Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. METHODS: We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. RESULTS: Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. CONCLUSIONS: We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

Vasorin (VASN) overexpression promotes pulmonary metastasis and resistance to adjuvant chemotherapy in patients with locally advanced rectal cancer.

BACKGROUND: LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection. METHODS: Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome. RESULTS: Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value < 0.001) and a predictor of adjuvant therapy efficacy in rectal cancer. CONCLUSIONS: Our study highlights the role of VASN in decreasing drug sensitivity and activating the NOTCH and MAPK pathways, which leads to tumorigenesis and pulmonary metastasis. Both experimental and clinical data support that rectal cancer patients with VASN overexpression detected in biopsies have a higher risk of pulmonary metastasis and adjuvant chemotherapy resistance.

PTEN and P-4E-BP1 might be associated with postoperative recurrence of rectal cancer patients undergoing concurrent radiochemotherapy.

BACKGROUND: Local recurrence after surgery and radiochemotherapy seriously affects the prognosis of locally advanced rectal cancer (LARC) patients. Studies on molecular markers related to the radiochemotherapy sensitivity of cancers have been widely carried out, which might provide valued information for clinicians to carry out individual treatment. AIM: To find potential biomarkers of tumors for predicting postoperative recurrence. METHODS: In this study, LARC patients undergoing surgery and concurrent radiochemotherapy were enrolled. We focused on clinicopathological factors and PTEN, SIRT1, p-4E-BP1, and pS6 protein expression assessed by immunohistochemistry in 73 rectal cancer patients with local recurrence and 76 patients without local recurrence. RESULTS: The expression of PTEN was higher, while the expression of p-4E-BP1 was lower in patients without local recurrence than in patients with local recurrence. Moreover, TNM stage, lymphatic vessel invasion (LVI), PTEN and p-4E-BP1 might be independent risk factors for local recurrence after LARC surgery combined with concurrent radiochemotherapy. CONCLUSIONS: This study suggests that PTEN and p-4E-BP1 might be potential biomarkers for prognostic prediction and therapeutic targets for LARC.

The Clinical Value of Apparent Diffusion Coefficient of Readout Segmentation of Long Variable Echo Trains and Correlation With Ki-67 Expression in Distal Rectal Cancer.

OBJECTIVE: The aim of the study is to explore the clinical value of the apparent diffusion coefficient (ADC) derived from the readout segmentation of long variable echo trains (RESOLVE) technique for identifying clinicopathologic features of distal rectal cancer and correlations between ADC and Ki-67 expression. METHODS: The data of 112 patients with a proven pathology of distal rectal cancer who underwent preoperative magnetic resonance imaging were retrospectively analyzed. The mean ADC value was measured using the "full-layer and center" method. Differences in ADC values and Ki-67 expression in different clinical stages, pathological types, and tumor differentiation were compared using analysis of variance. Correlations between ADC value and clinicopathologic features were assessed using Spearman correlation analysis. RESULTS: Interobserver agreement of confidence levels from 2 radiologists was excellent for ADC measurement ( k =  0.85). Patients with a lower clinical stage, well-differentiated adenocarcinomas, and a higher possibility of mucinous adenocarcinoma exhibited a positive correlation with higher ADC values, but these factors were negatively correlated with Ki-67 expression (all P < 0.05). We found that ADC value was negatively correlated with Ki-67 expression ( r = -0.62, P < 0.001). CONCLUSIONS: The ADC value generated by RESOLVE sequences was significantly associated with clinicopathologic features and Ki-67 expression in patients with distal rectal cancer in this study. Thus, the ADC value could be considered a new noninvasive imaging biomarker that could be helpful in predicting the biological properties of distal rectal cancer.

Chitinase-3 like-protein-1 (YKL-40) Promotes Anorectal Mucosal Melanoma Progression via the PI3K-AKT Signaling Pathway.

