen (HLA)-A, HLA-E, and HLA-G were also significantly higher in the positive-STAT1 group than those in the negative-STAT1 group., Conclusion: Our study provides a novel rationale for the addition of bortezomib, a proteasome inhibitor, into new immunotherapy combinations., (© 2021. The Author(s).)

Background: The aim of the study is to determine the anticancer activity of Thymus algeriensis (TS) and its underlying mechanisms using in vitro and in animal models., Methods: HCT116 cells were treated with TS essential oil alone or with TRAIL, and then its anticancer effect was determined by using MTT assay, live dead assay, caspase activation and PARP cleavage. Further mechanisms of its anticancer effects was determined by analyzing expression of death receptor signaling pathway using Western blotting. A mouse model was also used to assess the antitumor potential of thyme essential oil., Results: TS oily fraction showed tumor growth inhibitory effect even at lower concentration. TS induces apoptotic cell death as indicated by cleavage of PARP, and activation of the initiator and effector caspases (caspase-3, -8 and -9). Further, results showed that TS increases the expression of death receptors (DRs) and reduces the expression of TRAIL decoy receptors (DcRs). In addition, upregulation of signaling molecules of MAPK pathway (p38 kinase, ERK, JNK), down-regulation of c-FLIP, and overexpression of SP1 and CHOP were observed by TS. Further in animal model, intragastric administration of TS (12.5 mg/ml and 50 mg/ml) prevented colorectal carcinogenesis by blocking multi-steps in carcinoma., Conclusion: Overall, these results indicate that thymus essential oil promotes apoptosis in HCT116 cells and impedes tumorigenesis in animal model. Moreover, thyme potentiates TRAIL-induced cell death through upregulation of DRs, CHOP and SP1 as well as downregulation of antiapoptotic proteins in HCT116 cells. However, therapeutic potential of TS needs to be further explored.

Colon cancer is a life-threatening disease all over the world and is linked to constant oxidative stress and inflammation. Epigallocatechin gallate (EGCG), is a naturally occurring flavone possessing health benefiting pharmacological properties including antioxidant, anti-inflammatory and free radical scavenging properties. Our study investigates the role of EGCG on N,N'-dimethylhydrazine (DMH), a toxic environmental pollutant, induced colon toxicity. To investigate the effect of EGCG, Wistar rats were given EGCG for 7 days at the two doses of 10 and 20 mg/kg body weight and DMH was injected on the seventh day in all the group rats except the control. Our results indicate that DMH administration increased the oxidative stress (MDA) and depleted the glutathione and antioxidant enzyme activities (SOD, CAT, GR, GST and GPx) which was significantly ameliorated by EGCG treatment. Additionally DMH treatment upregulated inflammatory markers expression (NF-κB, COX-2 and IL-6) and enhanced mucosal damage in the colon. EGCG treatment significantly reduced inflammation and restored the normal histoarchitecture of the colon. We can conclude from the present study findings that EGCG protects the colon from DMH toxicity through its antioxidant and anti-inflammatory potential.

Background: The development and progression of colon cancer are significantly affected by the tumor microenvironment, which has attracted much attention. The goal of our study was primarily to find out all possible tumor microenvironment-related genes in colon cancer., Method: This study quantified the immune and stromal landscape using the ESTIMATION algorithm using the gene expression matrix obtained from the UCSC Xena database. Dysregulated genes were harvested using the limma R package, and relevant pathways and biofunctions were identified using enrichment analysis. A least absolute shrinkage and selection operator (LASSO) regression was used to select the pivotal genes from the DEGs. Then, survival analysis was performed to determine the hub genes and a prognostic model was constructed by these hub genes with (or) TNM stage. Besides, associations between hub gene expressions and immune cell infiltration were assessed., Results: A total of 725 DEGs were identified. Most of the results of the enrichment analysis were immune-related items. 13 genes were selected as the hub genes and a moderate-to-strong positive correlation between most hub genes and several immune cells were observed. Besides, the prognostic value of the hub genes were comparable to TNM staging., Conclusions: Our study provides a better understanding of how interactions between the 13 immune-prognostic hub genes and immune cells in the tumor microenvironment affect biological processes in colon cancer. These genes exhibit an equivalent ability to TNM staging in prognosis prediction. They are particularly expected to become novel prognostic biomarkers and targets of immunotherapies for colon cancer., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

We conducted a prospective randomized study to investigate the effect of daikenchuto (DKT) on abdominal symptoms following laparoscopic colectomy in patients with left-sided colon cancer. Patients who suffered from abdominal pain or distention on postoperative day 1 were randomized to either the DKT group or non-DKT group. The primary endpoints were the evaluation of abdominal pain, abdominal distention, and quality of life. The metabolome and gut microbiome analyses were conducted as secondary endpoints. A total of 17 patients were enrolled: 8 patients in the DKT group and 9 patients in the non-DKT group. There were no significant differences in the primary endpoints and postoperative adverse events between the two groups. The metabolome and gut microbiome analyses showed that the levels of plasma lipid mediators associated with the arachidonic acid cascade were lower in the DKT group than in the non-DKT group, and that the relative abundance of genera Serratia and Bilophila were lower in the DKT group than in the non-DKT group. DKT administration did not improve the abdominal symptoms following laparoscopic colectomy. The effects of DKT on metabolites and gut microbiome have to be further investigated., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Colon cancer cells can migrate and metastasize by undergoing epithelial-to-mesenchymal transition (EMT). Mesenchymal stem cells (MSCs) are non-cancerous, multipotent adult stem cells, which can also migrate. In this study, we wanted to compare the biological, physical, and functional properties of these migratory cells., Materials and Methods: HT-29 and HCT-116, two human colon carcinoma cell lines, represent less aggressive and more aggressive cancer cells, respectively. MSCs were isolated from human bone marrow. After confirming the identity of all the cell types, they were evaluated for E-cadherin, β1-integrin, Vimentin, ZEB-1, β-catenin, and 18S rRNA using Q-PCR. MMP-2 and MMP-9 activity were evaluated using gelatin zymography. Functional tests like wound healing assay, migration assay, and invasion assay were also done. Biomechanical properties like cell stiffness and non-specific adhesion (between indenter probe and cell membrane) were evaluated through nanoindentation using atomic force microscopy (AFM)., Results: Expression of EMT and stem cell markers showed typical expression patterns for HT-29, HCT-116, and MSCs. Functional tests showed that MSCs migrated faster than malignant cells. MMP-2 and MMP-9 activity reinforced this behavior. Interestingly, the migration/invasion capacity of MSCs was comparable to aggressive HCT-116, and more than HT-29. MSCs also showed the maximum cell stiffness and non-specific cell-probe adhesions, followed by HCT116 and HT29 cells., Conclusions: Our findings indicate that the migratory properties of MSCs is comparable or even greater than that of cancer cells and despite their high migration potential, they also have the maximum stiffness., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease., (© 2021. The Author(s).)

