Tumor-derived semaphorin 3D promoting cancer cachexia via regulating hypothalamic pro-opiomelanocortin neurons.

Cachexia is very common in cancer patients and predicts a poor prognosis; however, the molecular basis for progress in these individuals remains unclear, especially the effect of tumors on the hypothalamus energy regulation center. To investigate the regulatory pathway of tumors associated with hypothalamic pro-opiomelanocortin (POMC) neurons known as appetite-inhibiting neurons, we conducted observations both on patients and mice models. Results showed that the highly expressed exocrine semaphorin 3D (SEMA3D) both in cachexia patients and mice was positively related to the expression of POMC and its proteolytic peptide. Compared with the control group, mice inoculated with the SEMA3D-knockout C26 cell line decreased the activity of POMC neurons resulting in a 1.3-fold increase in food intake, a 22.2% increase in body weight, and reduced skeletal muscle and fat catabolism. The effect of SEMA3D on cachexia progression can be partially alleviated by knocking-down POMC expression in the brain. In terms of mechanism, SEMA3D enhances the activity of POMC neurons by activating the expression of NRP2 (membrane receptor) and PlxnD1 (intracellular receptor). Our research revealed the overexpression of SEMA3D in tumors works as an activator of POMC neurons, which may play a vital role in suppressing appetite and promoting catabolic metabolism.

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function.

Prolyl hydroxylase domain proteins (PHDs) control cellular adaptation to hypoxia. PHDs are found involved in inflammatory bowel disease (IBD); however, the exact role of PHD3, a member of the PHD family, in IBD remains unknown. We show here that PHD3 plays a critical role in maintaining intestinal epithelial barrier function. We found that genetic ablation of Phd3 in intestinal epithelial cells led to spontaneous colitis in mice. Deletion of PHD3 decreases the level of tight junction protein occludin, leading to a failure of intestinal epithelial barrier function. Further studies indicate that PHD3 stabilizes occludin by preventing the interaction between the E3 ligase Itch and occludin, in a hydroxylase-independent manner. Examination of biopsy of human ulcerative colitis patients indicates that PHD3 is decreased with disease severity, indicating that PHD3 down-regulation is associated with progression of this disease. We show that PHD3 protects intestinal epithelial barrier function and reveal a hydroxylase-independent function of PHD3 in stabilizing occludin. These findings may help open avenues for developing a therapeutic strategy for IBD.

The Endoplasmic Reticulum Stress Sensor IRE1α in Intestinal Epithelial Cells Is Essential for Protecting against Colitis.

Intestinal epithelial cells (IECs) have critical roles in maintaining homeostasis of intestinal epithelium. Endoplasmic reticulum (ER) stress is implicated in intestinal epithelium homeostasis and inflammatory bowel disease; however, it remains elusive whether IRE1α, a major sensor of ER stress, is directly involved in these processes. We demonstrate here that genetic ablation of Ire1α in IECs leads to spontaneous colitis in mice. Deletion of IRE1α in IECs results in loss of goblet cells and failure of intestinal epithelial barrier function. IRE1α deficiency induces cell apoptosis through induction of CHOP, the pro-apoptotic protein, and sensitizes cells to lipopolysaccharide, an endotoxin from bacteria. IRE1α deficiency confers upon mice higher susceptibility to chemical-induced colitis. These results suggest that IRE1α functions to maintain the intestinal epithelial homeostasis and plays an important role in defending against inflammation bowel diseases.

The Effect of Silencing HIF-1α Gene in BxPC-3 Cell Line on Glycolysis-Related Gene Expression, Cell Growth, Invasion, and Apoptosis.

Hypoxia has been proved to be a typical character of solid tumors. Tumor cells prefer to use glucose through the glycolysis pathway instead of aerobic respiration. However, the precise molecular mechanism underlying this so-called Warburg effect remains elusive. In the current study, siRNA was synthesized and transfected into BxPC-3 cell line to silence the expression of HIF-1α gene. It was found that hypoxia induced hypoxia-inducible factor 1α (HIF-1α) overexpression in BxPC-3 cells, enhanced the expression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A, thus facilitating glycolysis and making tumor cells more tolerant to hypoxic stress. The silencing of HIF-1α gene significantly attenuated glycolysis under hypoxic conditions, inhibited the growth and invasion ability of BxPC-3 cells, and enhanced hypoxia-induced cell apoptosis.

The metabolite butyrate produced by gut microbiota inhibits cachexia-associated skeletal muscle atrophy by regulating intestinal barrier function and macrophage polarization.

