Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer.

Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.

Tumor-secreted IFI35 promotes proliferation and cytotoxic activity of CD8+ T cells through PI3K/AKT/mTOR signaling pathway in colorectal cancer.

BACKGROUND: A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate its effect on CAR-T cells against colorectal cancer. METHODS: Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. RESULTS: The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. CONCLUSION: Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells.

Cancer-associated fibroblasts impact the clinical outcome and treatment response in colorectal cancer via immune system modulation: a comprehensive genome-wide analysis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment are associated with poor prognosis and chemoresistance in multiple solid tumours. However, there is a lack of universal measures of CAFs in colorectal cancer (CRC). The aim of this study was to assess the utility of a fibroblast-related gene signature (FRGS) for predicting patient outcomes and reveal its relevant mechanism. METHODS: The GSE39582 dataset, which includes 316 CRC patients who did not receive adjuvant chemotherapy was used as a discovery cohort to identify the prognostic fibroblast-related genes (FRGs). A total of 1352 CRC patients were divided into one training cohort (GSE39582, n = 461) and two validation cohorts (TCGA, n = 338; meta-validation, n = 553) for the construction of the FRGS and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to explore the underlying mechanism. The ability of the FRGS to predict immunotherapy response was further tested in a clear cell renal cell carcinoma (ccRCC) cohort. RESULTS: An 11-gene signature that had prognostic value for stage II/III CRC patients in both validation cohorts was developed (TCGA cohort: HR = 1.90, 95% CI 1.16-3.12, P < 0.01; meta-validation cohort: HR = 1.95, 95% CI 1.39-2.73, P < 0.001). A high level of CAFs was correlated with worse prognosis in CRC patients who did not receive adjuvant chemotherapy (HR = 3.63, 95% CI 2.24-5.88, P < 0.001). Importantly, patients in the low-risk group were found to be benefit from chemotherapy (P < 0.01), but not in the high CAF group (P > 0.05). Similar results were found in the TCGA cohort. Integrated with clinical characteristics, the FRGS was confirmed to be an independent prognostic factor in the multivariate analysis after adjustment for tumour TNM stage (GSE39582 cohort: HR = 3.19, 95% CI 1.88-5.41, P < 0.001; TCGA cohort: HR = 5.00, 95% CI 1.58-15.85, P = 0.007; meta-validation cohort: HR = 2.99, 95% CI 1.44-6.21, P = 0.003). Furthermore, the enrichment analysis found that the antitumour immune response was suppressed and the infiltration of CD4 T cells and M1 macrophages was depressed in the high CAF group. The FRGS was also found to have value in predicting for immunotherapy response in the ccRCC cohort. CONCLUSIONS: The 11-gene FRGS had independent prognostic value for CRC patients, as well as utility in the prediction of benefit from chemotherapy. CAFs in the tumour microenvironment might have an impact on the prognosis of CRC patients via inhibiting immune response.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

BACKGROUND: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. MATERIALS AND METHODS: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. RESULTS: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. CONCLUSION: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. IMPLICATIONS FOR PRACTICE: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

Protein-protein interaction analysis reveals a novel cancer stem cell related target TMEM17 in colorectal cancer.

BACKGROUND: Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking. METHODS: Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC. RESULTS: By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/ß-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients. CONCLUSION: Collectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).

A next-generation sequencing-based strategy combining microsatellite instability and tumor mutation burden for comprehensive molecular diagnosis of advanced colorectal cancer.

