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Background: Patients with rectal cancer undergoing laparoscopic anterior resection and diverting stomas often suffer from bowel dysfunction after stoma closure, impairing their quality of life. This study aims to develop a machine learning tool to predict bowel function after diverting stoma closure. Methods: Clinicopathological data and post-operative follow-up information from patients with mid-low rectal cancer after diverting stoma closure were collected and analyzed. Patients were randomly divided into training and test sets in a 7:3 ratio. A machine learning model was developed in the training set to predict major low anterior resection syndrome (LARS) and evaluated in the test set. Decision curve analysis (DCA) was used to assess clinical utility. Results: The study included 396 eligible patients who underwent laparoscopic anterior resection and diverting stoma in Tongji Hospital affiliated with Huazhong University of Science and Technology from 1 January 2012 to 31 December 2020. The interval between stoma creation and closure, neoadjuvant therapy, and body mass index were identified as the three most crucial characteristics associated with patients experiencing major LARS in our cohort. The machine learning model achieved an area under the receiver operating characteristic curve (AUC) of 0.78 [95% confidence interval (CI): 0.74-0.83] in the training set (n=277) and 0.74 (95% CI: 0.70-0.79) in the test set (n=119), and area under the precision-recall curve (AUPRC) of 0.73 and 0.69, respectively, with sensitivity of 0.67 and specificity of 0.66 for the test set. DCA confirmed clinical applicability. Conclusions: This study developed a machine learning model to predict major LARS in rectal cancer patients after diverting stoma closure, aiding their decision-making and counseling.
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BACKGROUND: Previous studies have established the existence of the mesogastrium, dividing it into 6 sections. The mesogastrium is identified during surgery and used in surgical practice. The aim of the present study was to further investigate its role in gastric cancer prognosis. METHODS: Between January 2014 and January 2018, patients from the Tongji Hospital were included in this post hoc analysis, including data from a randomized clinical study (DCGC01; http://www. CLINICALTRIALS: gov, NCT01978444). Mesogastria containing metastatic lymph nodes were referred to as metastatic mesogastria. Pathology reports were examined to assess metastases in the mesogastrium. Survival was assessed using Kaplan-Meier curves and multivariable Cox models. RESULTS: Among the 479 patients, 230 (48.0%) had no lymph node metastasis, 34 (7.1%) had 1 metastatic mesogastrium, and 215 (44.9%) had 2 to 6 metastatic mesogastria. Multivariate analysis showed that the number of metastatic mesogastria and N stages were independent risk factors for patient prognosis. In general, a higher metastatic mesogastrium number is positively correlated with a worse prognosis. For identical N stages, 5-year survival rates for patients with 2 to 6 metastatic mesogastria were significantly lower than those for patients with 1 metastatic mesogastrium. CONCLUSION: The number of metastatic mesogastria serves as an independent prognostic factor from the N stage.
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Linfonodos , Metástase Linfática , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Masculino , Feminino , Pessoa de Meia-Idade , Metástase Linfática/patologia , Prognóstico , Idoso , Linfonodos/patologia , Estadiamento de Neoplasias , Gastrectomia , Adulto , Excisão de Linfonodo , Estimativa de Kaplan-Meier , Mesentério/patologiaRESUMO
Chemotherapy is a crucial treatment for colorectal tumors. However, its efficacy is restricted by chemoresistance. Recently, Golgi dispersal has been suggested to be a potential response to chemotherapy, particularly to drugs that induce DNA damage. However, the underlying mechanisms by which Golgi dispersal enhances the capacity to resist DNA-damaging agents remain unclear. Here, we demonstrated that DNA-damaging agents triggered Golgi dispersal in colorectal cancer (CRC), and cancer stem cells (CSCs) possessed a greater degree of Golgi dispersal compared with differentiated cancer cells (non-CSCs). We further revealed that Golgi dispersal conferred resistance against the lethal effects of DNA-damaging agents. Momentously, Golgi dispersal activated the Golgi stress response via the PKCα/GSK3α/TFE3 axis, resulting in enhanced protein and vesicle trafficking, which facilitated drug efflux through ABCG2. Identification of Golgi dispersal indicated an unexpected pathway regulating chemoresistance in CRC.