Importance: Obesity, particularly visceral obesity and sarcopenia, are poor prognostic indicators in colon cancer., Objectives: To explore the association between body composition profiles and 5-year colon cancer outcomes and delineate the associated underlying inflammatory processes., Design, Setting, and Participants: This multicenter translational cohort study included patients with nonmetastatic colon cancer who did not have underlying chronic inflammatory disorders and were not receiving anti-inflammatory drugs referred to tertiary cancer centers from 2009 to 2015. Preoperative acute phase proteins (white cell count, C-reactive protein, and albumin), cytokines (interleukin [IL]-1b, IL-2, IL-6, IL-10, interferon γ, and tumor necrosis factor α), vascular endothelial growth factor (VEGF), and cell surface receptor expression levels (CD11b and CD14) were measured. All patients underwent follow-up for at least 5 years. Data were analyzed in December 2020., Exposure: Nonmetastatic colon cancer., Main Outcomes and Measures: The associations of body composition profiles with 5-year cancer recurrence and disease-specific mortality were analyzed using Mantel Cox log-rank test and Kaplan-Meier curves., Results: A total of 28 patients were included (median [interquartile range] age, 67 [58-72] years; 22 [78.6%] men). Low skeletal muscle area (SMA) and high visceral to total fat ratio were associated with poor clinical and oncological outcomes, including increased 5-year recurrence (low SMA: hazard ratio [HR], 2.30 [95% CI, 1.41-2.89]; P = .04; high visceral to total fat ratio: HR, 5.78 [95% CI, 3.66-7.95]; P = .02). High visceral to total fat ratio was associated with increased 5-year disease-specific mortality (HR, 5.92 [95% CI, 4.04-8.00]; P = .02). Patients with low SMA who developed a cancer recurrence, compared with those who did not, had higher C-reactive protein (mean [SD], 31.24 [6.95] mg/dL vs 8.11 [0.58] mg/dL; P = .003), IL-6 (mean [SD], 1.93 [1.16] ng/mL vs 0.88 [0.14] ng/mL; P = .004), VEGF (mean [SD], 310.03 [122.66] ng/mL vs 176.12 [22.94] ng/mL; P = .007), and CD14 (mean [SD], 521.23 [302.02] ng/mL vs 322.07 [98.35] ng/mL; P = .03) expression and lower albumin (mean [SD], 3.8 [0.6] g/dL vs 43.50 [3.69] g/dL; P = .01), IL-2 (mean [SD], 0.45 [0.25] ng/mL vs 0.94 [0.43] ng/mL; P < .001), IL-10 (mean [SD], 8.15 [1.09] ng/mL vs 16.32 [4.43] ng/mL; P = .004), and interferon γ (mean [SD], 2.61 [1.36] ng/mL vs 14.87 [3.43] ng/mL; P = .02) levels. Patients with high visceral to total fat ratio who developed recurrence had higher levels of IL-6 (mean [SD], 5.26 [7.05] ng/mL vs 2.76 [3.11] ng/mL; P = .03) and tumor necrosis factor α (mean [SD], 5.74 [4.53] ng/mL vs 4.50 [1.99] ng/mL; P = .03)., Conclusions and Relevance: These findings suggest that low SMA and high visceral to total fat ratio were associated with worse colon cancer outcomes and with increased expression of proinflammatory cytokines and VEGF and inhibition of anti-inflammatory cytokines.

The aim of this study was to explore the effects of the lncRNA ENST00000623984 on colorectal cancer. In this study, the expression levels of ENST000000623984 were first examined in tumor tissue and adjacent normal tissue from 40 patients with colorectal cancer and LoVo cells using quantitative real-time PCR. By siRNA transfection, ENST00000623984 expression was knocked down. Using flow cytometry, cell cycle progression and cell viability were examined in basal and knockdown LoVo cells. The CCK-8 assay was used to assess the cell proliferation rate, and the Transwell assay was used to determine the migration and invasion abilities. The ENST000000623984 expression level was increased in colorectal cancer. Knockdown of ENST000000623984 reduced cell viability, proliferation rate, cell migration and invasion. These results suggested that lncRNA ENST000000623984 may be involved in colorectal cancer development.

During cancer therapy many patients experience significant malnutrition, leading to decreased tolerance to chemotherapy and decreased survival. Dietary citrulline supplementation improves nutritional status in situations such as short bowel syndrome and aging, and is of potential interest in oncology. However, a mandatory prerequisite is to test this amino acid for interaction with tumor growth and chemotherapy response. Dietary citrulline (Cit; 2%), or an isonitrogenous mix of non-essential amino acids (control), was given to Ward colon tumor-bearing rats the day before chemotherapy initiation. Chemotherapy included 2 cycles, one week apart, each consisting of one injection of CPT-11 (50 mg/kg) and of 5-fluorouracil (50 mg/kg) the day after. Body weight, food intake and tumor volume were measured daily. The day after the last injection, rats were killed, muscles (EDL, gastrocnemius), intestinal mucosa, tumor, spleen and liver were weighed. Muscle and intestinal mucosa protein content were measured. Phosphorylated 4E-BP1 was measured in muscle and tumor as a surrogate for biosynthetic activation. FRAPS (Ferric Reducing Ability of Plasma) and thiols in plasma, muscle and tumor were evaluated and plasma amino acids and haptoglobin were measured. Numerous parameters did not differ by diet overall: a) response of tumor mass to treatment, b) tumor antioxidants and phosphorylated 4E-BP1 levels, c) relative body weight and relative food intake, d) weight of EDL, gastrocnemius, intestinal mucosa, spleen and liver and e) plasma haptoglobin concentrations. Moreover, plasma citrulline concentration was not correlated to relative body weight, only cumulated food intake and plasma haptoglobin concentrations were correlated to relative body weight. Citrulline does not alter the tumor response to CPT-11/5FU based therapy but, has no effect on nutritional status, which could be due to the anorexia and the low amount of citrulline and protein ingested., Competing Interests: Conflict of interest CB, LC and CM are shareholders of Citrage company; AG, NN, AdR, VM and VB: no conflict to declare., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: Due to the fact that lymphocytes NK (natural killer cells) are the first line of defence of the body against cancer, one of the goals of modern immunotherapy is the enhancement of their natural activities for the effective recognition, detection, and elimination of cancer cells., Objective: The aim of the study was to evaluate the influence of selected phytochemicals (curcumin and resveratrol) and plant extracts (chlorella and goji berries) on NK cells viability and proliferation, as well as cytotoxic activity against colon cancer - one of the most common cancer worldwide., Material and Methods: The impact of phytochemicals, viability and proliferation of plant extracts on NK cells was examined in NK-92 cells using both LDH and MTT assays. The immunomodulatory properties of selected compounds were tested against human colon cancer cell line LS180 using the MTT test., Results: Extracts of chlorella and goji berries significantly increased NK cell proliferation, while curcumin and resveratrol did not affect this process. Curcumin, as well as extracts of chlorella and goji berries, did not impact NK viability, while resveratrol significantly increased it. LDH test revealed the cytotoxic effect of chlorella extract and curcumin in NK-92 cell cultures. On the contrary, goji berries extract significantly decreased LDH level, while resveratrol did not affect the integrity of NK cell membranes. Studies conducted in co-cultures NK cells, also directly eliminated colon cancer cells., Conclusions: Performed studies revealed immunomodulatory properties of goji berries extract, which improved viability and proliferation of NK cells, and above all, significantly increased their ability to recognize and eliminate colon cancer cells.

