Tumor Recurrence In Colorectal Cancer Research Articles

STING Membrane Prevents Post-Surgery Tissue Adhesion and Tumor Recurrence of Colorectal Cancer.

Surgery is the standard treatment regimen for resectable colorectal cancer (CRC). However, it is very hard to completely remove all cancer cells in clinical practice, leading to the high recurrence rates of the disease. Moreover, the post-surgery tissue adhesion greatly prevents the possibility of reoperation, significantly limiting the long-term surviving of CRC patients. To overcome CRC recurrence and avoid the post-surgery tissue adhesion, this work develops a novel stimulator of interferon genes "STING" membrane based on the coaxial electrospinning technology and hyaluronic acid modification. A reactive oxygen species responsive prodrug of gambogic acid (GB) and a potent STING agonist (CDN) are coloaded in the core-shell structure of the membrane, which endows the loaded drug with sustained and sequential release patterns. The localized delivery of GB and CDN can selectively induce efficient immunogenic cell death of cancer cells and then evoke the systemic anticancer immunity by activating the Cyclic GMP-AMP (cGAMP) synthase/STING pathway. As-designed "STING" membrane not only safely prevents tumor recurrence through the synergistic chemoimmunotherapy but also efficiently avoids the post-surgery tissue adhesion, facilitating the clinical intervention of CRC.

Long-term DEHP/MEHP exposure promotes colorectal cancer stemness associated with glycosylation alterations

Plasticizers are considered as environmental pollution released from medical devices and increased potential oncogenic risks in clinical therapy. Our previous studies have shown that long-term exposure to di-ethylhexyl phthalate (DEHP)/mono-ethylhexyl phthalate (MEHP) promotes chemotherapeutic drug resistance in colorectal cancer. In this study, we investigated the alteration of glycosylation in colorectal cancer following long-term plasticizers exposure. First, we determined the profiles of cell surface N-glycomes by using mass spectrometry and found out the alterations of α2,8-linkages glycans. Next, we analyzed the correlation between serum DEHP/MEHP levels and ST8SIA6 expression from matched tissues in total 110 colorectal cancer patients. Moreover, clinical specimens and TCGA database were used to analyze the expression of ST8SIA6 in advanced stage of cancer. Finally, we showed that ST8SIA6 regulated stemness in vitro and in vivo. Our results revealed long-term DEHP/MEHP exposure significantly caused cancer patients with poorer survival outcome and attenuated the expression of ST8SIA6 in cancer cells and tissue samples. As expected, silencing of ST8SIA6 promoted cancer stemness and tumorigenicity by upregulating stemness-associated proteins. In addition, the cell viability assay showed enhanced drug resistance in ST8SIA6 silencing cells treated with irinotecan. Besides, ST8SIA6 was downregulated in the advanced stage and positively correlated with tumor recurrence in colorectal cancer. Our results imply that ST8SIA6 potentially plays an important role in oncogenic effects with long-term phthalates exposure.

CRMP5 regulates cell proliferation and development of colorectal cancer via MAPK-dependent signaling.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that serve a major role in neural development. CRMP5 has been identified as a biomarker of numerous cancer types, including lung cancer and glioblastoma. However, the role of CRMP5 in CRC remains unclear. In the present study, CRMP5 was characterized as a novel biomarker of poor survival in CRC. CRMP5-overexpression in CRC cells promoted cell proliferation and migration while CPMP5-knockdown decreased cell growth and migration. A novel mechanism was uncovered, by which CRMP5 regulates MAPK signaling to drive CRC cell proliferation and development. Furthermore, CRMP5-overexpression induced chemotherapy resistance and tumor recurrence in CRC. Taken together, these results demonstrated the important role of CRMP5 in the development and proliferation of CRC cells and suggested that CRMP5 may be a novel therapeutic target for CRC.

Identification of Hub Genes and Construction of a Transcriptional Regulatory Network Associated With Tumor Recurrence in Colorectal Cancer by Weighted Gene Co-expression Network Analysis.