BACKGROUND: Mismatch repair (MMR)/microsatellite instability (MSI) and tumor mutational burden (TMB) are independent biomarkers that complement each other for predicting immune checkpoint inhibitors (ICIs) efficacy. Here we aim to establish a strategy that integrates MSI and TMB determination for colorectal cancer (CRC) in one single assay. METHODS: Surgical or biopsy specimens retrospectively collected from CRC patients were subjected to NGS analysis. Immunohistochemistry (IHC) and polymerase chain reaction (PCR) were also used to determine MMR/MSI for those having enough tissues. The NGS-MSI method was validated against IHC and PCR. The MSI-high (MSI-H) or microsatellite stable (MSS) groups were further stratified based on tumor mutational burden, followed by validation using the The Cancer Genome Atlas (TCGA) CRC dataset. Immune microenvironment was evaluated for each subgroup be profiling the expression of immune signatures. RESULTS: Tissues from 430 CRC patients were analyzed using a 381-gene NGS panel. Alterations in KRAS, NRAS, BRAF, and HER2 occurred at a significantly higher incidence among MSI-H tumors than in MSS patients (83.6% vs. 58.4%, p = 0.0003). A subset comprising 98 tumors were tested for MSI/MMR using all three techniques, where NGS proved to be 99.0 and 93.9% concordant with PCR and IHC, respectively. Four of the 7 IHC-PCR discordant cases had low TMB (1.1-8.1 muts/Mb) and were confirmed to have been misdiagnosed by IHC. Intriguingly, 4 of the 66 MSS tumors (as determined by NGS) were defined as TMB-high (TMB-H) using a cut-off of 29 mut/Mb. Likewise, 15 of the 456 MSS tumors in the TCGA CRC cohort were also TMB-H with a cut-off of 9 muts/Mb. Expression of immune signatures across subgroups (MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-L) confirmed that the microenvironment of the MSS-TMB-H tumors was similar to that of the MSI-H-TMB-H tumors, but significantly more immune-responsive than that of the MSS-TMB-L tumors, indicating that MSI combined with TMB may be more precise than MSI alone for immune microenvironment prediction. CONCLUSION: This study demonstrated that NGS panel-based method is both robust and tissue-efficient for comprehensive molecular diagnosis of CRC. It also underscores the importance of combining MSI and TMB information for discerning patients with different microenvironment.

Impact of pelvic dimensions on anastomotic leak after anterior resection for patients with rectal cancer.

AIM: The impact of pelvis on the development of anastomotic leak (AL) in rectal cancer (RC) patients who underwent anterior resection (AR) remains unclear. The aim of this study was to evaluate the impact of pelvic dimensions on the risk of AL. METHODS: A total of 1058 RC patients undergoing AR from January 2013 to January 2016 were enrolled. Pelvimetric parameters were obtained using abdominopelvic computed tomography scans. RESULTS: Univariate analyses showed that pelvic inlet, pelvic outlet, interspinous distance, and intertuberous distance were significantly associated with the risk for AL (P < 0.05). Multivariate analysis confirmed that pelvic inlet and intertuberous distance were independent risk factors for AL (P < 0.05). Significant factors from multivariate analysis were assembled into the nomogram A (without pelvic dimensions) and nomogram B (with pelvic dimensions). The area under curve (AUC) of nomogram B was 0.72 (95% CI 0.67-0.77), which was better than the AUC of nomogram A (0.69, [95% CI 0.65-0.74]), but didn't reach a statistical significance (P = 0.199). Decision curve supported that nomogram B was better than nomogram A. CONCLUSION: Pelvic dimensions, specifically pelvic inlet and intertuberous distance, seemed to be independent predictors for postoperative AL in RC patients. Pelvic inlet and intertuberous distance incorporated with preoperative radiotherapy, preoperative albumin, conversion, and tumor diameter in the nomogram might provide a clinical tool for predicting AL.

Risk factors for the critical illness in SARS-CoV-2 infection: a multicenter retrospective cohort study.

BACKGROUND: Prior studies reported that 5 ~ 32% COVID-19 patients were critically ill, a situation that poses great challenge for the management of the patients and ICU resources. We aim to identify independent risk factors to serve as prediction markers for critical illness of SARS-CoV-2 infection. METHODS: Fifty-two critical and 200 non-critical SARS-CoV-2 nucleic acid positive patients hospitalized in 15 hospitals outside Wuhan from January 19 to March 6, 2020 were enrolled in this study. Multivariable logistic regression and LASSO logistic regression were performed to identify independent risk factors for critical illness. RESULTS: Age older than 60 years, dyspnea, respiratory rate > 24 breaths per min, leukocytosis > 9.5 × 109/L, neutrophilia > 6.3 × 109/L, lymphopenia < 1.1 × 109/L, neutrophil-to-lymphocyte ratio > 3.53, fibrinogen > 4 g/L, d-dimer > 0.55 µg/mL, blood urea nitrogen > 7.1 mM, elevated aspartate transaminase, elevated alanine aminotransferase, total bilirubin > 21 µM, and Sequential Organ Failure Assessment (SOFA) score ≥ 2 were identified as risk factors for critical illness. LASSO logistic regression identified the best combination of risk factors as SOFA score, age, dyspnea, and leukocytosis. The Area Under the Receiver-Operator Curve values for the risk factors in predicting critical illness were 0.921 for SOFA score, 0.776 for age, 0.764 for dyspnea, 0.658 for leukocytosis, and 0.960 for the combination of the four risk factors. CONCLUSIONS: Our findings advocate the use of risk factors SOFA score ≥ 2, age > 60, dyspnea and leukocytosis > 9.5 × 109/L on admission, alone or in combination, to determine the optimal management of the patients and health care resources.