OBJECTIVE: Cachexia, marked by muscle atrophy, poses substantial challenges for prevention and treatment. This study delves into the unclear role of butyrate, a gut microbiota metabolite, in cachexia by examining gut microbiota and short-chain fatty acid (SCFA) profiles in human and mouse fecal samples. METHODS: We analyzed cachexia-associated gut microbiota and SCFA profiles using 16S rRNA sequencing and metabolomic techniques. Mouse cachexia models were developed with C26 cells, and LPS was used to induce muscle cell atrophy in C2C12 cells. We evaluated butyrate's in vivo effects on intestinal health, muscle preservation, inflammation, and macrophage activity. In vitro studies focused on butyrate's influence on macrophage polarization and the subsequent effects on muscle cells. RESULTS: Both cachexia patients and mice exhibited gut microbiota imbalances, irregular butyrate concentrations, and a decline in butyrate-producing bacteria. In vivo tests showed that butyrate counteract cachexia-induced muscle atrophy by adjusting the Akt/mTOR/Foxo3a and Fbox32/Trim63 pathways. These butyrate also bolstered intestinal barrier integrity, minimized endotoxin migration, and mitigated oxidative stress. Furthermore, butyrate curtailed inflammation and macrophage penetration in muscles. In vitro experimental results demonstrate that butyrate inhibit macrophage polarization towards the M1 phenotype and promote polarization towards the M2 phenotype. Both M1 and M2 macrophages influence the aforementioned pathways and oxidative stress, participating in the regulation of muscle cell atrophy. CONCLUSION: Our study delineates the intricate interplay between gut microbiota dysbiosis, butyrate fluctuations, and cachexia progression. Butyrate not only reinforces the intestinal barrier but also orchestrates macrophage polarization, mitigating muscle atrophy and averting cachexia-induced muscle deterioration. Concurrently, the M1 and M2 macrophages play pivotal roles in modulating skeletal muscle cell atrophy. This highlights the potential of utilizing the gut-derived metabolite butyrate as a promising therapeutic approach for addressing cachexia-related issues.

Development and validation of a cancer cachexia risk score for digestive tract cancer patients before abdominal surgery.

BACKGROUND: Cancer cachexia is prevalent in digestive tract cancer patients and has significant impacts on prognosis; it is vital to identify individuals who are at risk of cancer cachexia to allow for appropriate evaluation and treatment. This study evaluated whether digestive tract cancer patients with a risk of cancer cachexia and who had a risk of adverse survival could be identified before abdominal surgery. METHODS: This large-scale cohort study involved patients who underwent abdominal surgery between January 2015 and December 2020 to treat digestive tract cancer. Participants were allocated to the development cohort, the validation cohort, or the application cohort. Univariate and multivariate analyses of the development cohort were performed to detect distinct risk variables for cancer cachexia to create a cancer cachexia risk score. The performance of the risk score across all the three cohorts was assessed through calculating the area under the receiver operating characteristic curve (AUC), as well as calibration and decision curves. We tested how well the score predicted survival outcomes in the application cohort. RESULTS: A total of 16 264 patients (median 64 years of age; 65.9% male) were included, with 8743 in the development cohort, 5828 in the validation cohort, and 1693 in the application cohort. Seven variables were identified as independent predictive factors and were included in the cancer cachexia risk score: cancer site, cancer stage, time from symptom onset to hospitalization, appetite loss, body mass index, skeletal muscle index, and neutrophil-lymphocyte ratio. The risk score predicting cancer cachexia owns a good discrimination, with the mean AUC of 0.760 (P < 0.001) in the development cohort, 0.743 (P < 0.001) in the validation cohort, and 0.751 (P < 0.001) in the application cohort, respectively, and had an excellent calibration (all P > 0.05). The decision curve analysis revealed net benefits of the risk score across a range of risk thresholds in the three cohorts. In the application cohort, compared with the high-risk group, the low-risk group experienced significantly longer overall survival [hazard ratio (HR) 2.887, P < 0.001] as well as relapse-free survival (HR 1.482, P = 0.01). CONCLUSIONS: The cancer cachexia risk score constructed and validated demonstrated good performance in identifying those digestive tract cancer patients before abdominal surgery at a higher risk of cancer cachexia and unfavourable survival. This risk score can help clinicians to enhance their capabilities to screen for cancer cachexia, assess patient prognosis, and strengthen early decision-making on targeted approaches to attune cancer cachexia for digestive tract cancer patients before abdominal surgery.