Objective: Anorectal mucosal melanoma is a rare and aggressive cancer with limited treatment options. Investigating specific molecular pathways may provide insight into the development and progression of this cancer. This study aims to investigate the role of chitinase-3-like protein-1 (YKL-40) in promoting the development of anorectal mucosal melanoma through the PI3K-AKT signaling pathway. Methods: Perianal cells from healthy volunteers and melanoma cells from patients with early, middle and advanced anorectal melanoma were obtained. Western blotting was performed to detect the protein expression of PI3K, AKT, and the downstream proteins mTOR, p-mTOR, ERK, and p-ERK, respectively. Subsequently, we constructed knockout and overexpression of YKL-40 melanoma cell lines, then used western blot assay to test for YKL-40, PI3K and AKT protein expression. Results: A significant increase in the expression of PI3K, AKT, and the downstream proteins mTOR, pmTOR, ERK, and pERK was observed in melanoma cells, and the expression of these proteins increased with the development of melanoma. After YKL-40 was knocked out, PI3K and AKT expression decreased in melanoma cells in patients with advanced melanoma. On the contrary, PI3K and AKT protein expression increased significantly after YKL-40 overexpression. Conclusion: There is a positive correlation between the expression levels of PI3K, AKT, mTOR, p-mTOR, ERK, and p-ERK and the stage of tumor development. The PI3K-AKT signaling pathway promotes the progress of anorectal mucosal melanoma. Chitinase-3-like protein-1 (YKL-40) regulates the progression of anorectal mucosal melanoma through the PI3K-AKT signaling pathway. Investigating specific molecular pathways may provide a better understanding of anorectal mucosal melanoma. The findings from this study could contribute to the development of new diagnosis and treatment strategies for this rare and aggressive cancer. Future research directions may include investigating other possible pathways involved in melanoma progression.

Metabolic Signatures: Pioneering the Frontier of Rectal Cancer Diagnosis and Response to Neoadjuvant Treatment with Biomarkers-A Systematic Review.

Colorectal cancer (CRC) is one of the most aggressive, heterogenous, and fatal types of human cancer for which screening, and more effective therapeutic drugs are urgently needed. Early-stage detection and treatment greatly improve the 5-year survival rate. In the era of targeted therapies for all types of cancer, a complete metabolomic profile is mandatory before neoadjuvant therapy to assign the correct drugs and check the response to the treatment given. The aim of this study is to discover specific metabolic biomarkers or a sequence of metabolomic indicators that possess precise diagnostic capabilities in predicting the efficacy of neoadjuvant therapy. After searching the keywords, a total of 108 articles were identified during a timeframe of 10 years (2013-2023). Within this set, one article was excluded due to the use of non-English language. Six scientific papers were qualified for this investigation after eliminating all duplicates, publications not referring to the subject matter, open access restriction papers, and those not applicable to humans. Biomolecular analysis found a correlation between metabolomic analysis of colorectal cancer samples and poor progression-free survival rates. Biomarkers are instrumental in predicting a patient's response to specific treatments, guiding the selection of targeted therapies, and indicating resistance to certain drugs.

Expression of Types I and III Collagens and Ultrastructure of the Extracellular Matrix in Rectal Adenocarcinoma of Different Differentiation Degree after Neoadjuvant Radiation Therapy.

The structural organization of the extracellular matrix of rectal adenocarcinoma of different differentiation degrees without and after neoadjuvant radiation therapy was studied on postoperative material using immunohistochemistry and electron microscopy. The differences in the expression of types I and III collagens, as well as in the ultrastructural organization of the extracellular matrix of rectal adenocarcinoma of different differentiation degrees without and after neoadjuvant radiation therapy were revealed. We observed high expression of collagen I and wide channels in the collagen matrix in the central areas of the well differentiated adenocarcinomas without neoadjuvant radiation therapy and in poorly differentiated adenocarcinomas after neoadjuvant radiation therapy, which can be associated with metastasis and poor prognosis for the patients.

[Application of ARHGAP8 in Predicting the Efficacy of Neoadjuvant Chemotherapy for Locally Advanced Mid-Low Rectal Cancer].