Risk factor analysis for inaccurate pre-operative MRI staging in rectal cancer.

BACKGROUND: Various tumor characteristics might lead to inaccurate local MRI-defined stage of rectal cancer and the purpose of this study was to explore the clinicopathological factors that impact on the precision pre-treatment MRI-defined stage of rectal cancer. METHODS: A retrospectively analysis was conducted in non-metastatic rectal cancer patients who received radical tumor resection without neoadjuvant treatment during 2007-2015 in the Sixth Affiliated Hospital of Sun Yat-sen University. Clinical T stage and N stage defined by pelvic enhanced MRI and pathological stage were compared and patients were subdivided into accurate-staging, over-staging and under-staging subgroups. Logistic regressions were used to explore risk factors for over-staging or under-staging. RESULTS: Five hundred fifty-one cases of patients were collected. Among them, 109 cases (19.4%) of patients were over-T-staged and 50 cases (8.9%) were under-T-staged, while 78 cases (13.9%) were over-N-staged and 75 cases (13.3%) were under-N-staged. Logistic regression suggested that pre-operative bowel obstruction was risk factor for over-T-staging (OR = 3.120, 95%CI: 1.662-5.857, P < 0.001) as well as over-N-staging (OR = 3.494, 95%CI: 1.797-6.794, P < 0.001), while mucinous adenocarcinoma was a risk factor for under-N-staging (OR = 4.049, 95%CI: 1.876-8.772, P < 0.001). Patients with larger tumor size were at lower risk for over-T-staging (OR = 0.837, 95%CI: 0.717-0.976, P = 0.024) and higher risk for over-N-staging (OR = 1.434, 95%CI: 1.223-1.680, P < 0.001). CONCLUSION: Bowel obstruction, mucinous adenocarcinoma and tumor size might have impact on the pre-operative MRI T staging or N staging of rectal cancer. Our results reminded clinicians to assess clinical stage individually in such rectal cancer patients.

Clinical outcomes of curative treatment for colorectal liver metastases combined with cytoreductive surgery and intraperitoneal chemotherapy for peritoneal metastases: a systematic review and meta-analysis of current evidence.

BACKGROUND: The optimal treatment for colorectal cancer (CRC) with synchronous peritoneal carcinomatosis (PC) and liver metastases (LM) remains controversial. We aimed to investigate clinical outcomes in patients with CRC and concomitant PC and LM who had undergone curative surgery, including resections at both metastatic sites and synchronous intraabdominal chemotherapy. METHODS: We searched PubMed, EMBASE, and Web of Science databases for eligible studies. Studies focusing on the clinical effects of curative surgery and synchronous intraabdominal chemotherapy for patients with CRC and concomitant PC and LM were included. Meta-analysis results were recorded as hazard ratios (HRs), risk ratios (RRs) and mean differences. RESULTS: We included 9 of 998 identified studies in the meta-analysis, involving 746 patients (221 patients with PC + LM, 525 patients with PC). Overall survival (pooled HR 1.68, 95% confidence interval [CI] 1.33-2.13, p < 0.01) and disease-free survival (pooled HR 1.82, 95% CI 1.51-2.20, p < 0.01) were both lower in patients with PC + LM. A higher recurrence rate (RR 1.22, 95% CI 1.04-1.44, p = 0.02) and major postoperative morbidity (RR 1.47, 95% CI 1.19-1.82, p < 0.01) were also observed in patients with PC + LM. CONCLUSION: Liver resection in combination with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for patients with CRC and synchronous hepatic and peritoneal metastases may be associated with worse survival and higher morbidity compared with patients with isolated PC. More restricted patient inclusion criteria should be established to facilitate an optimal prognosis for this patient group.