Development and application of the Cancer Cachexia Staging Index for the diagnosis and staging of cancer cachexia.

OBJECTIVE: The current tools for evaluating cancer cachexia are either too simple to reflect the far-reaching effects of cachexia or too complicated to be used in daily practice. This study aimed to develop a cancer cachexia staging index (CCSI) that is both practical and comprehensive. METHODS: Patients with gastrointestinal cancers were prospectively included in the study. Clinical data including weight change, body composition, systematic inflammation, nutrition, and function status were entered into regression models to determine the best variable combination as well as their respective cutoff values and score distribution in the CCSI. The CCSI's ability to predict outcomes and evaluate the consequences of cachexia for patients were then assessed. RESULTS: Clinical information and test results from 10 568 patients were used to develop a CCSI composed of subjective and objective measures. Subjective measures included body mass index-adjusted weight loss grade, rate of weight loss, inflammation (neutrophil-to-lymphocyte ratio and C-reactive protein level), and prealbumin level. Objective measures included appetite status and physical status. Patients were diagnosed and stratified by the total CCSI score into 3 subgroups: no cachexia, mild or moderate cachexia, and severe cachexia. The CCSI grades showed good survival discrimination and were independently predictive of survival in multivariate analysis. Compared with the traditional Fearon criteria for diagnosing cancer cachexia, the CCSI was more accurate in predicting postoperative complications (net reclassification index [NRI], 2.8%; 95% CI, 0.0104-0.0456%), death (NRI, 10.68%; 95% CI, 0.0429-0.1708%), recurrence (NRI, 3.71%; 95% CI, 0.0082-0.0685%), and overall survival (NRI, 8.5%; 95% CI, 0.0219-0.1533%). The CCSI also had better discriminative ability than Fearon criteria in discriminating nutritional status, body composition, and systematic inflammation in patients with or without cachexia. A more detailed evaluation of a randomly selected subgroup (n = 1566) showed that CCSI grades had good discrimination of appetite and food intake status, physical function and muscle strength, symptom burden, and quality of life. CONCLUSIONS: The CCSI is a comprehensive and practical evaluation tool for cancer cachexia. It can predict postoperative outcomes and survival. The CCSI stages showed good discrimination when evaluating patients with cancer in terms of nutritional status, physical function, systematic inflammation, body composition, symptom burden, and quality of life.

Postoperative Loss of Skeletal Muscle Mass Predicts Poor Survival After Gastric Cancer Surgery.

BACKGROUND: Skeletal muscle mass deterioration is common in gastric cancer (GC) patients and is linked to poor prognosis. However, information regarding the effect of skeletal muscle mass changes in the postoperative period is scarce. This study was to investigate the link between postoperative loss of skeletal muscle mass and survival following GC surgery. METHODS: Patients who underwent GC surgery between January 2015 and December 2016 were recruited into the study. Computed tomography at L3 vertebral level was used to examine skeletal muscle index prior to surgery and about 6 months after surgery. Skeletal muscle index changes were categorized as presence or absence of ≥5% loss. Overall survival (OS) and disease-free survival (DFS) were analyzed, and Cox proportional hazard models used to identify their predictors. RESULTS: The study comprised of 318 gastric cancer patients of which 63.5% were male. The group's mean age was 58.14 ± 10.77 years. Sixty-five patients experienced postoperative skeletal muscle index loss ≥5% and had poorer OS (P = 0.004) and DFS (P = 0.020). We find that postoperative skeletal muscle index loss ≥ 5% predicts OS [hazard ratio (HR): 2.769, 95% confidence interval (CI): 1.865-4.111; P < 0.001] and DFS (HR: 2.533, 95% CI: 1.753-3.659; P < 0.001). CONCLUSIONS: Loss of skeletal muscle mass postoperatively is linked to poor survival following GC surgery. Further studies are needed to determine whether stabilizing or enhancing skeletal muscle mass after surgery improves survival.

Post-discharge oral nutritional supplements with dietary advice in patients at nutritional risk after surgery for gastric cancer: A randomized clinical trial.