Objective To analyze the sensitivity of ARHGAP8 in predicting the efficacy of neoadjuvant chemotherapy in the patients with locally advanced mid-low colorectal cancer and provide accurate evidence for the treatment of advanced colorectal cancer. Methods The differentially expressed gene ARHGAP8 was screened out by bioinformatics analysis.Cancer tissue and rectal tissue of 68 patients with primary rectal cancer were selected.The rectal cancer tissue samples and the rectal tissue samples were collected for clinical validation of ARHGAP8 expression by quantitative real-time PCR,Western blotting,and immunohistochemistry.The clinical and pathological features such as gender,age,tumor stage,differentiation degree,and pathological type of the patients were collected for functional validation.Forty-four patients with locally advanced mid-low rectal cancer who received neoadjuvant chemotherapy were selected for immunohistochemical examination of ARHGAP8 expression.The expression level of ARHGAP8 was compared between before and after chemotherapy and among different efficacy groups. Results The bioinformatics analysis revealed differences in the expression level of ARHGAP8 between the cancer tissue and rectal tissue (P<0.001).The expression level of ARHGAP8 was correlated with tumor stage (P=0.024),lymph node metastasis (P=0.007),and age (P=0.005).Quantitative real-time PCR results showed that the mRNA level of ARHGAP8 in the cancer tissue was higher than that in the rectal tissue (P<0.001).Western blotting and immunohistochemistry results demonstrated that the protein level of ARHGAP8 in the cancer tissue was higher than that in the rectal tissue (P=0.011).The expression of ARHGAP8 was correlated with tumor size (P=0.010) and pathological stage (P=0.005),while it showed no significant association with tumor differentiation degree,lymph node metastasis,liver metastasis,Ki-67,or microsatellite instability expression level.The 44 patients receiving neoadjuvant chemotherapy included 13,8,8,and 15 patients of tumor regression grades 0,1,2,and 3,respectively.Among them,65.91% (29/44) patients showed responses to the treatment.After neoadjuvant chemotherapy,the expression of ARHGAP8 in the cancer tissue was down-regulated in the patients who responded to the chemotherapy (P<0.001).The response rate in the patients with low protein level of ARHGAP8 was 92.86%,which was higher than that (53.33%) in the patients with high protein level of ARHGAP8 (P=0.033). Conclusion ARHGAP8 is highly expressed in the rectal cancer tissue.The patients with locally advanced mid-low rectal cancer and low ARHGAP8 expression are more sensitive to neoadjuvant chemotherapy with the XELOX protocol.ARHGAP8 can serve as a potential biomarker for the occurrence and development of rectal cancer and an important index for evaluating the efficacy of neoadjuvant chemotherapy with the XELOX protocol in the patients with locally advanced mid-low rectal cancer.

Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer.

Locally advanced rectal cancer is typically treated with chemoradiotherapy followed by surgery. Most patients do not display a complete response to chemoradiotherapy, but resistance mechanisms are poorly understood. ST6GAL-1 is a sialyltransferase that adds the negatively charged sugar, sialic acid (Sia), to cell surface proteins in the Golgi, altering their function. We therefore hypothesized that ST6GAL-1 could mediate resistance to chemoradiation in rectal cancer by inhibiting apoptosis. Patient-derived xenograft and organoid models of rectal cancer and rectal cancer cell lines were assessed for ST6GAL-1 protein with and without chemoradiation treatment. ST6GAL-1 mRNA was assessed in untreated human rectal adenocarcinoma by PCR assays. Samples were further assessed by Western blotting, Caspase-Glo apoptosis assays, and colony formation assays. The presence of functional ST6GAL-1 was assessed via flow cytometry using the Sambucus nigra lectin, which specifically binds cell surface α2,6-linked Sia, and via lectin precipitation. In patient-derived xenograft models of rectal cancer, we found that ST6GAL-1 protein was increased after chemoradiation in a subset of samples. Rectal cancer cell lines demonstrated increased ST6GAL-1 protein and cell surface Sia after chemoradiation. ST6GAL-1 was also increased in rectal cancer organoids after treatment. ST6GAL-1 knockdown in rectal cancer cell lines resulted in increased apoptosis and decreased survival after treatment. We concluded that ST6GAL-1 promotes resistance to chemoradiotherapy by inhibiting apoptosis in rectal cancer cell lines. More research will be needed to further elucidate the importance and mechanism of ST6GAL-1-mediated resistance.

Rectal Cancer Tissue Lipidome Differs According to Response to Neoadjuvant Therapy.