Purpose: Delayed gastric emptying (DGE) is associated with prolonged hospital stay and higher healthcare costs. This study aimed to investigate the risk factors for DGE after D3 radical resection for colon cancer and to build a nomogram for this complication., Methods: We analyzed, retrospectively, 1160 consecutive patients who underwent surgery with D3 lymphadenectomy for colon cancer between January, 2012 and June, 2018. A multivariate logistic regression analysis was used to identify the risk factors for DGE and to build a DGE nomogram model., Results: There were ten, six and four patients with DGE classified as grades A, B and C, respectively, representing a DGE rate of 1.7%. Multivariate analysis revealed that age (P = 0.001), dissection of the gastrocolic ligament lymph nodes (GCLNs) (P = 0.001), surgical duration (P = 0.017) and preoperative hemoglobin level (P = 0.016) were independent risk factors, and were included to build a predictive model for DGE. The therapeutic index of GCLN dissection was approximately half that of D3 lymphadenectomy (2.9 vs. 5.6)., Conclusions: DGE is more likely to develop in patients aged > 75 years, those with a preoperative hemoglobin < 90 g/L, those with a surgical duration > 210 min, and those who undergo GCLN dissection. The nomogram may facilitate the stratification of patients at risk for DGE following D3 lymphadenectomy for colon cancer. Assessing long-term outcomes will help to evaluate the survival benefit of GCLN dissection in the future, to avoid unnecessary dissection and reduce the incidence of DGE.

Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome.

Although colon cancer is a leading and typical gastrointestinal tumor, there is little published data on the underlying molecular mechanisms of endoplasmic reticulum (ER) stress. Here, we investigated the role of ERO1α and its impact on microRNA (miR)-101 expression and ER stress in colon cancer cells. Cell ER stress was established by treating RKO or HT-29 cells with 1 μM thapsigargin (THG). Cell biological behaviors were detected using CCK-8, bromodeoxyuridine assay, flow cytometry and western blot. We also investigated the expression of ERO1α and miR-101 after THG treatment using RT-qPCR. Moreover, effects of ERO1α and miR-101 on ER stress of colon cancer cells were detected. Additionally, miR-101 impact on EZH2 expression and relevance of this regulation was confirmed by RT-qPCR and luciferase reporter. The regulation of miR-101/EZH2 axis and Wnt/β-catenin pathway in ER stress were investigated. Our results demonstrated that THG induced ER stress in colon cancer cells. Silencing ERO1α further promoted ER stress-induced cell apoptosis. ERO1α knockdown up-regulated miR-101 expression and promoted colon cancer cell apoptosis via regulating miR-101. Surprisingly, miR-101 negatively regulated EZH2 expression via miRNA-mRNA targeting. Moreover, ER stress promoted colon cancer cell apoptosis via regulating miR-101/EZH2 axis. Wnt/β-catenin pathway was also involved in the regulation of ERO1α/miR-101/EZH2 in ER stress of colon cancer cells. These findings illustrated that silencing ERO1α regulated ER stress-induced apoptosis via miR-101/EZH2 axis in RKO and HT-29 cells.

Introduction: As survival rates of colon cancer increase, knowledge about functional outcomes is becoming ever more important. The primary aim of this systematic review and meta-analysis was to quantify functional outcomes after surgery for colon cancer. Secondly, we aimed to determine the effect of time to follow-up and type of colectomy on postoperative functional outcomes., Materials and Methods: A systematic literature search was performed to identify studies reporting bowel function following surgery for colon cancer. Outcome parameters were bowel function scores and/or prevalence of bowel symptoms. Additionally, the effect of time to follow-up and type of resection was analyzed., Results: In total 26 studies were included, describing bowel function between 3 to 178 months following right hemicolectomy (n = 4207), left hemicolectomy/sigmoid colon resection (n = 4211), and subtotal/total colectomy (n = 161). In 16 studies (61.5%) a bowel function score was used. Pooled prevalence for liquid and solid stool incontinence was 24.1% and 6.9%, respectively. The most prevalent constipation-associated symptoms were incomplete evacuation and obstructive, difficult emptying (33.3% and 31.4%, respectively). Major Low Anterior Resection Syndrome was present in 21.1%. No differences between time to follow-up or type of colectomy were found., Conclusion: Bowel function problems following surgery for colon cancer are common, show no improvement over time and do not depend on the type of colectomy. Apart from fecal incontinence, constipation-associated symptoms are also highly prevalent. Therefore, more attention should be paid to all possible aspects of bowel dysfunction following surgery for colon cancer and targeted treatment should commence promptly., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During the final stages of cell division, newly-formed daughter cells remain connected by a thin intercellular bridge containing the midbody (MB), a microtubule-rich organelle responsible for cytokinetic abscission. Following cell division the MB is asymmetrically inherited by one daughter cell where it persists as a midbody remnant (MB-R). Accumulating evidence shows MB-Rs are secreted (sMB-Rs) into the extracellular medium and engulfed by neighbouring non-sister cells. While much is known about intracellular MB-Rs, sMB-Rs are poorly understood. Here, we report the large-scale purification and biochemical characterisation of sMB-Rs released from colon cancer cells, including profiling of their proteome using mass spectrometry. We show sMB-Rs are an abundant class of membrane-encapsulated extracellular vesicle (200-600 nm) enriched in core cytokinetic proteins and molecularly distinct from exosomes and microparticles. Functional dissection of sMB-Rs demonstrated that they are engulfed by, and accumulate in, quiescent fibroblasts where they promote cellular transformation and an invasive phenotype.