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Complexo de Golgi , Células-Tronco Neoplásicas , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Humanos , Complexo de Golgi/metabolismo , Complexo de Golgi/efeitos dos fármacos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Dano ao DNA , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: It is unknown whether D2 lymphadenectomy + complete mesogastric excision for gastric cancer improves survival compared with just D2 lymphadenectomy. METHODS: Between September 2014 and June 2018, patients with advanced gastric cancer were randomly assigned (1 : 1) to laparoscopic D2 lymphadenectomy or D2 lymphadenectomy + complete mesogastric excision gastrectomy. The modified intention-to-treat population was defined as patients who had pathologically confirmed gastric adenocarcinoma (pT1 N1-3 M0 and pT2-4 N0-3 M0). The primary endpoint was 3-year disease-free survival. Secondary endpoints were the recurrence pattern and overall survival. RESULTS: The median follow-up of patients in the D2 lymphadenectomy group (169 patients) and patients in the D2 lymphadenectomy +complete mesogastric excision group (169 patients) was 55 (interquartile range 37-60)â months and 51 (interquartile range 40-60)â months respectively. Recurrence occurred in 50 patients in the D2 lymphadenectomy group (29.6%) versus 33 patients in the D2 lymphadenectomy + complete mesogastric excision group (19.5%) (P = 0.032). The 3-year disease-free survival was 75.5% (95% c.i. 68.3% to 81.3%) in the D2 lymphadenectomy group versus 85.0% (95% c.i. 78.7% to 89.6%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.042). The HR for recurrence in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 0.99) by Cox regression (P = 0.045). The 3-year overall survival rate was 77.5% (95% c.i. 70.4% to 83.1%) in the D2 lymphadenectomy group versus 85.8% (95% c.i. 79.6% to 90.2%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.058). The HR for death in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 1.02) (P = 0.058). CONCLUSION: Compared with conventional D2 dissection, D2 lymphadenectomy + complete mesogastric excision is associated with better disease-free survival, but there is no statistically significant difference in overall survival. REGISTRATION NUMBER: NCT01978444 (http://www.clinicaltrials.gov).
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Adenocarcinoma , Gastrectomia , Excisão de Linfonodo , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Gastrectomia/métodos , Excisão de Linfonodo/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adenocarcinoma/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Laparoscopia/métodos , Intervalo Livre de Doença , Recidiva Local de Neoplasia , Adulto , Taxa de Sobrevida , Estadiamento de NeoplasiasRESUMO
Abnormal nuclear enlargement is a diagnostic and physical hallmark of malignant tumors. Large nuclei are positively associated with an increased risk of developing metastasis; however, a large nucleus is inevitably more resistant to cell migration due to its size. The present study demonstrated that the nuclear size of primary colorectal cancer (CRC) cells at an advanced stage was larger than cells at an early stage. In addition, the nuclei of CRC liver metastases were larger than those of the corresponding primary CRC tissues. CRC cells were sorted into large-nucleated cells (LNCs) and small-nucleated cells (SNCs). Purified LNCs exhibited greater constricted migratory and metastatic capacity than SNCs in vitro and in vivo. Mechanistically, ErbB4 was highly expressed in LNCs, which phosphorylated lamin A/C at serine 22 via the ErbB4-Akt1 signaling pathway. Furthermore, the level of phosphorylated lamin A/C was a negative determinant of nuclear stiffness. Taken together, CRC LNCs possessed greater constricted migratory and metastatic potential than SNCs due to ErbB4-Akt1-mediated lamin A/C phosphorylation and nuclear softening. These results may provide a potential treatment strategy for tumor metastasis by targeting nuclear stiffness in patients with cancer, particularly CRC.