BACKGROUND & AIMS: Malnutrition frequently occurs and deteriorates in patients after surgery for gastric cancer, especially after hospital discharge, which has been consistently associated with negative outcomes. However, information regarding the impact of post-discharge nutritional interventions is poorly described. The aim of this study was thus to evaluate the impact of post-discharge oral nutritional supplements (ONS) with dietary advice compared with dietary advice alone on nutritional outcomes, including body mass index (BMI) and skeletal muscle index (SMI), sarcopenia prevalence, chemotherapy tolerance, the 90-day readmission rate, and quality of life in patients at nutritional risk after surgery for gastric cancer. METHODS: Three hundred and fifty-three patients who underwent surgery for gastric cancer and were at nutritional risk (Nutritional Risk Screening 2002 [NRS 2002] score ≥3 points) in our institution were randomly assigned to receive either ONS with dietary advice or dietary advice alone (control) for 3 months after discharge. The primary endpoints were nutritional outcomes and sarcopenia prevalence; the secondary endpoints included chemotherapy tolerance, the 90-day readmission rate, and quality of life. RESULTS: Three hundred and thirty-seven patients completed the study and were included in the analyses, consisting of 171 in the ONS group and 166 in the control group. The average daily intake of ONS in the intervention group was 370 mL. After 3 months of the intervention, the patients who received ONS and dietary advice had significantly less weight loss and higher BMI and SMI than those given dietary advice alone (P < 0.05). The incidence of sarcopenia was significantly lower in the ONS group than in the control group (P < 0.05). Similar number of patients in the two groups underwent postoperative chemotherapy, but the patients who received ONS and dietary advice had significantly less chemotherapy modifications, including delay, dose reduction, or termination (P < 0.05). The two groups had no significant differences in the 90-day readmission rate (P > 0.05). Regarding the quality of life, the patients who received ONS and dietary advice reported significantly less fatigue and appetite loss than those given dietary advice alone (P < 0.05), but the two groups showed no significant differences in the other outcomes (P > 0.05). CONCLUSIONS: Post-discharge ONS with dietary advice in patients at nutritional risk after surgery for gastric cancer improved nutritional outcomes, skeletal muscle maintenance, chemotherapy tolerance and some quality of life variables. These findings strongly support the concept of the introduction of post-discharge ONS with dietary advice to this patient cohort.

Phosphorylation of Dynamin-Related Protein 1 (DRP1) Regulates Mitochondrial Dynamics and Skeletal Muscle Wasting in Cancer Cachexia.

BACKGROUND: Cancer-associated cachexia (CAC) is a syndrome characterized by skeletal muscle atrophy, and the underlying mechanisms are still unclear. Recent research studies have shed light on a noteworthy link between mitochondrial dynamics and muscle physiology. In the present study, we investigate the role of dynamin-related protein 1 (DRP1), a pivotal factor of mitochondrial dynamics, in myotube atrophy during cancer-associated cachexia. METHODS: Seventy-six surgical patients, including gastrointestinal tumor and benign disease, were enrolled in the study and divided to three groups: control, non-cachexia, and cancer-associated cachexia. Demographic data were collected. Their rectus abdominis samples were acquired intraoperatively. Muscle fiber size, markers of ubiquitin proteasome system (UPS), mitochondrial ultrastructure, and markers of mitochondrial function and dynamics were assayed. A cachexia model in vitro was established via coculturing a C2C12 myotube with media from C26 colon cancer cells. A specific DRP1 inhibitor, Mdivi-1, and a lentivirus of DRP1 knockdown/overexpression were used to regulate the expression of DRP1. Muscle diameter, mitochondrial morphology, mass, reactive oxygen species (ROS), membrane potential, and markers of UPS, mitochondrial function, and dynamics were determined. RESULTS: Patients of cachexia suffered from a conspicuous worsened nutrition status and muscle loss compared to patients of other groups. Severe mitochondrial swelling and enlarged area were observed, and partial alterations in mitochondrial function were found in muscle. Analysis of mitochondrial dynamics indicated an upregulation of phosphorylated DRP1 at the ser616 site. In vitro, cancer media resulted in the atrophy of myotube. This was accompanied with a prominent unbalance of mitochondrial dynamics, as well as enhanced mitochondrial ROS and decreased mitochondrial function and membrane potential. However, certain concentrations of Mdivi-1 and DRP1 knockdown rebalanced the mitochondrial dynamics, mitigating this negative phenotype caused by cachexia. Moreover, overexpression of DRP1 aggravated these phenomena. CONCLUSION: In clinical patients, cachexia induces abnormal mitochondrial changes and possible fission activation for the atrophied muscle. Our cachexia model in vitro further demonstrates that unbalanced mitochondrial dynamics contributes to this atrophy and mitochondrial impairment, and rebuilding the balance by regulating of DRP1 could ameliorate these alterations.

Impact of oral nutritional supplements in post-discharge patients at nutritional risk following colorectal cancer surgery: A randomised clinical trial.