Rectal cancer (RC) is a gastrointestinal cancer with a poor prognosis. While some studies have shown metabolic reprogramming to be linked to RC development, it is difficult to define biomolecules, like lipids, that help to understand cancer progression and response to therapy. The present study investigated the relative lipid abundance in tumoral tissue associated with neoadjuvant therapy response using untargeted liquid chromatography-mass spectrometry lipidomics. Locally advanced rectal cancer (LARC) patients (n = 13), clinically staged as T3-4 were biopsied before neoadjuvant chemoradiotherapy (nCRT). Tissue samples collected before nCRT (staging) and afterwards (restaging) were analyzed to discover lipidomic differences in RC cancerous tissue from Responders (n = 7) and Non-responders (n = 6) to nCRT. The limma method was used to test differences between groups and to select relevant feature lipids from tissue samples. Simple glycosphingolipids and differences in some residues of glycerophospholipids were more abundant in the Non-responder group before and after nCRT. Oxidized glycerophospholipids were more abundant in samples of Non-responders, especially those collected after nCRT. This work identified potential lipids in tissue samples that take part in, or may explain, nCRT failure. These results could potentially provide a lipid-based explanation for nCRT response and also help in understanding the molecular basis of RC and nCRT effects on the tissue matrix.

Mismatch repair system deficiency is associated with chemoradiotherapy resistance in locally advanced rectal adenocarcinoma patients.

BACKGROUND AND OBJECTIVES: Previous studies have concluded that colorectal cancer patients with deficient mismatch repair (dMMR) usually have a good prognosis. However, some studies have suggested that the prognosis of rectal cancer patients with dMMR appears to be worse. Our aim was to investigate chemoradiotherapy resistance in dMMR rectal tumors. METHODS: A retrospective study of 217 patients with locally advanced rectal adenocarcinoma treated with chemoradiotherapy and total mesorectal excision surgery was conducted using immunohistochemistry to determine MMR status and propensity score matching models to reduce potential confounders. Kaplan-Meier analysis, log-rank test, and Cox regression models were used to assess overall survival (OS) and disease-free survival (DFS) in patient subgroups. RESULTS: The 3-year DFS rates were 77.1% and 56.7% in the pMMR and dMMR groups, respectively. The pMMR group had significantly better DFS than the dMMR group (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.10-3.91; p = 0.019). However, there was no significant difference in OS between the two groups (45.7 [interquartile range, IQR], 39.3-72.1] vs. 47.5 [IQR, 29.5-72.1]) (HR, 1.39; 95% CI, 0.70-2.77; p = 0.35). Neither OS nor DFS was significantly different between the neoadjuvant chemoradiotherapy and postoperative chemoradiotherapy groups. CONCLUSION: Locally advanced dMMR rectal adenocarcinoma exhibits greater chemoradiotherapy resistance than pMMR.

The role of the PTEN/mTOR axis in clinical response of rectal cancer patients.

BACKGROUND: Preoperative chemoradiotherapy has long been accepted as a method to improve survival and lifetime quality of rectal cancer patients. However, physiologic effects of these therapies largely depend on the resistance of cells to the radiation, type of chemotherapeutic agents and individual responses. As one of the signaling cascades involved in chemo- or radiation- resistance, the present study focused on several proteins involved in pTEN/Akt/mTOR pathway to explore their prognostic significance. MATERIALS AND METHODS: Samples from advanced stage rectal cancer patients were analyzed to detect expression levels of pTEN/Akt/mTOR pathway related proteins pTEN, mLST8, REDD1, BNIP3, SAG and NOXA, together with p53, by RT-qPCR. Kaplan-Meier analysis was used to assess expression-survival relation and correlations among all proteins and clinicopathological features were statistically analyzed. RESULTS: Except p53, none of the proteins showed prognostic significance. High p53 expression presented clear impact on overall survival and disease free survival. It was also significantly related to pathologic complete response. p53 showed high correlation to local recurrence as well. On the other hand, strong correlation was observed with PTEN expression and tumor response, but not with survival. High associations were also observed between mLST8/REDD1, PTEN and NOXA, confirming their role in the same cascade. CONCLUSION: The contentious role of p53 as a prognostic biomarker in colorectal cancer was further affirmed, while PTEN and REDD1 could be suggested as potential candidates. Additionally, NOXA emerges as a conjunctive element for different signaling pathways.