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Núcleo Celular , Neoplasias Colorretais , Lamina Tipo A , Proteínas Proto-Oncogênicas c-akt , Receptor ErbB-4 , Transdução de Sinais , Animais , Feminino , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Movimento Celular , Núcleo Celular/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Lamina Tipo A/metabolismo , Camundongos Nus , Metástase Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-4/metabolismo , Receptor ErbB-4/genéticaRESUMO
BACKGROUND: Benign anastomotic strictures (BAS) significantly impact patients' quality of life and long-term prognosis. However, the current clinical practice lacks accurate tools for predicting BAS. This study aimed to develop a machine-learning model to predict BAS in patients with rectal cancer who have undergone anterior resection. METHODS: Data from 1973 patients who underwent anterior resection for rectal cancer were collected. Multiple machine learning classification models were integrated to analyze the data and identify the optimal model. Model performance was evaluated using receiver operator characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves. The Shapley Additive exPlanation (SHAP) algorithm was utilized to assess the impact of various clinical characteristics on the optimal model to enhance the interpretability of the model results. RESULTS: A total of 10 clinical features were considered in constructing the machine learning model. The model evaluation results indicated that the random forest (RF)model was optimal, with the area under the test set curve (AUC: 0.888, 95% CI: 0.810-0.965), accuracy: 0.792, sensitivity: 0.846, specificity: 0.791. The SHAP algorithm analysis identified prophylactic ileostomy, operative time, and anastomotic leakage as significant contributing factors influencing the predictions of the RF model. CONCLUSION: We developed a robust machine-learning model and user-friendly online prediction tool for predicting BAS following anterior resection of rectal cancer. This tool offers a potential foundation for BAS prevention and aids clinical practice by enabling more efficient disease management and precise medical interventions.
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Qualidade de Vida , Neoplasias Retais , Humanos , Constrição Patológica , Neoplasias Retais/cirurgia , Algoritmos , Aprendizado de MáquinaRESUMO
BACKGROUND: Low anterior resection syndrome (LARS) severely impairs patient postoperative quality of life, especially major LARS. However, there are few tools that can accurately predict major LARS in clinical practice. AIM: To develop a machine learning model using preoperative and intraoperative factors for predicting major LARS following laparoscopic surgery of rectal cancer in Chinese populations. METHODS: Clinical data and follow-up information of patients who received laparoscopic anterior resection for rectal cancer from two medical centers (one discovery cohort and one external validation cohort) were included in this retrospective study. For the discovery cohort, the machine learning prediction algorithms were developed and internally validated. In the external validation cohort, we evaluated the trained model using various performance metrics. Further, the clinical utility of the model was tested by decision curve analysis. RESULTS: Overall, 1651 patients were included in the present study. Anastomotic height, neoadjuvant therapy, diverting stoma, body mass index, clinical stage, specimen length, tumor size, and age were the risk factors associated with major LARS. They were used to construct the machine learning model to predict major LARS. The trained random forest (RF) model performed with an area under the curve of 0.852 and a sensitivity of 0.795 (95%CI: 0.681-0.877), a specificity of 0.758 (95%CI: 0.671-0.828), and Brier score of 0.166 in the external validation set. Compared to the previous preoperative LARS score model, the current model exhibited superior predictive performance in predicting major LARS in our cohort (accuracy of 0.772 for the RF model vs 0.355 for the preoperative LARS score model). CONCLUSION: We developed and validated a robust tool for predicting major LARS. This model could potentially be used in the clinic to identify patients with a high risk of developing major LARS and then improve the quality of life.