BACKGROUND & AIMS: Guidelines on clinical nutrition recommend the use of appropriate nutritional support therapy for surgical cancer patients at risk of malnutrition both during hospital care and following discharge from the hospital. However, previous studies regarding nutritional interventions have mainly focused on patients during their hospital stay; there is limited evidence supporting the recommendation of nutritional interventions for post-discharge patients after cancer surgery, particularly those who underwent gastrointestinal cancer surgery and at high risk of malnutrition. To clearly address this issue, we designed and conducted two independent studies on two different groups of post-discharge patients at nutritional risk after gastrointestinal cancer surgery. The present study aimed to assess the impact of oral nutritional supplements (ONS) in post-discharge patients at nutritional risk following colorectal cancer surgery. Meanwhile, the sister study on the use of ONS in post-discharge patients following gastric cancer surgery will be reported separately. METHODS: Between January 2017 and June 2019, post-discharge patients following colorectal cancer surgery in our institution were randomised to receive either dietary advice alone (control group) or dietary advice in combination with ONS (ONS group) for three months if they were at nutritional risk based on the tool of Nutritional Risk Screening 2002. The primary endpoints were nutritional outcomes and sarcopenia prevalence. The secondary endpoints were 90-day readmission rate, chemotherapy tolerance, and quality of life (QoL). RESULTS: Of the 232 eligible patients, 212 (107 in the control group and 105 in the ONS group) completed the trial. Their data were then analyzed. The mean ONS intake was 410 mL every day. By the three-month intervention, the skeletal muscle index in the ONS group was significantly higher than that in the control group (39.75 ± 5.83 vs 38.01 ± 6.18 cm2/m2, P = 0.037), but no significant differences between the two groups were noted in weight, weight loss, body mass index, serum albumin and hemoglobin (P > 0.05). In addition, the ONS group had a significantly lower sarcopenia prevalence (28.6% vs 42.1%, P = 0.040). No significant difference between the two groups was found in the 90-day readmission rate (P > 0.05). The number of patients undergoing postoperative chemotherapy in the two groups was similar, but chemotherapy modifications, such as delay, dose reduction, or termination, were significantly reduced in the ONS group (21.2% vs 36.8%, P=0.024). However, ONS had no significant effect on QoL (P > 0.05). CONCLUSIONS: In post-discharge patients at nutritional risk following colorectal cancer surgery, the use of ONS may reduce skeletal muscle loss and sarcopenia prevalence, as well as improve chemotherapy tolerance, compared with dietary advice alone. These findings underline the importance of ONS treatment in post-discharge patients at nutritional risk following colorectal cancer surgery.

Beta-1 blocker reduces inflammation and preserves intestinal barrier function after open abdominal surgery.

BACKGROUND: Open abdominal surgery is frequently related to excessive inflammation and a compromised intestinal barrier, leading to poor clinical outcomes. The administration of beta-1 blocker has been shown to effectively reduce inflammation and preserve intestinal barrier function in patients with sepsis, shock, or other critical illnesses. The underlying mechanism of these effects may be associated with the autonomic nervous system's activation via cholecystokinin receptors. This study aimed to investigate the effect of beta-1 blocker on systemic and local inflammatory responses and the intestinal barrier function in the context of open abdominal surgery. METHODS: A rat model of open abdominal surgery was induced through peritoneal air exposure for 3 hours and treated via gavage with the beta-1 blocker, metoprolol, or saline. Cholecystokinin-receptor antagonists were administered before the metoprolol treatment. Peritoneal lavage fluid, serum, and tissues were collected 24 hours after surgery to determine systemic and local inflammation and intestinal integrity. RESULTS: The intervention with metoprolol significantly reduced serum tumor necrosis factor-alpha and interleukin-6 (P < .05) and peritoneal interleukin-6 (P < .01) compared with those of animals treated with saline. The intestinal myeloperoxidase indicating the influx of neutrophils was also significantly prevented by the administration of metoprolol (P < .05). Above all, this intervention resulted in a significant decrease in serum D-lactate and intestinal fatty acid-binding protein, intestinal permeability, bacterial translocation, and Chiu's score for intestinal mucosa injury (P < .05). However, the anti-inflammatory and intestinal integrity protective effects of metoprolol were prevented by the blockage of cholecystokinin receptors (P < .05). CONCLUSION: Our data indicate that beta-1 blocker reduces systemic and local inflammatory responses and preserves intestinal barrier function after open abdominal surgery through a mechanism that depends on cholecystokinin receptors. Clinically, these findings imply that perioperative intervention with a beta-1 blocker may be an effective new therapy to enhance recovery after open abdominal surgery.