Tumor recurrence is one of the most important risk factors that can negatively affect the survival rate of colorectal cancer (CRC) patients. However, the key regulators dictating this process and their exact mechanisms are understudied. This study aimed to construct a gene co-expression network to predict the hub genes affecting CRC recurrence and to inspect the regulatory network of hub genes and transcription factors (TFs). A total of 177 cases from the GSE17536 dataset were analyzed via weighted gene co-expression network analysis to explore the modules related to CRC recurrence. Functional annotation of the key module genes was assessed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The protein and protein interaction network was then built to screen hub genes. Samples from the Cancer Genome Atlas (TCGA) were further used to validate the hub genes. Construction of a TFs-miRNAs–hub genes network was also conducted using StarBase and Cytoscape approaches. After identification and validation, a total of five genes (TIMP1, SPARCL1, MYL9, TPM2, and CNN1) were selected as hub genes. A regulatory network of TFs-miRNAs-targets with 29 TFs, 58 miRNAs, and five hub genes was instituted, including model GATA6-MIR106A-CNN1, SP4-MIR424-TPM2, SP4-MIR326-MYL9, ETS1-MIR22-TIMP1, and ETS1-MIR22-SPARCL1. In conclusion, the identification of these hub genes and the prediction of the Regulatory relationship of TFs-miRNAs-hub genes may provide a novel insight for understanding the underlying mechanism for CRC recurrence.

12-Chemokine signature, a predictor of tumor recurrence in colorectal cancer.

Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12-chemokine (CCL2, -3, -4, -5, -8, -18, -19, -21, CXCL9, -10, -11, -13) signature status from tumor tissue and the TLS expression. However, the potential significance of 12-chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12-chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12-chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12-chemokine signature status had a significant shorter relapse-free survival in discovery cohort (HR: 1.61, 95% CI: 1.11-2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33-10.08, p = 0.0087). High 12-chemokine signature status had significant associations with right-sided tumor, high tumor-localized TLS expression, BRAF mutant, CIMP-high status and MSI-high status. Furthermore, RNA-seq based analysis showed that high 12-chemokine signature status was strongly associated with inflammation-related, immune cells-related and apoptosis pathways (using gene set enrichment analysis), and more tumor-infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP-counter analysis). We investigated a promising effect of 12-chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.

Angiotensin I-converting enzyme inhibitors/angiotensin II receptor blockers may reduce tumor recurrence in left-sided and early colorectal cancers.

Angiotensin signaling is suggested to be involved in tumorigenesis, tumor proliferation, and metastases. In colorectal cancer (CRC), it was demonstrated that angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may reduce the risk of CRC; however, their impact on tumor recurrence remains unknown. Therefore, in this study, we evaluated the impact of ACEIs/ARBs on tumor recurrence in CRC patients. We retrospectively investigated the clinicopathological data of 461 stage I-III CRC patients. We divided the patients into those who took an ACEI and/or ARB (the ACEI/ARB+ group) and those who did not (the ACEI/ARB- group), and we compared the two groups' recurrence-free survival (RFS) using a Kaplan-Meier curve analysis and log rank test. We also examined the impact of AGTR1 expression on tumor recurrence, using two public CRC datasets. The Kaplan-Meier curves showed a trend toward improved RFS in the ACEI/ARB+ group versus the ACEI/ARB- group (p= 0.063). Subgroup analyses demonstrated that the RFS was significantly better in the ACEI/ARB+ group versus the ACEI/ARB- group in the patients with left-sided CRC (p= 0.030) and those with stage I CRC (p= 0.009). Consistent with these findings, the AGTR1 expression was higher in the left-sided versus right-sided colon (p= 0.048). High AGTR1 expression levels were associated with poor RFS in the GSE39582 dataset's stage I-III CRC patients (p< 0.001), and this finding was also validated in the GSE17536 dataset (p= 0.023). ACEI/ARB treatment may reduce tumor recurrence in left-sided CRC and early-stage CRC.

Serum-based microRNA signature predicts relapse and therapeutic outcome of adjuvant chemotherapy in colorectal cancer patients.