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Laparoscopia , Neoplasias Retais , Humanos , Neoplasias Retais/patologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Síndrome de Ressecção Anterior Baixa , Qualidade de Vida , Laparoscopia/efeitos adversosRESUMO
Background: The purpose of this study is to construct a novel and practical nomogram and risk stratification system to accurately predict cancer-specific survival (CSS) of early-onset locally advanced rectal cancer (EO-LARC) patients. Methods: A total of 2440 patients diagnosed with EO-LARC between 2010 and 2019 were screened from the Surveillance, Epidemiology, and End Results (SEER) database. The pool of potentially eligible patients was randomly divided into two groups: a training cohort (N=1708) and a validation cohort (N=732). The nomogram was developed and calibrated using various methods, including the coherence index (C-index), receiver operating characteristic curve (ROC), calibration curves, and decision curves (DCA). A new risk classification system was established based on the nomogram. To compare the performance of this nomogram to that of the American Joint Committee on Cancer (AJCC) staging system, DCA, net reclassification index (NRI), and integrated discrimination improvement (IDI) were employed. Result: Seven variables were included in the model. The area under the ROC curve (AUC) for the training cohort was 0.766, 0.736, and 0.731 at 3, 6, and 9 years, respectively. Calibration plots displayed good consistency between actual observations and the nomogram's predictions. The DCA curve further demonstrated the validity of the nomination form in clinical practice. Based on the scores of the nomogram, all patients were divided into a low-risk group, a middle-risk group, and a high-risk group. NRI for the 3-, 6-, and 9-year CSS(training cohort: 0.48, 0.45, 0.52; validation cohort: 0.42, 0.37, 0.37), IDI for the 3-, 6-, and 9-year CSS (training cohort: 0.09, 0.10, 0.11; validation cohort: 0.07, 0.08, 0.08). The Kaplan-Meier curve revealed that the new risk classification system possesses a more extraordinary ability to identify patients in different risk groups than the AJCC staging. Conclusion: A practical prognostic nomogram and novel risk classification system have been developed to efficiently predict the prognosis of EO-LARC. These tools can serve as a guide to individualize patient treatment and improve clinical decision-making.
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BACKGROUND: Due to the difficult evaluation of the risk of anastomotic leakage (AL) after rectal cancer resection, the decision to perform a temporary ileostomy is not easily distinguishable. The aim of the present study was to develop an artificial intelligence (AI) model for identifying the risk of AL to assist surgeons in the selective implementation of a temporary ileostomy. MATERIALS AND METHODS: The data from 2240 patients with rectal cancer who received anterior resection were collected, and these patients were divided into one training and two test cohorts. Five AI algorithms, such as support vector machine (SVM), logistic regression (LR), Naive Bayes (NB), stochastic gradient descent (SGD) and random forest (RF) were employed to develop predictive models using clinical variables and were assessed using the two test cohorts. RESULTS: The SVM model indicated good discernment of AL, and might have increased the implementation of temporary ileostomy in patients with AL in the training cohort (p < 0.001). Following the assessment of the two test cohorts, the SVM model could identify AL in a favorable manner, which performed with positive predictive values of 0.150 (0.091-0.234) and 0.151 (0.091-0.237), and negative predictive values of 0.977 (0.958-0.988) and 0.986 (0.969-0.994), respectively. It is important to note that the implementation of temporary ileostomy in patients without AL would have been significantly reduced (p < 0.001) and which would have been significantly increased in patients with AL (p < 0.05). CONCLUSION: The model (https://alrisk.21cloudbox.com/) indicated good discernment of AL, which may be used to assist the surgeon's decision-making of performing temporary ileostomy.
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Neoplasias Retais , Cirurgiões , Humanos , Ileostomia , Inteligência Artificial , Teorema de Bayes , Neoplasias Retais/cirurgia , Fístula Anastomótica/cirurgia , Anastomose Cirúrgica , Estudos RetrospectivosRESUMO