Role of beta1-adrenoceptor in increased lipolysis in cancer cachexia.

Increased production of hormone-sensitive lipase (HSL) protein has been demonstrated to be the major cause behind enhanced lipolysis in cancer cachexia. The mechanism governing this alteration is unknown and was presently investigated. This study was conducted to detect the expression of relevant receptors in the adipocytes of cancer cachexia patients, and to elucidate their implication in the increased lipolysis. Gene expressions of beta1-adrenoceptor (ADRB1), beta2-adrenoceptor (ADRB2), beta3-adrenoceptor (ADRB3), alpha2C-adrenoceptor (ADRA2C), natriuretic peptide receptor A (NPRA), insulin receptor (INSR), and HSL were determined in adipose tissues of 34 patients by real-time PCR. Protein levels of ADRB1 and HSL were determined by western blot analysis. beta1-Adrenoceptor (ADRB1) was also detected by immunofluorescence staining. mRNA expressions of both ADRB1 and HSL were approximately 50% elevated selectively in the cachexia group, whereas mRNA levels of the other receptors were unchanged. beta1-Adrenoceptor (ADRB1) protein expression was 1.5-fold increased in cachexia as compared with the cancer controls, and 3-fold increased as compared with nonmalignant controls, and was confirmed as a membrane protein in adipocytes by immunofluorescence. Hormone-sensitive lipase (HSL) protein expression was 2-2.5-fold increased selectively in cachectic patients. There was a positive correlation between the protein expressions of ADRB1 and HSL. As much as approximately 50% of the variations in HSL protein expression could be explained by variations in ADRB1 protein expression. There was a link between ADRB1 protein level and lipolytic rate. Increased ADRB1 expression may account for some of the functional changes of HSL in patients with cancer cachexia.

Sarcopenia as a predictor of poor surgical and oncologic outcomes after abdominal surgery for digestive tract cancer: A prospective cohort study.

BACKGROUND & AIMS: Sarcopenia has been widely recognized as an important predictor of poor outcomes in patients with cancer after surgery, but the controversy remains, and its impact on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer is poorly described. The aim of this study was to evaluate the prognostic impact of sarcopenia on surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. METHODS: Six thousand four hundred and forty-seven consecutive patients who underwent abdominal surgery for digestive tract cancer in our institution were prospectively included. Sarcopenia was defined as skeletal muscle index below the lowest sex-specific quartile using computed tomography scan at L3 before surgery. The surgical and oncologic outcomes were recorded, and univariate and multivariate analyses were performed. RESULTS: Sarcopenia was present in 1638 of 6447 patients (25.4%) with digestive tract cancer before surgery based on the diagnostic cut-off values (43.13 cm2/m2 for men and 37.81 cm2/m2 for women). The incidence of postoperative total and pulmonary complications, and 30-day readmission were significantly higher in sarcopenic group than in nonsarcopenic group (37.4% vs 12.9%, P < 0.001; 3.1% vs 2.1%, P = 0.026; 1.1% vs 0.4%, P = 0.003, respectively). The postoperative hospital stay was significantly longer in sarcopenic patients (9.42 ± 3.40 vs 8.51 ± 3.17 days, P < 0.001). There were significantly more patients receiving postoperative chemotherapy or radiotherapy in sarcopenic group than in nonsarcopenic group (73.1% vs 69.2%, P = 0.003; 10.6% vs 8.8%, P = 0.038, respectively), and patients with sarcopenia had significantly more chemotherapy modifications including delay, dose reduction, or termination (48.5% vs 44.2%, P = 0.018). In addition, during the follow-up period, sarcopenic patients had significantly lower rate of overall survival and disease-free survival than nonsarcopenic patients (53.9% vs 69.3%, P = 0.002; 36.8% vs 59.7%, P = 0.000, respectively). In multivariate analysis, sarcopenia was found to be a risk factor for postoperative complications [odds ratio (OR) = 5.418, 95% confidence interval (CI) = 2.986-9.828, P < 0.001], and was an unfavorable prognostic factor for poor overall survival [hazard ratio (HR) = 0.649, 95% CI = 0.426-0.991, P = 0.045] and disease-free survival (HR = 0.514, 95% CI = 0.348-0.757, P = 0.001). CONCLUSIONS: Sarcopenia could be used as a strong and independent prognostic factor for poor surgical and oncologic outcomes in patients after abdominal surgery for digestive tract cancer. Identification of preoperative sarcopenia in digestive surgery for cancer and targeted approaches may improve its negative outcomes.