Laparoscopic versus open pancreatoduodenectomy: a meta-analysis of randomized controlled trials.

INTRODUCTION: the evidence with regard to the benefit of laparoscopic surgery for pancreatoduodenectomy is conflicting. The aim of this meta-analysis was to compare the short-term outcomes in patients undergoing laparoscopic or open pancreatoduodenectomy via randomized controlled trial studies. METHODS: PubMed, Embase and Cochrane Library databases were searched for studies addressing laparoscopic versus open pancreatoduodenectomy up to February 2019. Only randomized controlled trial studies were included. RESULTS: three randomized controlled trial studies were identified, which included a total of 224 patients. Statistically significant differences were found with regard to estimated blood loss in favor of laparoscopic pancreatoduodenectomy (WMD, -150.9 ml; 95% CI, -167.61 to -134.18; p < 0.001) but with longer operative time (WMD, 97.66 min; 95% CI, 21.28 to 174.05; p = 0.01). No significant differences were found for severe postoperative complications (defined as Clavien-Dindo grade ≥ III complications), complication-related mortality within 90 days, blood transfusion requirements, length of hospital stay, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, surgical site infection, readmission rate, reoperation rate, harvested lymph nodes and R0 resection rate. CONCLUSIONS: the perioperative safety of laparoscopic pancreatoduodenectomy, which may have an advantage of lower estimated blood loss, is comparable to that of open pancreatoduodenectomy. Currently, a small volume of cases may be an important reason that affects the evaluation between laparoscopic and open pancreatoduodenectomy. Further evaluation of laparoscopic pancreatoduodenectomy will require large randomized control trials.

A signature of hypoxia-related factors reveals functional dysregulation and robustly predicts clinical outcomes in stage I/II colorectal cancer patients.

BACKGROUND: The hypoxic tumor microenvironment accelerates the invasion and migration of colorectal cancer (CRC) cells. The aim of this study was to develop and validate a hypoxia gene signature for predicting the outcome in stage I/II CRC patients that have limited therapeutic options. METHODS: The hypoxic gene signature (HGS) was constructed using transcriptomic data of 309 CRC patients with complete clinical information from the CIT microarray dataset. A total of 1877 CRC patients with complete prognostic information in six independent datasets were divided into a training cohort and two validation cohorts. Univariate and multivariate analyses were conducted to evaluate the prognostic value of HGS. RESULTS: The HGS consisted of 14 genes, and demarcated the CRC patients into the high- and low-risk groups. In all three cohorts, patients in the high-risk group had significantly worse disease free survival (DFS) compared with those in the low risk group (training cohort-HR = 4.35, 95% CI 2.30-8.23, P < 0.001; TCGA cohort-HR = 2.14, 95% CI 1.09-4.21, P = 0.024; meta-validation cohort-HR = 1.91, 95% CI 1.08-3.39, P = 0.024). Compared to Oncotype DX, HGS showed superior predictive outcome in the training cohort (C-index, 0.80 vs 0.65) and the validation cohort (C-index, 0.70 vs 0.61). Pathway analysis of the high- and low-HGS groups showed significant differences in the expression of genes involved in mTROC1, G2-M, mitosis, oxidative phosphorylation, MYC and PI3K-AKT-mTOR pathways (P < 0.005). CONCLUSION: Hypoxic gene signature is a satisfactory prognostic model for early stage CRC patients, and the exact biological mechanism needs to be validated further.

MicroRNA 26b promotes colorectal cancer metastasis by downregulating phosphatase and tensin homolog and wingless-type MMTV integration site family member 5A.