BackgroundApproximately 60% of patients with colorectal cancer (CRC) undergo either local recurrence or distant metastases after surgery. Current prognostic biomarkers are insufficient to predict recurrence of CRC and provide little forecast information about what patients are likely to receive benefit from the adjuvant chemotherapy. As microRNAs (miRNAs) constantly exist in human serum and being used to predict the prognosis of a various cancers, this study was designed to identify miRNA-based circulating biomarkers to predict clinical outcomes of CRC.MethodsA serum-focused miRNA expression was used to investigate if miRNA expression profiles could predict the clinical outcomes of patients with CRC. We created miRNA signature profiles associated in the training set (n = 40), and further validated its prediction in two independent testing cohorts.ResultsUsing Cox regression and risk-score analysis, we identified a four-miRNA signature (miR-652-3p, miR-342-3p, miR-501-3p and miR-328-3p) for the prediction of tumor relapse and the overall survival(OS) of patients with CRC in the training set (n = 40). This miRNA signature was further validated in a testing set (n = 226) and another independent cohort (n = 56). A high-risk signature score was significantly associated with CRC tumor recurrence and poor treatment outcome. Multivariable Cox regression models indicated that the risk score, based on the four-miRNA signature, was an independent prognostic classifier for patients with CRC.ConclusionsThe serum miRNA signature may serve as a minimally invasive predictor for tumor relapse and treatment outcome in patients with CRC and provide a useful reference for treatment selection.

Serum-Based MicroRNA Signature Predicts Relapse and Therapeutic Outcome of Adjuvant Chemotherapy in Colorectal Cancer Patients

Background: Approximately 60% of patients with colorectal cancer (CRC) undergo either local recurrence or distant metastases after surgery. Current prognostic biomarkers are insufficient to predict recurrence of CRC and provide little forecast information about what patients are likely to receive benefit from the adjuvant chemotherapy. As microRNAs (miRNAs) constantly exist in human serum and being used to predict the prognosis of a various cancers, this study was designed to identify miRNA-based circulating biomarkers to predict clinical outcomes of CRC. Methods: A serum-focused miRNA expression was used to investigate if miRNA expression profiles could predict the clinical outcomes of patients with CRC. We created miRNA signature profiles associated in the training set (n = 40), and further validated its prediction in two independent testing cohorts. Results: Using Cox regression and risk-score analysis, we identified a four-miRNA signature (miR-652, miR-342, miR-501, and miR-328) for the prediction of tumor relapse and the overall survival(OS) of patients with CRC in the training set (n = 40). This miRNA signature was further validated in a testing set (n = 226) and another independent cohort (n = 56). A high-risk signature score was significantly associated with CRC tumor recurrence and poor treatment outcome. Multivariable Cox regression models indicated that the risk score, based on the four-miRNA signature, was an independent prognostic classifier for patients with CRC. Conclusions: The serum miRNA signature may serve as a minimally invasive predictor for tumor relapse and treatment outcome in patients with CRC and provide a useful reference for treatment selection. Funding Statement: This work was supported by the National Natural Science Foundation of China (81372593, 81201965, 81772565), Beijing Natural Science Foundation (7132052), and the National High Technology Research and Development Program of China (863 Program) (No.2012AA02A506, 2014AA020801). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This research was approved by the ethics committee of the Health Science Center of Peking University and the Oncology Center at Peking University and Zhejiang University. Written informed consent was obtained from all participants before enrollment to the study.

