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.

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).

Circular RNA: metabolism, functions and interactions with proteins.

Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals. Important advances have been made in the biogenesis, regulation, localization, degradation and modification of circRNAs. CircRNAs exert biological functions by acting as transcriptional regulators, microRNA (miR) sponges and protein templates. Moreover, emerging evidence has revealed that a group of circRNAs can serve as protein decoys, scaffolds and recruiters. However, the existing research on circRNA-protein interactions is quite limited. Hence, in this review, we briefly summarize recent progress in the metabolism and functions of circRNAs and elaborately discuss the patterns of circRNA-protein interactions, including altering interactions between proteins, tethering or sequestering proteins, recruiting proteins to chromatin, forming circRNA-protein-mRNA ternary complexes and translocating or redistributing proteins. Many discoveries have revealed that circRNAs have unique expression signatures and play crucial roles in a variety of diseases, enabling them to potentially act as diagnostic biomarkers and therapeutic targets. This review systematically evaluates the roles and mechanisms of circRNAs, with the hope of advancing translational medicine involving circRNAs.

Dissipative rogue waves induced by long-range chaotic multi-pulse interactions in a fiber laser with a topological insulator-deposited microfiber photonic device.

We reported on the generation of dissipative rogue waves (DRWs) induced by long-range chaotic multi-pulse interactions in a fiber laser based on a topological insulator (TI)-deposited microfiber photonic device. By virtue of the simultaneous saturable absorption effect and high nonlinearity provided by the TI-deposited microfiber, a localized, chaotic multi-pulse wave packet with strong long-range nonlinear interactions could be obtained, which gives rise to the formation of DRWs. The results might enhance the understanding of DRWs in optical systems, and further demonstrated that the TI-deposited microfiber could be considered as an excellent photonic device with both saturable absorption and highly nonlinear effects for the application field of nonlinear optics.

Circular RNAs: Emerging regulators of glucose metabolism in cancer.

Aberrant glucose metabolism is one of the most striking characteristics of metabolic reprogramming in cancer. Thus, clarifying the regulatory mechanism of glucose metabolism is crucial to understanding tumor progression and developing novel therapeutic strategies for cancer patients. Recent developments in circular RNAs have explained the regulatory mechanism of glucose metabolism from a new dimension. In this review, we briefly summarize the recent advances in circRNA research on cancer glucose metabolism and emphasize the different regulatory mechanisms, including acting as miRNA sponges, interacting with proteins and being translated into proteins. Additionally, we discuss the future research directions of circular RNAs in the field of glucose metabolism.

Pulse dynamics of dissipative soliton resonance with large duration-tuning range in a fiber ring laser.

The pulse dynamics operating in dissipative soliton resonance (DSR) region is experimentally investigated in a fiber ring laser. With the increase of pump power, the pulse profile transit from sech-like to rectangular shape was observed. The generated pulse in DSR region exhibits the conventional soliton spectrum with sideband generation. The duration-tuning range of the rectangular pulse is up to the cavity roundtrip time. Particularly, during the process of pulse duration broadening it was found that the rectangular pulse would trap a weak pulse generated from cw background. The obtained results may be useful for better understanding the DSR phenomenon.

Genome-Wide Analysis Reveals Hypoxic Microenvironment Is Associated With Immunosuppression in Poor Survival of Stage II/III Colorectal Cancer Patients.