Altered expression of cellular redox genes and proteins contributes to invasion, metastasis, and drug resistance in cancer. NADPH oxidase (NOX) isoforms are the pro-oxidant enzymes that generate ROS as a primary product. Dysregulation of NOX activity and expression alters ROS generation, which either directly or indirectly modulates cell death and survival signaling during the progression of cancer. Nuclear factor erythroid 2-related factor 2 (Nrf-2) is an inducible transcription factor, which transcribes an array of antioxidant genes and protects cancer cells from the oxidative stress. Both NOXs and Nrf-2 participate in the regulation of cellular redox homeostasis; but their dysregulation promotes oxidative stress, which contributes to the progression of different types of cancer. Indeed, the role of NOX isoforms and Nrf-2 in developing the drug resistance in cancer is largely unknown. In the present study, we have explored the association of NOX isoforms and Nrf-2 signaling with the MDR1 gene expression in colon carcinoma cells (HCT-116/R). The MDR1 gene was overexpressed to develop resistant HCT-116/R cells and the NOX activation and ROS generation were monitored. We also assessed the role of NOX isoforms and Nrf-2 in the 5-fluorouracil (5-FU) mediated apoptotic cell death of HCT-116/R cells. The HCT-116/R cells demonstrated higher expression of HIF-1α, Nrf-2, and HO-1 and were highly resistant to 5-FU; they also displayed upregulated expression and activity of NOX-2, as well as elevated ROS levels. Interestingly, the treatment with HDC, a specific NOX-2 inhibitor, reduced the ROS levels in HCT-116/R cells. The treatment with HDC and ML-385 (specific inhibitor of Nrf-2) augmented the 5-FU-mediated apoptotic cell death of HCT-116/R cells, which suggests that NOX-2 and Nrf-2 are involved in the development of the chemoresistant phenotype of these cells. Taken together, NOX-2 and Nrf-2 are associated with developing drug resistance of colorectal cancer cells and might be potential targets to overcome drug resistance during cancer therapy.

Here we present the case of a 73-year-old male with rectal adenocarcinoma with heterotopic ossification (HO). Cancer-associated HO in the digestive system is rare. Thus, the precise mechanism and clinicopathological significance of HO have not yet been defined. To clarify the molecular mechanisms of HO, we analyzed the expression levels of signaling molecules related to epithelial-mesenchymal transition (EMT) that lead to ossification in the tumor cells discriminating the ossified area (HO-area) and non-ossified area (non-HO area). Expression levels of BMP4 were elevated in both areas, whereas BMP2 was specifically increased in the HO-area by qPCR. EMT-related molecules such as Snail and Slug were especially higher in the HO-area. By immunohistochemistry, the expression of Smad4, nuclear staining of β-catenin, and the phosphorylated form of GSK-3β were detectable in both areas, and GSK-3β was highly phosphorylated in the HO-area. The tumor growth rate was extremely high, with the Ki-67 labeling index at 90%. In the HO-area, osteoblasts with alkaline phosphatase expression were distributed surrounding the tumor cells. This is the first demonstration of the involvement of EMT in HO of colon cancer through BMP/SMAD and WNT/β-catenin signaling pathways, which are especially prominent in the HO-area leading to the osteogenic property., (© 2021 by the Association of Clinical Scientists, Inc.)

The impact of tumour associated stroma on cancer metastasis is an emerging field. However, cancer associated genes in peritumoral adipose tissue (pAT) in human colon cancer have not been explored. The aim of this study was to identify differentially expressed genes (DEGs) associated with cancer pathways in mesenteric pAT compared with adjacent adipose tissue. In total, nine patients with colon cancer pathological stage T2/T4 were employed in this study. DEGs were identified in 6 patients employing Nanostring PanCancer Pathway Panel and pathway enrichment analyses were performed. Differential expression of the 5 most up-regulated and 2 down regulated genes was validated with qRT-PCR. Results showed collagen type I alpha 1 chain ( COL1A1 ) p = 0.007; secreted frizzled related protein ( SFRP2 ) p = 0.057; fibroblast growth factor 7 ( FGF7 ) not significant (ns); phospholipase A2, group IIA ( PLA2G2A ) ns; nerve growth factor receptor ( NGFR ) ns; lymphoid enhancer binding factor 1 ( LEF1 ) p = 0.03; cadherin 1, Type 1, E-cadherin (epithelial) ( CDH1 ) 0.09. Results have highlighted down-regulation of the Wingless/Integrated (Wnt) pathway in mesenteric pAT compared to distal adipose tissue. Highly upregulated genes in mesenteric pAT were involved in extracellular matrix (ECM)-receptor interactions and focal adhesion. Highly down regulated genes were involved in the cell cycle. Immunohistochemistry revealed differential distribution of COL1A1 showing maximum levels in tumour tissue and gradually decreasing in distant adipose tissue. COL1A1 and down regulation of Wnt pathway may have a role in local invasion and distant metastasis. COL1A1 may represent a stromal prognostic biomarker and therapeutic target in colon cancer.

Targeting autophagy and lysosome may serve as a promising strategy for cancer therapy. Tea polysaccharide (TP) has shown promising antitumor effects. However, its mechanism remains elusive. Here, TP was found to have a significant inhibitory effect on the proliferation of colon cancer line HCT116 cells. RNA-seq analysis showed that TP upregulated autophagy and lysosome signal pathways, which was further confirmed through experiments. Immunofluorescence experiments indicated that TP activated transcription factor EB (TFEB), a key nuclear transcription factor modulating autophagy and lysosome biogenesis. In addition, TP inhibited the activity of mTOR, while it increased the expression of Lamp1. Furthermore, TP ameliorated the lysosomal damage and autophagy flux barrier caused by Baf A1 (lysosome inhibitor). Hence, our data suggested that TP repressed the proliferation of HCT116 cells by targeting lysosome to induce cytotoxic autophagy, which might be achieved through mTOR-TFEB signaling. In summary, TP may be used as a potential drug to overcome colon cancer.

In the current study, via utilizing H 5 L (H 5 L = 2,4-di(3',5'-dicarboxylphenyl)benzoic acid), the symmetrical rigid polycarboxylic acid ligand with V-shape geometry, two new coordination polymers containing Cu(II) and Co(II) have been produced, and their chemical formulae respectively are {[Co 5 (L) 2 (H 2 O) 12 ]·6H 2 O} n (1) and {[H 2 N(Me) 2 ][Cu 2 (L)(H 2 O)]·DMF·H 2 O} n (2), leading to a variety kinds of coordination patterns of H 5 L and multifunctional skeletons. Their inhibitory activity on the insulin resistance of colon cancer patients was assessed. In addition, the detailed mechanism of the compound was also investigated. Firstly, the detection of enzyme-linked immunosorbent assay was carried out and the Tumor Necrosis Factor-α (TNF-α) level and the Interleukin-1β (IL-1β) level was detected. Then, the glucose concentration was determined with blood glucose meter. Next, the insulin receptor expression levels of β cells were determined with the real time reverse transcription-polymerase chain reaction assay. Ultimately, the cytotoxicity of compounds 1 and 2 was determined with Cell Counting Kit-8 assay.