MiR-363-3p inhibits the epithelial-to-mesenchymal transition and suppresses metastasis in colorectal cancer by targeting Sox4

Epithelial-to-mesenchymal transition (EMT) plays an essential role in cancer invasion and metastasis and is associated with tumor recurrence in colorectal cancer (CRC). However, the mechanism that contributes to EMT have not been fully understood in CRC. In the present study, we showed that miR-363-3p was frequently down-regulated in CRC tissue specimens with lymph node metastasis. Moreover, we demonstrated that down-regulation of miR-363-3p promoted CRC cell migration and invasion, and induced EMT in vitro and in vivo, revealing that miR-363-3p playes a potential tumor-suppressive role in CRC. Analysis of the underlying mechanisms revealed that miR-363-3p could regulate Sox4 expression by directly targeting its 3'untranslated region. Down-regulation of miR-363-3p increased Sox4 expression and induced EMT, while overexpression of miR-363-3p decreased Sox4 expression. Taken together, our findings indicate that miR-363-3p is involved in CRC metastasis and functions as a tumor suppressor via negatively regulating Sox4. Therefore, the up-regulation of miR-363-3p in human CRC may have therapeutic benefits.

Visual and quantitative comparison of 18F-fluorodeoxyglucose PET/CT findings in the detection of pelvic tumor recurrence in colorectal cancer

This study aimed to visually and quantitatively compare (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging in determining postoperative pelvic recurrence in colorectal cancer (CRC). This retrospective analysis focused on 96 patients (age: mean 62.6±10.5) with surgically resected CRC (time interval after surgery: 19.2±20.4months). The standard of reference was histopathologic confirmation (n=27) or imaging follow-up (n=69). For visual analysis, three independent nuclear physicians interpreted the PET/CT findings. For the quantitative analysis, the normalized standardized uptake values (nSUVs: nSUVmax, nSUVpeak, nSUVmean) were calculated by applying the mean SUV of a normal liver. We evaluated the areas under the receiver operating characteristic curves (AUCs) for all the quantitative parameters. Of the 96 patients, 49 showed pelvic recurrence and 47 revealed no tumor recurrence. Sensitivity and specificity were 85.7 and 80.9%, respectively, for visual analysis, and 65.3 and 83.0%, respectively, for quantitative analysis. The AUC (0.766, CI: 0.668-0.846) of nSUVmax was largest comparing nSUVpeak and nSUVmean values, without significant difference (p value >0.316). Sensitivity of lesion detection was superior in visual analysis (p value = 0.02), but specificity was not significantly different (p=0.80). After inclusive and exclusive combinations, sensitivity and specificity were slightly increased to 89.8% (p=0.54) and 91.5% (p=0.14), respectively. Visual interpretation was superior to quantitative analysis in pelvic tumor recurrence in CRC. Though it was possible to improve diagnostic performance through combinatory analysis, the effect was not statistically significant.

Prognostic Significance of MicroRNA‐16 Expression in Human Colorectal Cancer

MicroRNAs (miRNAs), small noncoding RNAs, have been reported to be highly involved in the formation and progression of all types of human cancer including colorectal cancer (CRC). Therefore, miRNAs are also potential prognostic biomarkers in CRC patients. The aim of this study was to detect the expression of miR-16 in human CRC tissues and investigate its clinicopathologic or prognostic significance. TaqMan quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay was performed to determine the expression of miR-16 in 143 primary CRC tissues and 18 corresponding normal colonic mucosa from patients who had undergone surgery. The association of miR-16 expression with clinicopathologic features of CRC patients was statistically analyzed. Kaplan-Meier analyses were used to assess patient survival. Univariate and multivariate Cox analyses were performed. The relative level of miR-16 in 18 CRC tissues was significantly lower than that in corresponding normal colonic mucosa (p < 0.001). Statistical analyses revealed that the status of miR-16 expression was closely associated with tumor differentiation, lymph node metastasis, L category, V category, TNM stage, and tumor recurrence of CRC (p = 0.001, 0.003, 0.001, 0.005, 0.003, and 0.017, respectively). Kaplan-Meier analyses indicated that patients with low-miR-16 had lower 5-year overall survival than those with high-miR-16 (31.2 vs. 58.3 %; p = 0.0012). Multivariate Cox regression analyses indicated that the status of miR-16 expression might be an independent prognostic factor for CRC patients (hazard ratio 1.67; 95 % confidence interval 1.22-2.54; p = 0.018). Down-regulation of miR-16 plays critical roles in CRC progression. Low miR-16 expression is an independent factor predicting a poor prognosis for CRC patients.