Prognostic role of cyclin D2/D3 in multiple human malignant neoplasms: A systematic review and meta-analysis.

Cyclin D2/D3 (CCND2/3) are core components of the machinery that drives cell cycle progression and therefore, are associated with tumorigenesis. Currently, there are contradictory evidences on the function of CCND2/3 in tumorigenesis. Thus, we conducted a comprehensive meta-analysis to derive a precise predictive value of CCND2/3 in various tumors. We searched PubMed, EMBASE, Web of Science for eligible studies up to October 8, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of OS or DFS/PFS/RFS were calculated using Forest plot analysis to demonstrate their associations. A total of 14 studies were ultimately included in this meta-analysis. Our results indicated CCND2/3 played an oncogenic role in all of the cancer patients (CCND2: pooled HR = 2.21, 95% CI: 1.67-2.93; CCND3: pooled HR = 2.29, 95% CI: 1.05-5.03). In tumor subgroup, CCND2 was associated with shorter OS in patients with gastric cancer (HR = 2.20, 95% CI: 1.66-2.92), whereas it might be a tumor suppressor in NSCLC (HR = 0.28, 95% CI: 0.12-0.64). In addition, CCND3 was correlated to reduced OS in breast cancer patients (HR = 1.64, 95% CI: 1.07-2.52) and shorter DFS/PFS/RFS in bladder cancer patients (HR = 4.60, 95% CI: 1.89-12.57). Taken together, CCND2/3 could be the promising biomarkers for predicting the prognosis of patients with malignant neoplasms.

[Association of serum inflammatory cytokines and Resolvin D1 concentration with pathological stage of colon cancer].

OBJECTIVE: To investigate the levels of serum inflammatory cytokines and Resolvin D1 (RvD1) and their association with pathological staging of colon cancer. METHODS: Clinical data of 50 colon cancer patients (colon cancer group) admitted to the General Surgery Department of Zhongshan Hospital of Fudan University from January to December 2016 and 5 ml of whole blood specimen were collected at admission. During the same period, 50 healthy volunteers were enrolled (healthy volunteer group). Inclusion criteria for the colon cancer group: colon cancer diagnosed by preoperative colonoscopy and pathology; no recent enteral or parenteral nutrition support treatment or use of oral nutrition preparation; age ≤85 years; no surgical contraindications by preoperative evaluation; no history of taking fish oil-related preparations; no radiotherapy or chemotherapy before surgery. Healthy volunteer group enrollment criteria: no history of malignant tumors; no organ with organic lesions detected by the healthy examination center of our hospital; detection indicators in normal reference range; no administration of fish oil-related preparations; age ≤ 85 years. Serum inflammatory factors(IL-1ß, IL-6, IL-10 and TNF-α) concentrations were detected by chemiluminescence immunoassay; serum RvD1 concentration was measured by enzyme-linked immunosorbent assay. The levels of inflammatory factors and RvD1 were compared between the two groups, and their associations with TNM staging of colon cancer patients were analyzed. RESULTS: There were no significant differences in age, gender and nutrition-related indicators between the two groups (all P>0.05). There were 31 males and 19 females in the healthy volunteer group with age of (61.8±11.6) years. There were 23 males and 27 females in the colon cancer group with age of (65.4±12.4) years. According to the 7th edition of the American Cancer Society TNM staging criteria, 10 cases were stage I, 13 cases stage II, 17 cases stage III, and 10 cases stage IV. Compared with healthy volunteer group, colon cancer group had higher serum IL-1ß [(3.89±0.24)×10 3 µg/L vs.(1.55±0.37)×10 3 µg/L, t=37.52, P<0.01], higher IL-6 [(129.14±3.07)×10 3 µg/L vs.(51.46±3.14)×10 3 µg/L, t=125.08, P<0.01], higher IL-10 [(100.59±8.69)×103 µg/L vs.(27.57±4.77)×10 3 µg/L, t=52.09, P<0.01] and higher TNF-α [(114.31±4.43)×10 3 µg/L vs.(41.04±5.27)×10 3 µg/L, t=75.25, P<0.01], while lower RvD1 [(34.19±1.93)×10 3 µg/L vs.(77.76±1.02)×10 3 µg/L, t=140.56, P<0.01], all the differences were statistically significant. Subgroup analysis revealed that concentrations of IL-6, IL-1ß, IL-10 and TNF-α gradually increased with the advancement of TNM staging (P<0.01). In stage III, concentrations of IL-6, IL-1ß, and IL-10 were the highest, TNF-α concentration was the highest in stage IV. RvD1 concentration gradually decreased with the advancement of TNM staging(P<0.01). CONCLUSIONS: Compared with healthy volunteers, the levels of serum inflammatory cytokines in colon cancer patients increase significantly while the level of RvD1 decreases significantly. Both are associated with higher TNM stage of colon cancer.