Background: The objective of this study was to compare functional and surgical outcomes of patients undergoing ileocecal resection for Crohn's disease (CD) to patients undergoing oncological right colectomy., Methods: Retrospective single-center cohort study including consecutive patients undergoing right colectomy for adenocarcinoma (oncological resection) or CD (mesentery-sparing resection) between July 2011 and November 2017. Outcome measures were pathological details (lymph node yield), postoperative recovery (pain levels, return to flatus and stool, intake of fluids, weight change, and mobilization), and early (30-day) outcomes (surgical/medical complications, hospital stay, readmissions)., Results: A total of 195 patients (153 [78%] with cancer and 42 [22%] with CD) were included. Overall compliance with the institutional enhanced recovery protocol was comparable between the 2 groups (compliance ≥70%: 60% in CD patients vs. 62% in cancer, p = 0.458). The adenocarcinoma group had a larger lymph node yield than the CD group (26 ± 13 vs. 2.4 ± 5, respectively, p < 0.001). While the CD group experienced significantly more pain (3.7 ± 1.9/10 vs. 2.8 ± 2.5/10, p = 0.007, patients requiring opioids: 65 vs. 28%, p = 0.001), return of flatus (2.3 ± 1.2 days vs. 2.4 ± 2.8 days, p = 0.642) and stool (4.1 ± 6.0 vs. 3.0 ± 1.8 days, p = 0.292) was no different in both groups. No difference was observed regarding postoperative complications, length of stay, and readmission rate., Conclusion: This study revealed no differences in both functional and surgical outcomes in CD and cancer patients undergoing mesentery-sparing or formal oncological right colectomy, respectively., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Motility of the large bowel may be grossly subdivided in two types of contractile activity: low-amplitude single or cyclic propagated waves and high-amplitude propagated activity. The latter is mainly apt to shift relatively large amounts of colonic contents, and it is related to defecation. The main component of this propagated activity is represented by the radiologically identified mass movements that have a manometric equivalent known as high-amplitude propagated contractions (HAPC). The present article reviews origins and characterization of HAPC in the time course of colonic motility investigations, and correlates it with technological advancements in recent years, putting into perspective the future possible options to better detect and investigate these important physiological events.

Caffeic acid phenethyl ester (CAPE) has various biological activities but low water solubility and poor bioavailability. In this study, CAPE was encapsulated in skim milk powder (SMP) by spray drying warm aqueous ethanol solutions with different mass ratios of SMP and CAPE. The loading capacity and encapsulation efficiency were up to 10.1 and 41.7%, respectively. Differential scanning calorimetry and X-ray diffraction results confirmed the loss of crystallinity of CAPE after encapsulation. Fourier-transform infrared and fluorescence spectroscopy results indicated the hydrophobic binding between CAPE and caseins. Scanning electron microscopy and static light scattering results showed spherical capsules with an average diameter of around 26 μm. The CAPE loaded in SMP microcapsules showed significantly improved in vitro bioaccessibility and antiproliferation activity against human colon cancer cells compared to free CAPE. The simple, scalable, and low-cost approach in the present study may be significant for industrial encapsulation of CAPE and other lipophilic bioactive compounds.

Purpose: The prognostic nutritional index (PNI) is calculated using the serum albumin and peripheral lymphocyte counts. We sought to assess the correlation between the preoperative PNI and postoperative outcomes in patients with colon cancer treated with laparoscopic surgery., Methods: We included 896 colon cancer patients who underwent curative laparoscopic colectomy between January 2013 and March 2016. To identify any predictors of the postoperative outcomes, we compared the clinical characteristics and immunonutritional parameters, including the PNI, between patients classified as the Clavien-Dindo grade 2 or higher (n = 99) with those classified as grade 0 or 1 (n = 797)., Results: A longer surgical time and a preoperative low PNI (< 49.8) (odds ratio; 1.913, p = 0.002) were independent predictors of postoperative complications according to a multivariate analysis. A preoperative low PNI was significantly associated with an older age, a lower performance status, a lower BMI, higher CEA levels, an advanced T status, lymph node metastasis, a longer operative time, a higher blood loss, a larger tumor size, treatment with a combined resection, a longer time to bowel recovery, a longer postoperative hospital stay, and a poor overall survival., Conclusions: A preoperative low PNI was found to be significantly associated with the incidence of postoperative complications, an advanced tumor status, and a poor prognosis. Further research is needed to understand how to best clinically utilize this promising parameter.

This study aimed at investigating the anticancer activity of an exopolysaccharide (EPS) isolated from Lactobacillus helveticus MB2-1. The crude EPS from L. helveticus MB2-1 (LHEPS) was fractionated into three fractions, namely LHEPS-1, LHEPS-2 and LHEPS-3. LHEPS-1 exhibited the most effective anti-proliferative activity, which was associated with a stronger inhibition rate and increased lactate dehydrogenase leakage of human colon cancer HT-29 cells. Flow cytometry analysis and colorimetric assay revealed that LHEPS-1 induced cell cycle arrest by preventing G1 to S transition and increased the apoptosis rate. Furthermore, LHEPS-1 enhanced the production of intracellular reactive oxygen species (ROS) and the activity of caspases-8/9/3, increased the levels of pro-apoptotic Bax and mitochondrial cytochrome c, while decreased the anti-apoptotic Bcl-2 level, indicating that LHEPS-1 might induce the apoptosis of HT-29 cells through a ROS-dependent pathway and a mitochondria-dependent pathway. These findings suggest that LHEPS-1 may be developed as an effective food and/or drug for the prevention and therapeutics of cancer, especially human colon cancer.

Ferritinophagy is a form of selective autophagy responsible for degrading intracellular ferritin, mediated by nuclear receptor coactivator 4 (NCOA4). NCOA4 plays significant roles in systemic iron homeostasis, and its disruption leads to simultaneous anemia and susceptibility to iron overload. The importance of iron colorectal cancer pathogenesis is well studied; however, the role of ferritinophagy in colon cancer cell growth has not been assessed. Disruption of ferritinophagy via NCOA4 knockout leads to only marginal differences in growth under basal and iron-restricted conditions. Moreover, NCOA4 played no significant role in cell death induced by 5-fluorouracil and erastin. Western blotting analysis for ferritin and transferrin receptor 1 found a dose-dependent effect on expression in both proteins in wild-type and NCOA4 knockout cell lines, but further investigation revealed no difference in growth response when treated at both high and low doses. Our data demonstrate a marginal role for ferritinophagy in growth both under normal and cytotoxic conditions in colon cancer cells, as well as a possible compensatory mechanism in colon cancer cells in response to ferroptosis induction., (© 2020 International Federation for Cell Biology.)