Combined use of preoperative 18F FDG-PET imaging and intraoperative gamma probe detection for accurate assessment of tumor recurrence in patients with colorectal cancer

BackgroundThe purpose of this study was to combine intraoperative gamma probe (GP) detection with preoperative fluorine 18-fluoro-2-deoxy-glucose positron emission tomography (18F FDG-PET) imaging in order to improve detection of tumor recurrence in colorectal cancer (CRC) patients.MethodsTwenty-one patients (12 females, 9 males) with a mean age of 54 years (range 31–78) were enrolled. Patients were suspected to have recurrent CRC by elevated CEA (n = 11), suspicious CT findings (n = 1), and clinically suspicious findings (n = 9). Preoperative FDG-PET scan and intraoperative GP study were performed in all patients. Mean time interval between preoperative FDG-PET scan and surgery was 16 days (range 1–41 days) in 19 patients. For intraoperative GP studies, 19 patients were injected with a dose of 10–15 mCi 18F FDG at approximately 30 minutes before the planned surgery time. In two patients, the intraoperative GP study was performed immediately after preoperative FDG-PET scan.ResultsPreoperative FDG-PET and intraoperative GP detected 48 and 45 lesions, respectively. A total of 50 presumed site of recurrent disease from 20 patients were resected. Thirty-seven of 50 presumed sites of recurrent disease were histological-proven tumor positive and 13 of 50 presumed sites of recurrent disease were histological-proven tumor negative. When correlated with final histopathology, the number of true positive lesions and false positive lesions by preoperative FDG-PET and intraoperative GP were 31/9 and 35/8, respectively. Both preoperative FDG-PET and intraoperative GP were true positive in 29 lesions. Intraoperative GP detected additional small lesions in the omentum and pelvis which were not seen on preoperative FDG-PET scan. FDG-PET scan demonstrated additional liver metastases which were not detected by intraoperative GP. Preoperative FDG-PET detected distant metastasis in the lung in one patient. The estimated radiation dose received by a surgeon during a single 18F FDG GP surgery was below the occupational limit.ConclusionThe combined use of preoperative FDG-PET and intraoperative GP is potentially helpful to the surgeon as a roadmap for accurately locating and determining the extent of tumor recurrence in patients with CRC. While intraoperative GP appears to be more sensitive in detecting the extent of abdominal and pelvic recurrence, preoperative FDG-PET appears to be more sensitive in detecting liver metastases. FDG-PET is also a valuable method in detecting distant metastases.

Clinical significance of preoperative serum sialic acid levels in colorectal cancer: utility in the detection of patients at high risk of tumor recurrence.

This study was conducted to evaluate the significance of preoperative serum sialic acid levels in the diagnosis and prognosis of colorectal cancer (CRC). Total sialic acid (TSA) was determined by the thiobarbituric acid method and normalized to total protein (TP). A postoperative follow-up of CRC patients classified as Dukes' stages A, B or C was performed and survival analysis was carried out to evaluate the impact of sialic acid levels on tumor recurrence. Our diagnostic studies indicate that TSA/TP is a better marker than either TSA or carcinoembryonic antigen (CEA), especially for the detection of CRC patients at an early stage. At a cutoff of 30.90 nmol/mg of protein, TSA/TP showed a sensitivity of 85% with a specificity of 97% to discriminate CRC patients from healthy donors. In survival analysis, both TSA and TSA/TP were found to be significant prognostic factors for tumor recurrence in CRC. Furthermore, TSA/TP could distinguish patients at high risk of recurrence within Dukes' stage B and in multivariate analysis it was identified as the best independent prognostic factor. According to our results, preoperative serum TSA/TP content could supply additional information to that provided by Dukes' stage about the prognosis of CRC patients.