Invasion and metastasis are crucially important factors in the survival of malignant tumors. Epithelial-mesenchymal transition (EMT) is an early step in metastatic progression and the presence of cancer stem cells is closely related to tumor survival, proliferation, metastasis, and recurrence. Herein we report that ectopic overexpression of microRNA 26b (miR-26b) in colorectal cancer (CRC) cell lines promoted EMT and stem cell-like phenotypes in vitro. Furthermore, miR-26b directly targeted and suppressed multiple tumor suppressors, including phosphatase and tensin homolog (PTEN) and wingless-type MMTV integration site family member 5A (WNT5A). Notably, miR-26b is markedly upregulated in tumor samples from patients with lymphatic metastases. These results indicate that miR-26b promotes CRC metastasis by downregulating PTEN and WNT5A, and may represent a therapeutic target for metastatic CRC.

Surface plasmon propelled high-performance CdSe nanoribbons photodetector.

In this work, we present a plasmonic photodetector (PPD) with high sensitivity to red light illumination. The ultrasensitive PPD was composed of high-crystalline CdSe nanoribbons (NRs) decorated with plasmonic hollow gold nanoparticles (HGNs) on the surface, which were capable of coupling the incident light due to localized surface plasmon resonance (LSPR). Device analysis reveals that after modification of HGNs, both responsivity and detectivity were considerably improved. Further device performance analysis and theoretical simulation based on finite element method (FEM) find that the optimized performance is due to HGNs induced localized field enhancement and direct electron transfer.

Bone marrow mesenchymal stem cells ameliorate colitis-associated tumorigenesis in mice.

BACKGROUND AND AIMS: Bone marrow-derived mesenchymal stem cell (MSC) is widely studied in inflammatory bowel disease (IBD) in basic and clinical research. However, patients with IBD have higher risk of developing colorectal cancer and MSC has dual effect on tumorigenesis. This study aims to evaluate the role of MSC on tumorigenesis of IBD. METHODS: MSCs were isolated from the bone marrow of allogenic mice and identified by flow cytometry. Mice in the model of colitis-associated tumorigenesis induced by azoxymethane and dextran sulfate sodium were injected with MSCs. Colon length, spleen size and tumors formation were assessed macroscopically. Pro-inflammatory cytokines and STAT3 phosphorylation in colon tissues were analyzed. RESULTS: MSCs ameliorated the severity of colitis associated tumorigenesis compared with PBS control, with attenuated weight loss, longer colons and smaller spleens. Tumor number and tumor load were significantly less in the MSC group while tumor size remained comparable. Histological assessment indicated MSCs could reduce histological damage of the colon tissue. Decreased expression of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), and down-regulation of STAT3 phosphorylation in colon tissue were found after MSC treatment. CONCLUSION: MSCs might ameliorate the tumorigenesis of inflammatory bowel disease by suppression of expression of pro-inflammatory cytokines and STAT3 activation.

Prognostic Impact of Para-Aortic Lymph Node Dissection in Colorectal Cancer Patients Suspected of Para-Aortic Lymph Node Metastasis: A Retrospective Cohort Study.

BACKGROUND: Para-aortic lymph node metastasis (PALNM) is a rare occurrence in colorectal cancer (CRC), and the high risk of radical lymphadenectomy leads to persistent debate about the best treatment strategy. This study aims to evaluate the predictor for PALNM and the clinical value of para-aortic lymph node dissection (PALND) in CRC patients with radiologically suspected synchronous PALNM. METHODS: Patients who have synchronous radiologically suspected PALNM and underwent primary tumor resection were included. Logistic regression and receiver operating characteristic curve analysis were used to assess the predictive value of lymph node short axis in preoperative CT, identifying the optimal cut-off value. Propensity score matching and Cox regression explored factors affecting overall and disease-free survival, while Kaplan-Meier curves and decision tree models identified patient characteristics suitable for synchronous para-aortic lymph node dissection. RESULTS: A total of 578 patients were enrolled, and 125 patients received synchronous PALND. We found that simultaneous PALND significantly improved overall survival (HR, 0.56; 95% CI, 0.35-0.91; P = .019) in multivariate analysis, while disease-free survival showed no significant difference (P = .41). The short axis diameter of PALN on preoperative CT is a crucial predictor of PALNM (P < .001, AUC = 0.759) with a threshold of > 7 mm. N-stage and distant metastasis were included as independent predictors in the diagnostic model to enhance accuracy. A larger short axis diameter of PALN correlated with advanced tumor stage and poorer prognosis. Subgroup analysis revealed that PALND offers survival benefits for colorectal cancer patients at all stages with a short axis diameter >10 mm on preoperative CT (P = .037) and for stage III patients with a diameter between 7 to10 mm (P < .001, AUC = 0.810). CONCLUSION: Synchronous PALND can improve overall survival in CRC patients with suspected PALNM, with the maximum short axis diameter of PALN serving as a key criterion for selecting patients for surgery.