Background: This pilot trial explores the feasibility of measuring muscle contractile properties in patients with cancer, effects of exercise during chemotherapy on muscle contractile properties and the association between changes in contractile muscle properties and perceived fatigue., Method: Patients who received (neo)adjuvant chemotherapy for breast or colon cancer were randomized to a 9-12 week exercise intervention or a waitlist-control group. At baseline and follow-up, we measured knee extensor strength using maximal voluntary contraction (MVC), contractile muscle properties of the quadriceps muscle using electrical stimulation, and perceived fatigue using the Multidimensional Fatigue Inventory. Feasibility was assessed by the proportion of patients who successfully completed measurements of contractile muscle properties. Exercise effects on muscle contractile properties were explored using linear regression analyses. Between-group differences >10% were considered potentially relevant. Pearson correlation (r p ) of changes in contractile muscle properties and changes in perceived fatigue was calculated., Results: Twenty two of 30 patients completed baseline and follow-up assessments. Measurements of contractile properties were feasible except for muscle fatigability. We found a potentially relevant between-group difference in the rate of force development favoring the intervention group (1192 N/s, 95% CI = -335; 2739). Change in rate of force development was negatively correlated with change in perceived general (r p  = -0.54, P = .04) and physical (r p  = -0.59, P = .02) fatigue., Conclusion: Chemotherapy induces a decrease in the rate of force development, which may reflect a larger loss in type II muscle fibers. This may be attenuated with (resistance) exercise. The increase in the rate of force development was related to a decrease in perceived fatigue., (© 2020 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Homology of medicine and food-zizyphi spinosi semen (ZSS) exhibits abundant pharmacological activities, such as sedation, hypnosis and anti-depression. In the present study, the water soluble polyphenols extracted from ZSS via the acid digestion method were named ZSSP, and exhibited significant anti-colorectal cancer (CRC) activity, characterized by restraining cell proliferation, promoting cell apoptosis and increasing chemo-sensitivity of CRC cells. The potential of ZSSP in vivo was further evaluated in an AOM/DSS-induced colitis-associated carcinogenesis (CAC) mouse model. Intriguingly, ZSSP diminished the number and volume of CAC polyps in mice in a dose-dependent manner, and effectively limited the damage of mice organs induced by AOM/DSS. The immunohistochemistry result showed that the elevated CRC early markers in CAC mice, such as COX-II, EMR1, and Ki67, were potently prevented by the ZSSP treatment. Further, the component in ZSSP with the anti-CRC activity was identified as spinosin by the macroporous resin of SP207 and RP-HPLC-MS/MS. Interestingly, during the extraction process, sodium ions were introduced forming spinosin·Na+, which had better water solubility and more remarkable anti-CRC activity than the spinosin. This study provides a new pharmacological property of spinosin derived from ZSS, inhibiting the growth of human CRC cells and colitis-associated CRC in mice, which indicates its potential use as a natural agent against CRC.

Purpose: Differentiation of the histopathologic subtypes can be clinically important as it can affect the course of treatment and the prognosis. The aim of this study was to investigate both the clinicopathological features and prognosis of histologic subtypes in right-sided colon cancer., Methods: This study included 138 patients who underwent surgery for right-sided colon cancer. The patients were divided into three groups according to histopathological subtypes as follows: medullary carcinoma (MC, n=11), mucinous adenocarcinoma (MAC, n=29), and classic adenocarcinoma (AC, n=98). The groups were compared in terms of demographic characteristics, type of surgery, pathological outcomes and survival., Results: The rate of laparoscopic surgery was significantly lower in the MC group compared with MAC and AC groups (45.4% vs 54.5% vs 35.7%, respectively, p=0.001). In MC group, T4 stage was significantly higher than in other groups (90.0% vs 34.5% vs 35.7%, respectively, p=0.001). While patients with MAC had no distant metastasis, 18.2% and 15.3% of patients with MC and AC respectively, had distant metastasis (p=0.07). MAC vs MC, p=0.01, MAC vs AC, p=0.03). Tumor size, tumor volume, and the rate of microsatellite instability were found significantly higher in the MC group (p<0.05). The 5-year overall (OS) and disease-free survival (DFS) were better in the MAC group compared with MC and AC groups, but these differences did not reach statistical significance (OS: 92.8% vs 72.7% and 68.7%, p=0.16 and DFS 87.3% vs 58.2% and 64%, p=0.10, respectively)., Conclusion: MC is associated with more advanced tumor size and T stages, and therefore entails reduced rate of minimally invasive procedures. In our series, the absence of distant metastasis in the patients of MAC also had a positive effect on survival.

Background: Cancer patients are at increased risk of novel coronavirus disease 2019 (COVID-19). Currently, surgeries for cancer patients with COVID-19 are generally suggested to be properly delayed., Case Presentation: We presented a 69-year-old Chinese female colon cancer patient with COVID-19, the first case accepted the surgical treatment during the pandemic in China. The patient developed a fever on January 28, 2020. After treatments with Ceftriaxone and Abidol, her fever was not moderated yet. A repeat chest computed tomography (CT) scan showed significantly exacerbated infectious lesions with a positive result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid. An abdomen CT scan indicated the tumor of ascending colon with local wrapped changes. She was diagnosed with 'Severe novel coronavirus pneumonia' and 'Incomplete bowel obstruction: Colon cancer?'. After actively anti-inflammatory and anti-viral therapies, a right colectomy with lymph node dissection was performed on March 11, followed by a pathological examination. The patient successfully recovered from COVID-19 pneumonia and incomplete bowel obstruction after surgery without any postoperative related complications and was discharged on the 9th day after operation. Significant degeneration, necrosis and slough of focal intestinal and colonic mucosal epithelial cells were observed under microscope. No surgeons, nurses or anesthetists in our team were infected with SARS-CoV-2., Conclusions: It is meaningful and imperative to share our experience of protecting health care personnels from SARS-CoV-2 infection and providing references for optimizing treatment of cancer patients, at least for the operative intervention with absolute necessity or surgical emergency, during the outbreak of COVID-19.

Biophysical studies on single cells have linked cell mechanics to physiology, functionality and disease. Evaluation of mass and viscoelasticity versus cell cycle can provide further insights into cell cycle progression and the uncontrolled proliferation of cancer. Using our pedestal microelectromechanical systems resonant sensors, we have developed a non-contact interferometric measurement technique that simultaneously tracks the dynamic changes in the viscoelastic moduli and mass of adherent colon (HT-29) and breast cancer (MCF-7) cells from the interphase through mitosis and then to the cytokinesis stages of their growth cycle. We show that by combining three optomechanical parameters in an optical path length equation and a two-degree-of-freedom model, we can simultaneously extract the viscoelasticity and mass as a function of the nano-scaled membrane fluctuation of each adherent cell. Our measurements are able to discern between soft and stiff cells across the cell cycle and demonstrated sharp viscoelastic changes due to cortical stiffening around mitosis. Cell rounding before division can be detected by measurement of mechanical coupling between the cells and the sensors. Our measurement device and method can provide for new insights into the mechanics of single adherent cells versus time.