Background: Hypoxia is associated with a poorer clinical outcome and resistance to chemotherapy in solid tumors; identifying hypoxic-related colorectal cancer (CRC) and revealing its mechanism are important. The aim of this study was to assess hypoxia signature for predicting prognosis and analyze relevant mechanism. Methods: Patients without chemotherapy were selected for the identification of hypoxia-related genes (HRGs). A total of six independent datasets that included 1,877 CRC patients were divided into a training cohort and two validation cohorts. Functional annotation and analysis were performed to reveal relevant mechanism. Results: A 12-gene signature was derived, which was prognostic for stage II/III CRC patients in two validation cohorts [TCGA, n = 509, hazard ratio (HR) = 2.14, 95% confidence interval (CI) = 1.18 - 3.89, P = 0.01; metavalidation, n = 590, HR = 2.46, 95% CI = 1.59 - 3.81, P < 0.001]. High hypoxic risk was correlated with worse prognosis in CRC patients without adjuvant chemotherapy (HR = 5.1, 95% CI = 2.51 - 10.35, P < 0.001). After integration with clinical characteristics, hypoxia-related gene signature (HRGS) remained as an independent prognostic factor in multivariate analysis. Furthermore, enrichment analysis found that antitumor immune response was suppressed in the high hypoxic group. Conclusions: HRGS is a promising system for estimating disease-free survival of stage II/III CRC patients. Hypoxia tumor microenvironment may be via inhibiting immune response to promote chemoresistance in stage II/III CRC patients.

CD73 promotes colitis-associated tumorigenesis in mice.

Patients with inflammatory bowel disease (IBD) are at a higher risk of developing colitis-associated colorectal cancer. The aim of the present study was to investigate the role of CD73 in IBD-associated tumorigenesis. A mouse model of colitis-associated tumorigenesis (CAT) induced by azoxymethane and dextran sulfate sodium was successfully constructed. Model mice were injected with CD73 inhibitor or adenosine receptor agonist. Colon length, body weight loss and tumor formation were assessed macroscopically. Inflammatory cytokine measurement and RNA sequencing on colon tissues were performed. Inhibition of CD73 by adenosine 5'-(α,ß-methylene) diphosphate (APCP) suppressed the severity of CAT with attenuated weight loss, longer colons, lower tumor number and smaller tumor size compared with the model group. Activation of adenosine receptors using 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-ß-D-ribofuranuronamide (NECA) exacerbated CAT. Histological assessment indicated that inhibition of CD73 reduced, while activation of adenosine receptors exacerbated, the histological damage of the colon. Increased expression of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6) in colonic tissue was detected in the NECA group. According to RNA sequencing results, potential oncogenes such as arachidonate 15-lipoxygenase (ALOX15), Bcl-2-like protein 15 (Bcl2l15) and N-acetylaspartate synthetase (Nat8l) were downregulated in the APCP group and upregulated in the NECA group compared with the model group. Therefore, inhibition of CD73 attenuated IBD-associated tumorigenesis, while activation of adenosine receptors exacerbated tumorigenesis in a C57BL/6J mouse model. This effect may be associated with the expression of pro-inflammatory cytokines and the regulation of ALOX15, Bcl2l15 and Nat8l.

Immune-related gene signature in predicting prognosis of early-stage colorectal cancer patients.

AIM: Immune-related genes are associated with the prognosis of colorectal cancer (CRC) patients. The aim of this study was to evaluate the impact of an immune-related gene signature (IRGS) in predicting the prognosis of early-stage CRC patients. METHODS: In total, 309 CRC patients were selected for the identification of prognostic IRGS using the CIT/GSE39582 microarray dataset. Five independent datasets including 1587 CRC patients were divided into a training cohort (n = 566) and two validation cohorts (n = 624 in validation-1 and n = 397 in meta-validation). Prognostic analyses were performed to test the predictive value of IRGS. RESULTS: A prognostic IRGS that included 23 immune-related genes was constructed and significantly stratified patients into immune low-vs. high-risk groups in terms of disease-free survival using patients with early-stage disease (I or II) in the training cohort. Similarly, a higher IRGS was correlated with significantly worse prognosis of early-stage patients in validation-1 and meta-validation cohorts. Compared with Oncotype DX colon, we found that IRGS exhibited an improved survival correlation in the training cohort. After integration with clinical characteristics, IRGS remained as an independent prognostic factor in multivariate analysis. Furthermore, IRGS-stratified immune low-risk group patients gained less benefit from adjuvant chemotherapy in the validation-1 cohort. Several biological processes, including inflammatory response, were enriched among genes in identified the immune high-risk group. Consistent with this finding, the IRGS-identified immune high-risk group exhibited significantly increased immune and stromal cell infiltration. CONCLUSION: The proposed prognostic IRGS is a promising system for estimating DFS of colorectal cancer patients, especially those with early-stage disease.