CCL18 as an independent favorable prognostic biomarker in patients with colorectal cancer.

BACKGROUND: CCL18 has been shown to have an important role in the progression of gastric and breast cancers. However, the prognostic value of CCL18 in colorectal cancer (CRC) remains unknown. MATERIALS AND METHODS: We used immunohistochemistry to examine the expression of CCL18 in CRC patients. We applied both univariate and multivariate analysis to evaluate the prognostic value of CCL18 on CRC patients' survival. We used double staining to investigate the relationship between CCL18 and macrophages. RESULTS: A total 371 CRC patient samples were enrolled in immunohistochemical analysis. According to our criteria, 118 samples (31.8%) showed a high CCL18 expression level. Clinicopathologic analysis revealed an association between the expression level of CCL18 and the preoperative carcino embryonic antigen level (P = 0.001), and the preoperative carbohydrate antigen 19-9 level (P = 0.003). Survival analysis and multivariate analysis revealed that CCL18 was an independent favorable prognostic factor in patients with CRC (P = 0.033). Double staining implied that CCL18 was expressed by macrophages. CONCLUSIONS: A high CCL18 level might be an independent biomarker for predicting better survival of patients with CRC.

IGSF6 is a novel biomarker to evaluate immune infiltration in mismatch repair-proficient colorectal cancer.

Immunotherapy has dramatically changed the landscape of treatment for colorectal cancer (CRC), but currently lack of effective predictive biomarker, especially for tumors with mismatch repair (MMR) proficiency. The response of immunotherapy is associated with the cell-cell interactions in tumor microenvironment, encompassing processes such as cell-cell recognition, binding, and adhesion. However, the function of immunoglobulin superfamily (IGSF) genes in tumor immune microenvironment remains uncharacterized. This study quantified the immune landscape by leveraging a gene expression matrix from publicly accessible databases. The associations between IGSF6 gene expression and immune cell infiltration were assessed. The expression levels of IGSF6, CD8+ T cells, CD4+ T cells and CD68+ macrophage cells in cancer tissues from CRC patients and CRC cell lines were evaluated. IGSF6 was more highly expressed in CRC tumor tissues than adjacent normal tissues. And IGSF6 was significantly correlated with immune cell infiltration in MMR-proficient patients. Remarkably, MMR-proficient patients with high IGSF6 expression showed more sensitive to immunotherapy and chemotherapy than those with low IGSF6 expression. In summary, IGSF6 could be a novel biomarker to evaluate immune infiltration and predict therapeutic effect for MMR-proficient CRC.

High expression of CD73 as a poor prognostic biomarker in human colorectal cancer.

BACKGROUND AND OBJECTIVES: To investigate the expression dynamics of CD73 and its prognostic significance in human colorectal cancer (CRC). METHODS: CD73 expression dynamics were detected by Western blotting. Immunohistochemistry was used to examine the expression of CD73 in CRC tissues from two independent cohorts by tissue microarrays. The optimal cutpoint of CD73 expression was assessed by the X-tile program. RESULTS: Western blotting analysis demonstrated that CD73 expression in CRC was significantly higher than in normal colorectal tissues. According to the X-tile program, the cutpoint for high expression of CD73 in CRC was determined when CD73 expression index was more than 5.9. High expression of CD73 was observed in 44.8% and 50.4% of CRC in the training and validation cohorts, respectively. Overexpression of CD73 was significantly correlated with tumor differentiation, nodal status, American Joint Committee on Cancer stage. Patients with high expression of CD73 had a poorer overall survival rate compared with patients with low expression of CD73 in both cohorts. In multivariate Cox regression analysis, overexpression of CD73 was proven to be an independent prognostic biomarker for CRC. CONCLUSIONS: High expression of CD73 can be an independent and useful biomarker for predicting the poor survival of patients with CRC.