Clinical significance of preoperative serum sialic acid levels in colorectal cancer: utility in the detection of patients at high risk of tumor recurrence

This study was conducted to evaluate the significance of preoperative serum sialic acid levels in the diagnosis and prognosis of colorectal cancer (CRC). Total sialic acid (TSA) was determined by the thiobarbituric acid method and normalized to total protein (TP). A postoperative follow-up of CRC patients classified as Dukes' stages A, B or C was performed and survival analysis was carried out to evaluate the impact of sialic acid levels on tumor recurrence. Our diagnostic studies indicate that TSA/TP is a better marker than either TSA or carcinoembryonic antigen (CEA), especially for the detection of CRC patients at an early stage. At a cutoff of 30.90 nmol/mg of protein, TSA/TP showed a sensitivity of 85% with a specificity of 97% to discriminate CRC patients from healthy donors. In survival analysis, both TSA and TSA/TP were found to be significant prognostic factors for tumor recurrence in CRC. Furthermore, TSA/TP could distinguish patients at high risk of recurrence within Dukes' stage B and in multivariate analysis it was identified as the best independent prognostic factor. According to our results, preoperative serum TSA/TP content could supply additional information to that provided by Dukes' stage about the prognosis of CRC patients.

Anastomotic leakage: impact on local recurrence and survival in surgery of colorectal cancer.

Anastomotic leakage is a serious complication in colorectal surgery, especially in the treatment of adenocarcinoma located in the left-sided colon and rectum. It is controversial whether anastomotic leakage is a prognostic factor for local recurrence and/or survival in this disease. To evaluate the impact of anastomotic dehiscence on the outcome of surgery we reviewed data on 467 consecutive patients with adenocarcinoma of the left colon and rectum treated between 1985 and 1995 in our Department. Of these, 41 (8.8%) developed anastomotic leakage. The overall-survival differed nonsignificantly (P = 0.57) between leakage and nonleakage groups. Of 331 patients with curative resection 29 showed an anastomotic leakage. There were 46 R0-resected patients who died under disease-related conditions: 7 patients in the leakage group (24.1%) and 39 in the nonleakage group (12.9%; P = 0.045). In the curatively resected group 5 of 29 patients developed local recurrence in the leakage group (17.2%) but only 26 of 302 patients in the nonleakage group (8.6%; P = 0.0357). Multivariate analysis showed only the factors of age, stage of resection, staging of lymph nodes, and tumor staging as independent prognostic factors for overall survival. For local recurrence the multivariate analysis revealed tumor staging and anastomotic leakage as independently significant. Anastomotic leakage thus appears to be a prognostic factor for local tumor recurrence of colorectal cancer. In addition, disease-related survival is considerably decreased under leakage conditions. Anastomotic leakage was not shown in this study to be an independent prognostic factor for overall survival due to the lack of statistical significance.

Prospective study of circulating T-lymphocyte subpopulations and disease progression in colorectal cancer.

It has recently been reported that CD4+ T-lymphocytes are reduced in advanced colorectal cancer patients. However, it is not clear whether such changes in T-lymphocyte subsets are an early or late event in such patients. The aim of this study was to examine the relationship between these subsets and disease progression in colorectal cancer. Flow cytometric analysis of T-lymphocyte subsets was performed in 39 patients who, approximately 12 months previously, had undergone surgery for colorectal cancer. These patients were grouped according to whether they developed a recurrence in the following two years. A group of healthy subjects was studied as controls. There was a significant increase in the median neutrophil count (4.3 vs. 3.7 10(6)/ml) and the median numbers of platelets (282 vs. 216 10(6)/ml) of the recurrence group compared with the control group, respectively (P < 0.05). The median numbers (0.28 vs. 0.73 10(6)/ml) and percentage (29 vs. 38 percent) of CD4+ T-lymphocytes of the recurrence group were significantly reduced compared with that of the control group (P < 0.05). There were also reductions in the median percentage of CD3+ cells (67 vs. 74 percent) and the median numbers of CD4+ T-lymphocytes (0.28 vs. 0.46 10(6)/ml) of the recurrence group compared with the no recurrence group (P < 0.05). Reduction of CD4+ T-lymphocytes occurs before detectable recurrence of colorectal cancer. Results of the present study are consistent with impaired immunity, as measured by such lymphocyte subset populations, being important in tumor recurrence in colorectal cancer.