PFKFB3 was overexpressed in gastric cancer patients and promoted the proliferation and migration of gastric cancer cells.

OBJECTIVE: Gastric cancer is one of the most common cancers worldwide, and the prognosis is still very poor due to the lack of specific and sensitive biomarkers. Aerobic glycolysis is one of the critical hallmarks of gastric cancer cells, and several glycolytic enzymes are highly expressed in gastric cancer patients. However, the expression and clinical significances of phosphofructokinase-2/fructose-2,6-bisphosphatase3 (PFKFB3, one of the glycolytic enzymes) in a large sample of gastric cancer patients remain unclear. METHODS: The expression of PFKFB3 was detected in 134 gastric cancer patients by qRT-PCR, immunohistochemistry, and western blot analyses. The correlation between PFKFB3 expression and clinicopathological factors was analyzed by χ 2 test. In addition, we also analyzed whether the knockdown of PFKFB3 by siRNAs could inhibit the ability of gastric cancer cells (MGC-803 and AGS) to proliferate and migrate by MTT analysis and transwell analyses. RESULTS: PFKFB3 was highly expressed in 81.3% (109/134) of gastric cancer patients. The overexpression of PFKFB3 was associated with lymph node metastasis (P = 0.045) and TNM stage (P = 0.033). Knockdown of PFKFB3 by siRNAs significantly inhibited the proliferation and migration abilities of gastric cancer cells. CONCLUSION: Our data suggest that PFKFB3 might be a potential biomarker for gastric cancer and anti-neoplastic targeting gene.

Fatty acid synthase regulates invasion and metastasis of colorectal cancer via Wnt signaling pathway.

Fatty acid synthase (Fasn) is the key metabolic enzyme that accounts for the terminal catalytic step in fatty acid synthesis, which is hyperactivated in various tumors. In this study, we depicted that Fasn expression was elevated in human colorectal cancer (CRC), which accordingly led to lymphatic and distant metastasis and a more advanced clinical phenotype. Genetic perturbations demonstrated that knocking down Fasn inhibited cell migration and invasion both in SW480 and HT29 CRC cell lines. Further mechanical exploration revealed that Fasn knockdown could attenuate Wnt signaling pathway via downregulating distinctive genes, namely Wnt5a, Wnt5b, Fzd2, which at least partly contributed to the decrease in metastasis. Clinical evidence verified a positive correlation between Fasn expression and Wnt signal marker gene expression in a cohort of 43 CRC patients. In conclusion, we shed light on metabolic switches took place during CRC carcinogenesis, among which Fasn is a critical factor and a potential therapeutic target.

DCAF4L2 promotes colorectal cancer invasion and metastasis via mediating degradation of NFκb negative regulator PPM1B.

DCAF4L2 is a member of WD-repeat proteins, which commonly serve as mediators of protein-protein interplay. In this study, we reported that elevated DCAF4L2 expression in human colorectal cancer (CRC) significantly correlated with a more advanced clinical stage as in lymphatic and distant metastasis. More importantly, elevated DCAF4L2 expression is an independent prognosis factor for survival. Genetic perturbations demonstrated that DCAF4L2 overexpression in CRC cells promoted cell migration and invasion, whereas knockdown of which had opposing effects. Moreover we discovered that DCAF4L2 overexpression could promote epithelial-mesenchymal-transition (EMT) through activating NFκB signal pathway. Mass spectrometry analysis showed that DCAF4L2 could form an E3 ligase complex with Cul4A and DDB1 thus mediated degradation of PPM1B, which has been reported to negatively regulate NFκB signaling. We identified PPM1B as a substrate of Cul4A-DDB1-DCAF4L2 E3 ligase complex, as knockdown of PPM1B abrogated shDCAF4L2 mediated inhibition of cell invasion in CRC cells. For further verification, DCAF4L2 expression inversely correlated with PPM1B expression in a cohort of 87 CRC patients. These findings may provide insight into the understanding of DCAF4L2 as a novel critical factor and a candidate target for CRC treatment.