Laparoscopic Surgery for Complex Crohn's Disease: A Meta-Analysis.

Aim: There is still no consensus on whether laparoscopic surgery can be routinely recommended as a safe approach for complex Crohn's disease (CD). Methods: PubMed, Embase, and Cochrane library databases were searched (up to February 2019). Comparative studies reporting laparoscopic surgery for complex CD (LC group) comparing with simple CD (LS group) were included. The outcomes were blood loss, operative time, conversion rate, length of hospital stay, postoperative complications, and reoperation rate within 30 days after surgery. Results: Thirteen retrospective studies with 1120 participants were included. The LC group has significantly more blood loss (weighted mean difference [WMD] 43.64 mL; 95% confidence interval (CI) 8.37-78.91; P = .020), longer operative time (WMD 17.59 minutes; 95% CI 6.38-28.81; P = .002), higher conversion rate (WMD 2.04%; 95% CI 1.43-2.91; P < .001), and longer length of hospital stay (WMD 0.86 day; 95% CI 0.53-1.19; P < .001). Overall postoperative complication rates (WMD 0.98; 95% CI 0.71-1.34; P = .90) did not differ significantly between the 2 groups. Conclusions: LC is safe and feasible with comparable postoperative complications, although there is a more blood loss, longer operative time, higher conversion rate, and longer length of hospital stay.

[Comparison of local immune microenvironment between liver-metastasis colorectal cancer and non-liver-metastasis colorectal cancer].

OBJECTIVE: To investigate the difference of local immune microenvironment in primary tumors between liver-metastasis and non-liver-metastasis cohort in stage III to IIII colorectal cancer patients. METHODS: Tumor samples from 167 patients of colorectal cancer were harvested, who received tumor resection for the first time in The First Affiliated Hospital of Sun Yat-sen University from 2000 to 2005. Patients were divided into two groups according to liver metastasis or not. Expressions of 18 immune markers, including CD3, CD4 and CD8 were examined and quantified by immunohistochemistry staining. RESULTS: No significant differences of gender, age, BMI, tumor differentiation, pathology type and preoperative CEA level were found between the two groups. The expressions of CD8, CD45RO, IL-17, tryptase and FAS were lower in liver-metastasis group as compared to non-liver-metastasis group (all P<0.05). CONCLUSIONS: Decrease of the number of T lymphocyte and mast cell may play an important role in local infiltration of immune microenvironment of stage III to IIII colorectal cancer with liver metastasis.

[Efficacy and safety of domestic biofragmentable anastomotic ring in the intestinal anastomosis].

OBJECTIVE: To investigate the efficacy and safety of the domestic biofragmentable anastomotic ring (BAR) from Hangzhou in the intestinal anastomosis. METHODS: A total of 134 patients who underwent intestinal anastomosis from February 2010 to April 2011 in the First Municipal People's Hospital of Guangzhou and the First Affiliated Hospital of Zhejiang University were randomized into two groups. The Valtrac BAR from USA was employed in the control group while the experimental group used domestic BAR. The operative performance of the BARs, as well as the patients vital signs and bowel function, complications, fragmentation status of the rings were compared between two groups. RESULTS: No significant difference was found between two groups in the operative performance, the fragmentation status of the BARs, the temperature, blood pressure, heart rate, and bowel function (P>0.05). CONCLUSION: The domestic BAR possesses similar safety and efficacy with the Valtrac BAR in intestinal anastomosis.