Immune profile by multiplexed immunohistochemistry associated with recurrence after chemoradiation in rectal cancer.

BACKGROUND AND AIM: Evidence has emerged that a pretreatment immune profile in rectal cancer is associated with response to chemoradiotherapy (CRT) and recurrence after CRT. However, few studies have evaluated the immune profile differences after CRT regarding recurrence and nonrecurrence. METHODS: We included patients with advanced rectal cancer treated with CRT and surgery with recurrence within 1 year in a recurrence group. After sex and age matching with the recurrence group, patients with no recurrence for 3 years after CRT were included in a nonrecurrence group. We extracted the immune profile, including CD3 and CD8, from the surgical specimen after CRT using multispectral fluorescence immunohistochemistry and compared the two groups. RESULTS: The immune profiles of 65 patients with rectal cancer were assessed; 30 were included in the recurrence group and 35 were included in the nonrecurrence group. CD3+ and CD8+ T lymphocyte densities were significantly higher in the nonrecurrence group than in the recurrence group (CD3+ ; P < 0.001, CD8+ ; P = 0.003) in the primary tumor. Consistent results were found in epithelial and stromal cells. Compared with the recurrence group, the distinct profiles of co-expressed immune markers in the nonrecurrence group were revealed (CD3+ CD8+ , P = 0.001; CD3+ CD8+ PD-L1- , P = 0.001; CD3+ CD8+ FOXP3- PD-L1- , P = 0.001). CONCLUSIONS: Vigorous CD3+ and CD8+ T cell priming post-CRT was prominent in the nonrecurrence group compared with that of the recurrence group. This finding suggests that differences in immune profiles may have clinical significance even after CRT.

Tissue-Based Markers as a Tool to Assess Response to Neoadjuvant Radiotherapy in Rectal Cancer-Systematic Review.

According to current guidelines, the current treatment for locally advanced rectal cancer is neoadjuvant therapy, followed by a total mesorectal excision. However, radiosensitivity tends to differ among patients due to tumor heterogeneity, making it difficult to predict the possible outcomes of the neoadjuvant therapy. This review aims to investigate different types of tissue-based biomarkers and their capability of predicting tumor response to neoadjuvant therapy in patients with locally advanced rectal cancer. We identified 169 abstracts in NCBI PubMed, selected 48 reports considered to meet inclusion criteria and performed this systematic review. Multiple classes of molecular biomarkers, such as proteins, DNA, micro-RNA or tumor immune microenvironment, were studied as potential predictors for rectal cancer response; nonetheless, no literature to date has provided enough sufficient evidence for any of them to be introduced into clinical practice.

Prognostic Value of Immunohistochemical Markers for Locally Advanced Rectal Cancer.

The aim of this study is to reveal the potential roles of apoptosis markers (Bcl2 and p53), proliferation markers (Ki-67 and CyclD1), and the neuroendocrine marker Chromogranin A as markers for the radioresistance of rectal cancer. Statistically significant differences were found in the expression of p53, Ki-67, and Chromogranin A in groups of patients with and without a favorable prognosis after radiotherapy. The survival analysis revealed that the marker of neuroendocrine differentiation, Chromogranin A, also demonstrated a high prognostic significance, indicating a poor prognosis. Markers of proliferation and apoptosis had no prognostic value for patients who received preoperative radiotherapy. Higher Chromogranin A values were predictors of poor prognosis. The results obtained from studying the Chromogranin A expression suggest that the secretion of biologically active substances by neuroendocrine cells causes an increase in tumor aggressiveness.

Agrin promotes the proliferation, invasion and migration of rectal cancer cells via the WNT signaling pathway to contribute to rectal cancer progression.