Mitochondrial metabolism has emerged as a promising target against the mechanisms of tumor growth. Herein, we have screened an FDA-approved library to identify drugs that inhibit mitochondrial respiration. The β1-blocker nebivolol specifically hinders oxidative phosphorylation in cancer cells by concertedly inhibiting Complex I and ATP synthase activities. Complex I inhibition is mediated by interfering the phosphorylation of NDUFS7. Inhibition of the ATP synthase is exerted by the overexpression and binding of the ATPase Inhibitory Factor 1 (IF1) to the enzyme. Remarkably, nebivolol also arrests tumor angiogenesis by arresting endothelial cell proliferation. Altogether, targeting mitochondria and angiogenesis triggers a metabolic and oxidative stress crisis that restricts the growth of colon and breast carcinomas. Nebivolol holds great promise to be repurposed for the treatment of cancer patients.

Yerba Mate (Ilex paraguariensis St. Hill. Aquifoliaceae) is a native South American tree and has a large amount of bioactive compounds. Colorectal cancer (CRC) is one of the so-called westernized diseases and is the third most common cancer in both men and women. Efficient strategies for the treatment of CRC are extensively being explored including dietary intervention. The objective of our research was to evaluate the effects of Yerba Mate extract on cell proliferation, invasive capacity of tumor cells, and angiogenesis. For this, in vitro and in vivo experimentation was carried out using CRC models. The extract was generated by aqueous extraction and prepared according to traditional American procedure of preparing mate infusion. In vitro results showed that the Yerba Mate extract inhibits CT26 and COLO 205 cell proliferation with IC 50 values of 0.25 and 0.46 mg/mL, respectively. We demonstrated by TUNEL assay that one of the mechanisms by which Yerba Mate extract decreases cell proliferation is by induction of apoptosis. In a murine syngeneic tumor model, oral administration of Yerba Mate extract in a dose of 1.6 g/kg/day significantly inhibited angiogenesis and tumor growth without affecting biological parameters or body weight. Our findings suggest that Yerba Mate may be a promising agent for the treatment of colon cancer and could be used as an herbal medicine or functional food ingredient. PRACTICAL APPLICATION: Considering the chemical composition and presence of phenolic compounds with their free-radical scavenging activities and bioactivities against colon cancer cells, Yerba Mate can be a promising candidate as healthy food sources in human nutrition, and also be considered a natural source of potential antitumor agents. Taking into account the economic importance of Yerba Mate in Argentina, this vegetable would have a greater commercial value as a functional food., (© 2020 Institute of Food Technologists®.)

Interleukin (IL)-33 is a member of the IL-1 family, participating in both helper T1 (Th1)- and Th2-type immune responses, but its ambiguous effects on tumor growth and related immune mechanisms remain unclear. Here, we report that recombinant mouse IL-33 (mIL-33) significantly inhibited colon cancer growth and metastasis to lung and liver in a murine CT26 or MC38 tumor-cell engraftment model. This effect could be associated with CD4 + T cells and CD40 L signaling, as depletion of CD4 + T cells or blocking CD40 L signaling in vivo partly abolished the antitumor function of IL-33. In addition, IL-33 treatment upregulated CD40 L expression on tumor-infiltrating lymphocytes, and promoted the activation of CD4 + T, CD8 + T and natural killer cells via CD40 L signaling. Furthermore, IL-33 was sufficient to induce the ST2 expression on CD4 + T cells, but not on CD8 + T and natural killer cells, indicating that IL-33 acted on CD4 + T cells via a positive-feedback loop. Our findings shed new light on the IL-33-mediated antitumor effects and mechanisms of Th1 action, and also suggest that IL-33 may serve as an activator to boost anticancer immune responses in singular or combinatory therapies., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Inflammatory microenvironment is an important factor for promoting cancer invasion and metastasis, but the underlying molecular mechanisms remain unclear. Here, we mimicked an inflammatory microenvironment both in vitro and in vivo and investigated its effects on the invasion and metastasis of colon cancer. Moreover, colon cancer patient samples were also analyzed statistically. Conditioned medium from the differentiated macrophages induced invasion and migration of colon cancer cells in vitro, which could be reversed by the treatment of a neutralizing anti-growth differentiation factor 15 (GDF15) antibody, indicating GDF15 involvement in inflammation-induced invasiveness. Also, we observed similar effects of human recombinant GDF15 on colon cancer cells. Mechanistically, GDF15 activated c-Fos by separating it from Lamin A/C, increasing transcriptional activity of c-Fos and regulating EMT gene expressions. However, c-Fos knockdown using lentivirus shRNA plasmid inhibited GDF15-triggered invasion and migration in vitro. In vivo, inflammation caused by lipopolysaccharides obviously increased GDF15 secretion, and c-Fos knockdown reduced the lung metastasis of colon cancer cells in mice model. In addition, c-Fos expressions in patient samples were found to be associated with colon cancer metastasis and TNM stages. Taken together, GDF15 in inflammatory microenvironment induces colon cancer invasion and metastasis by regulating EMT genes by activating c-Fos, which might be a potential therapeutic target for metastatic colon cancer., (© 2019 Wiley Periodicals, Inc.)

SLC6A14 is a Na+/Cl--coupled transporter for neutral and cationic amino acids. It is expressed at basal levels in the normal colon but is up-regulated in colon cancer. However, the relevance of this up-regulation to cancer progression and the mechanisms involved in the up-regulation remain unknown. Here, we show that SLC6A14 is essential for colon cancer and that its up-regulation involves, at least partly, Wnt signaling. The up-regulation of the transporter is evident in most human colon cancer cell lines and also in a majority of patient-derived xenografts. These findings are supported by publicly available TCGA (The Cancer Genome Atlas) database. Treatment of colon cancer cells with α-methyltryptophan (α-MT), a blocker of SLC6A14, induces amino acid deprivation, decreases mTOR activity, increases autophagy, promotes apoptosis, and suppresses cell proliferation and invasion. In xenograft and syngeneic mouse tumor models, silencing of SLC6A14 by shRNA or blocking its function by α-MT reduces tumor growth. Similarly, the deletion of Slc6a14 in mice protects against colon cancer in two different experimental models (inflammation-associated colon cancer and genetically driven colon cancer). In colon cancer cells, expression of the transporter is reduced by Wnt antagonist or by silencing of β-catenin whereas Wnt agonist or overexpression of β-catenin shows the opposite effect. Finally, SLC6A14 as a target for β-catenin is confirmed by chromatin immunoprecipitation. These studies demonstrate that SLC6A14 plays a critical role in the promotion of colon cancer and that its up-regulation in cancer involves Wnt signaling. These findings identify SLC6A14 as a promising drug target for the treatment of colon cancer., (© 2020 The Author(s).)