Rectal cancer is the most common malignant tumor in the digestive system with rapidly metastasis and highly recurrence. Agrin (AGRN) is a proteoglycan involving in a large number of human cancers. However, how AGRN regulates the progression of rectal cancer remains largely unknown. We aimed to determine the biological role of AGRN and its mechanism in rectal cancer. AGRN expression in rectal cancer tissues was detected based on TCGA. The survival curve was plotted using the Kaplan-Meier method. qRT-PCR and western blot were utilized to examine the expression level of AGRN in cells. Cell proliferation, clonogenic ability, invasion, and migration of rectal cancer cells were analyzed by CCK-8, colony formation and transwell experiments. GSEA was employed for the analysis of the potential pathways-related with AGRN in rectal cancer. The activity of WNT pathway was determined by western blot. AGRN expression was dramatically increased in rectal cancer, and its up-regulation was associated with poorer prognosis of rectal cancer patients. AGRN expression was an independent factor for the prognosis of rectal cancer. AGRN inhibition suppressed rectal cancer cell growth, invasion, and migration, whereas AGRN overexpression facilitated these behaviors of rectal cancer cells in vitro. Mechanistically, WNT signaling pathway was enriched in high AGRN-expressing patients with rectal cancer. AGRN elevated the activity of WNT pathway through increasing Cyclin D1, C-Myc, p-GSK-3ß, and p-ß-catenin expression. Our present study indicated that AGRN might function as an oncogenic indicator in rectal cancer via activating the WNT pathway, which would help develop optimized therapeutic therapies for rectal cancer.

Impact of the preoperative prognostic nutritional index as a predictor for postoperative complications after resection of locally recurrent rectal cancer.

BACKGROUND: Local recurrence is common after curative resections for rectal cancer. Surgical intervention is among the best treatment choices. However, achieving a negative resection margin often requires extensive pelvic organ resections; thus, the postoperative complication rate is quite high. Recent studies have reported that the inflammatory index could predict postoperative complications. This study aimed to validate the correlation between clinical factors, including inflammatory markers, and severe complications after surgery for local recurrent rectal cancer. METHODS: This retrospective study included 99 patients that underwent radical resections for local recurrences of rectal cancer. Postoperative complications were graded according to the Clavien-Dindo classification. Grades ≥3 were defined as severe complications. Risk factors for severe complications were identified with univariate and multivariate logistic regression models and assessed with receiver-operating characteristic curves. RESULTS: Severe postoperative complications occurred in 38 patients (38.4%). Analyses of correlations between inflammatory markers and severe postoperative complications revealed that the strongest correlation was found between the prognostic nutrition index and severe postoperative complications. The receiver-operating characteristic analysis showed that the optimal prognostic nutrition index cut-off value was 42.2 (sensitivity: 0.790, specificity: 0.508). In univariate and multivariate analyses, a prognostic nutrition index ≤44.2 (Odds ratio: 3.007, 95%CI:1.171-8.255, p = 0.02) and a blood loss ≥2850 mL (Odds ratio: 2.545, 95%CI: 1.044-6.367, p = 0.04) were associated with a significantly higher incidence of severe postoperative complications. CONCLUSIONS: We found that a low preoperative prognostic nutrition index and excessive intraoperative blood loss were risk factors for severe complications after surgery for local recurrent rectal cancer.

Identification of TRPV4 as a novel target in invasiveness of colorectal cancer.

BACKGROUND: Emerging evidence has indicated the critical role of TRPV4 in diverse human cancers. However, the underlying molecular mechanism of TRPV4 in colon cancer invasiveness is still unknown. METHODS: Immunohistochemistry staining was used to analyze the expression of TRPV4 and ZEB1 in clinical tissues; Wound healing and transwell assays were applied to determine the cell invasiveness; Western blot was used to explore the relation between TRPV4 and ZEB1. RESULTS: Colon cancer cells were transfected with siRNA against TRPV4 or HC067047 (a selective TRPV4 antagonist), TRPV4 full-length plasmid or siRNA against ZEB1, or both, in order to measure cell migration and invasion. And we found that TRPV4 silencing or inhibition exhibited an inhibitory role in colon cancer cell migration and invasion, coupled with compromised EMT process, and suppressed AKT activity. TRPV4 stimulated expression of ZEB1 and consequently contributed to EMT process and invasiveness. It was also revealed that overexpression of TRPV4 and ZEB1 in clinical patients with local metastasis, and positive correlation between TRPV4 and ZEB1. CONCLUSIONS: Our results uncovered the role of TRPV4 in tumor metastasis and highlighted the potential mechanism of TRPV4-ZEB1 axis in indicating EMT.