Opportunistic modification of the tumour microenvironment by cancer cells enhances tumour expansion and consequently eliminates tumour suppressor components. We studied the effect of fibroblasts on the circadian rhythm of growth and protein expression in colon cancer HCT116 cells and found diminished oscillation in the proliferation of HCT116 cells co-cultured with naive fibroblasts, compared with those co-cultured with tumour-associated fibroblasts (TAFs) or those cultured alone, suggesting that TAFs may have lost or gained factors that regulate circadian phenotypes. Based on the fibroblast paracrine factor analysis, we tested IL6, which diminished HCT116 cell growth oscillation, inhibited early phase cell proliferation, increased early phase expression of the differentiation markers CEA and CDX2, and decreased early phase ERK5 phosphorylation. In conclusion, our data demonstrate how the cancer education of naive fibroblasts influences the circadian parameters of neighbouring cancer cells and highlights a putative role for IL6 as a novel candidate for preoperative treatments.

Seven new daphnane-type diterpenoids, daphgenkins A-G ( 1 - 7 ), and 15 known analogues ( 8 - 22 ) were isolated from the flower buds of Daphne genkwa . Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all daphnane-type diterpenoids ( 1 - 22 ) obtained were evaluated against three human colon cancer cell lines (SW620, RKO, and LoVo). Compounds 1 , 12 , and 13 exhibited cytotoxic effects against the SW620 and RKO cell lines, with IC 50 values in the range of 3.0-9.7 μM. The most active new compound, 1 , with an IC 50 value of 3.0 μM against SW620 cells, was evaluated further for its underlying molecular mechanism. Compound 1 induced G 0 /G 1 cell cycle arrest, leading to the induction of apoptosis in SW620 cells. Also, it induced cancer cell apoptosis by an increased ratio of Bax/Bcl-2, activated cleaved caspase-3 and caspase-9, and upregulated PARP. Finally, compound 1 significantly inhibited PI3K/Akt/mTOR signaling in SW620 cells. Together, the results suggest that compound 1 may be a suitable lead compound for further biological evaluation.

The objective of this research was to investigate the effects of Lactobacillus acidophilus CICC 6074 S-layer protein on the viability, adhesion, cell cycle, and apoptosis of human colon cancer HT-29 cells and to explore their molecular mechanism of tumor suppression. The S-layer protein at doses of 0, 25, 50, and 100 mg/L significantly suppressed the proliferation of HT-29 cells. The S-layer protein exerts its cytotoxic activities against colon cancer HT-29 cells by arresting the cell cycle in the G1 phase through upregulating the expression of p53, p21, and p16 and downregulating the expression of CDK1 (cyclin-dependent kinases) and cyclin B. Morphological changes were further observed by transmission electron microscopy, and the cells treated with the S-layer protein showed obvious characteristic changes of apoptosis including chromatin condensation, nuclear fragmentation, vacuoles, and so on. Furthermore, our mechanism studies indicated that the S-layer protein may induce HT-29 cell apoptosis through the death receptor apoptotic pathway and mitochondrial pathway and impede cell invasion by inhibiting the synthesis of the PI3K/AKT pathway and FasL. These results demonstrated that the L. acidophilus CICC 6074 S-layer protein may be a potential anticarcinogenic agent.

MTA1, SOX4, EZH2, and TGF-β are all potent inducers of epithelial-mesenchymal transition (EMT) in cancer; however, the signaling relationship among these molecules in EMT is poorly understood. Here, we investigated the function of MTA1 in cancer cells and demonstrated that MTA1 overexpression efficiently activates EMT. This activation resulted in a significant increase in the migratory and invasive properties of three different cancer cell lines through a common mechanism involving SOX4 activation, screened from a gene expression profiling analysis. We showed that both SOX4 and MTA1 are induced by TGF-β and both are indispensable for TGF-β-mediated EMT. Further investigation identified that MTA1 acts upstream of SOX4 in the TGF-β pathway, emphasizing a TGF-β-MTA1-SOX4 signaling axis in EMT induction. The histone methyltransferase EZH2, a component of the polycomb (PcG) repressive complex 2 (PRC2), was identified as a critical responsive gene of the TGF-β-MTA1-SOX4 signaling in three different epithelial cancer cell lines, suggesting that this signaling acts broadly in cancer cells in vitro. The MTA1-SOX4-EZH2 signaling cascade was further verified in TCGA pan-cancer patient samples and in a colon cancer cDNA microarray, and activation of genes in this signaling pathway predicted an unfavorable prognosis in colon cancer patients. Collectively, our data uncover a SOX4-dependent EMT-inducing mechanism underlying MTA1-driven cancer metastasis and suggest a widespread TGF-β-MTA1-SOX4-EZH2 signaling axis that drives EMT in various cancers. We propose that this signaling may be used as a common therapeutic target to control epithelial cancer metastasis.

Objectives: The aim of this study was to better understand the role that physical, cognitive and social factors play in pain interference with activities of daily living among individuals with cancer and chronic pain., Method: In this cross-sectional study, interviews with 156 patients with chronic cancer pain were conducted across five tertiary level hospitals in the province of Tarragona (Spain). Participants were interviewed individually and provided information about the presence and characteristics of pain, fatigue, catastrophic thinking, social support and the impact of pain on their daily activities., Results: Pain intensity (β = 0.23, p = .003), fatigue (β = 0.26, p < .001) and pain catastrophising (β = 0.39, p < .001) were significantly and positively associated with pain interference in daily activities. Pain interference scores were not explained by social support (β = 0.12 p = .090) or socio-demographic factors (R 2  = .005; p = .94)., Conclusion: This study provides important new findings regarding the association between physical, cognitive and social factors and function of individuals with cancer and chronic pain, thus supporting a biopsychosocial approach to the management of chronic pain in individuals with cancer., (© 2019 John Wiley & Sons Ltd.)

The increased use of pesticides is the origin of multiple damages to the environment and to humans; thus, the search for new strategies to reduce or even protect the toxic effects caused by these synthetic products became a necessity. In this context, our study attempted to evaluate the protective effects of fennel essential oil (FEO), the main essential oil extracted from Faeniculum vulgare Mill., a plant with aromatic, flavorful, and medicinal uses, against toxicity induced by an insecticide-triflumuron (TFM)-in human carcinoma cells (HCT116). Our methodological approach consists of the cytotoxicity assay starting with the cell viability test, the ROS generation, the malondialdehyde (MDA) production, the DNA fragmentation, and the measurement of some antioxidant enzymes activities such as catalase (CAT) and superoxide dismutase (SOD). Also, we measured the mitochondrial transmembrane potential. The outcome of the current study showed clearly that after 2 h of HCT 116 cell pretreatment with FEO, there were increase in cell viability, reduction in ROS generation, and modulation in CAT and SOD activities induced by TFM. In the same manner, significant decreases in MDA levels were found. Mainly, the results indicated a perceptible decrease in DNA damages and a significant reduction in the mitochondrial membrane potential loss. Our work demonstrates that FEO can be an important protector against toxic effects induced by TFM in HCT 116 cells.