PET/MRI Characterization of Mucinous Versus Nonmucinous Components of Rectal Adenocarcinoma: A Comparison of Tumor Metabolism and Cellularity.

OBJECTIVE. The purpose of this study was to evaluate whether FDG PET/MRI can be used to differentiate the mucinous from the nonmucinous components of primary rectal tumors and to compare the glycolytic metabolism on PET with tumor cellularity on DWI in both components. SUBJECTS AND METHODS. Ninety-nine patients who underwent FDG PET/MRI for staging of primary rectal cancer were included in this prospective analysis. MRI depicted the mucin component through the tumor volume. Separate volumes of interest were drawn on both mucinous and nonmucinous components and propagated to PET and apparent diffusion coefficient (ADC) mapping. Maximum and mean standardized uptake values (SUVmax, SUVmean) and maximum, mean, and minimum ADC values (ADCmax, ADCmean, ADCmin) were recorded and compared between areas with mucinous and nonmucinous components. Whole-body PET/MRI was also used to evaluate for the presence of distant metastases. Nonparametric testing was used to compare the two groups of patients: those with tumors with a mucinous component and those with tumors without a mucinous component. Logistic regression analysis was performed to calculate the association risk between mucinous component and metastatic disease. RESULTS. Seventeen patients (17.2%) had a mucinous component within the tumor on T2-weighted MRI. Most of these patients had advanced disease, the mucinous component tumors being in significantly higher T categories than the tumors without a mucinous component (88.2% vs 61.0%; p = 0.032). SUVmax (7.4 vs 16.7; p = 0.002) and SUVmean (5.4 vs 13.4; p = 0.001) were significantly lower in tumors with a mucinous component than in those without a mucinous component. Tumor ADC measurements were not different between tumors with and those without a mucinous component (ADCmean, 1.4 vs 1.6; p = 0.361). There was no association between presence of a mucinous component within the primary rectal tumor and presence of synchronous metastases (odds ratio, 1.1 [0.4-3.0]; p = 0.904). Moreover, the occurrence of metastases in patients with mucinous component tumors (7/17 [41.2%]) was not different from that in patients with tumors without a mucinous component (28/82 [34.1%]) (p = 0.887). CONCLUSION. PET/MRI can be used to differentiate the mucinous and nonmucinous components within primary rectal adenocarcinoma on the basis of metabolic status. The FDG uptake is significantly lower in the mucinous component, but tumor cellularity based on MRI and DWI findings is not. Despite being associated with a higher T category in the sample of patients in this study, the presence of a mucinous component seems not to be associated with increased risk of synchronous metastases.

Oxidative Stress Level as a Predictor of Anastomotic Leakage after Rectal Surgery.

BACKGROUND: Early diagnosis of anastomotic leakage (AL) after rectal surgery can reduce the adverse effects of AL, thereby reducing morbidity and mortality. Currently, there are no accepted indicators or effective scoring systems that can clearly identify patients at risk of anastomotic leakage. METHODS: A prospective study with assessment of the diagnostic accuracy of oxidative stress level (CAT, SOD, MDA) in serum and drain fluid compared to white blood cell count (WBC), C-reactive protein (CRP), and neutrophil percentage (NEUT) in prediction of AL in patients undergoing elective rectal surgery with anastomosis. RESULTS: Most of the oxidative stress indicators we detected are of considerable significance in the diagnosis of anastomotic leakage. The level of MDA on postoperative day (POD)3 (areas under the curve (AUC): 0.831) and POD5 (AUC: 0.837) in the serum and on POD3 (AUC: 0.845) in the drain fluid showed the same excellent diagnostic accuracy as the level of CRP on the POD3 (AUC: 0.847) and POD5 (AUC: 0.896). CONCLUSIONS: The overall level of oxidative stress in serum and drain fluid is a reliable indicator for the early diagnosis of anastomotic leakage after rectal surgery. More specifically, among the redox indicators analyzed, MDA has almost the same predictive value as CRP, which provides another useful biomarker for the early diagnosis of anastomotic leakage.