BACKGROUND: Anastomotic leakage (AL) is a fatal complication in patients with rectal cancer after undergoing anterior resection. However, the role of abdominal composition in the development of AL has not been studied. AIM: To investigate the relationship between abdominal composition and AL in rectal cancer patients after undergoing anterior resection. METHODS: A retrospective case-matched cohort study was conducted. Complete data for 78 patients with AL were acquired and this cohort was defined as the AL group. The controls were matched for the same sex and body mass index (± 1 kg/m2). Parameters related to abdominal composition including visceral fat area (VFA), subcutaneous fat area (SFA), subcutaneous fat thickness (SFT), skeletal muscle area (SMA), skeletal muscle index (SMI), abdominal circumference (AC), anterior to posterior diameter of abdominal cavity (APD), and transverse diameter of abdominal cavity (TD) were evaluated based on computed tomography (CT) images using the following Hounsfield Unit (HU) thresholds: SFA: -190 to -30, SMA: -29 to 150, and VFA: -150 to -20. The significance of abdominal composition-related parameters was quantified using feature importance analysis; an artificial intelligence method was used to evaluate the contribution of each included variable. RESULTS: Two thousand two hundred and thirty-eight rectal cancer patients who underwent anterior resection from 2010 to 2020 in a large academic hospital were investigated. Finally, 156 cases were enrolled in the study. Patients in the AL group showed longer operative time (225.03 ± 55.29 vs 207.17 ± 40.80, P = 0.023), lower levels of preoperative hemoglobin (123.32 ± 21.17 vs 132.60 ±1 6.31, P = 0.003) and albumin (38.34 ± 4.01 vs 40.52 ± 3.97, P = 0.001), larger tumor size (4.07 ± 1.36 vs 2.76 ± 1.28, P < 0.001), and later cancer stage (P < 0.001) compared to the controls. Patients who developed AL exhibited a larger VFA (125.68 ± 73.59 vs 97.03 ± 57.66, P = 0.008) and a smaller APD (77.30 ± 23.23 vs 92.09 ± 26.40, P < 0.001) and TD (22.90 ± 2.23 vs 24.21 ± 2.90, P = 0.002) compared to their matched controls. Feature importance analysis revealed that TD, APD, and VFA were the three most important abdominal composition-related features. CONCLUSION: AL patients have a higher visceral fat content and a narrower abdominal structure compared to matched controls.
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Uneven oxygen supply in solid tumors leads to hypoxic and normoxic regions. Hypoxic cells exhibit increased secretion of lactate, which creates an acidic tumor microenvironment (TME). This acidic TME is positively associated with tumor metastasis. Despite the increased metastatic capacity of hypoxic cells, they are located relatively further away from the blood vessels and have limited access to the circulatory system. Studies have shown that cancer stem cells (CSCs) are enriched for tumor metastasis-initiating cells and generally undergo aerobic respiration, which could be enhanced by lactate. We therefore hypothesized that TME-derived lactate may promote the metastasis of normoxic CSCs. In the present study, the abundance of hypoxic and normoxic CSCs was analyzed in primary CRC tumors. It was found that the proportion of normoxic CSCs was positively associated with tumor stage. Using two human CRC cell lines, LoVo and SW480, and a patient-derived xenograft (XhCRC), it was found that treatment with lactate promoted normoxic CSC metastasis. Metabolism analysis indicated that, upon treatment with lactate, oxidative phosphorylation (OXPHOS) activity in normoxic CSCs was enhanced, whereas hypoxic CSCs were rarely altered. At the molecular level, the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of lactate oxidation, was found to be elevated in normoxic CSCs. Furthermore, PGC-1α knockdown markedly reduced the metastatic potential of normoxic CSCs. Notably, both the PGC-1α-mediated OXPHOS activity and metastatic potential were impaired when hypoxia-inducible factor-1α (HIF-1α) was activated in normoxic CSCs. Together, these findings provide a therapeutic strategy against tumor metastasis through the targeting of PGC-1α and, thus, the suppression of lactate-feeding OXPHOS in normoxic CSCs may improve the therapeutic benefit of patients with cancer, particularly CRC.
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Neoplasias Colorretais , Fosforilação Oxidativa , Linhagem Celular , Neoplasias Colorretais/patologia , Humanos , Hipóxia/patologia , Ácido Láctico , Células-Tronco Neoplásicas/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: The optimal timing of temporary ileostomy closure with respect to the time of adjuvant chemotherapy following sphincter-saving surgery for rectal cancer remains unclear. The aim of this study is to investigate the clinical and oncological outcomes of ileostomy closure before, during, and after adjuvant chemotherapy following curative rectal cancer resection. METHODS: Patients diagnosed with rectal adenocarcinoma who underwent low anterior resection and temporary loop ileostomy during May 2015 and September 2019 were retrospectively evaluated. Patients undergoing ileostomy closure before adjuvant chemotherapy (Group I) were compared to patients undergoing closure during (Group II) and after (Group III) adjuvant chemotherapy. RESULTS: A total of 225 patients were evaluated for eligibility, and 132 were finally selected and divided into 3 groups (24 in Group I, 53 in Group II, and 55 in Group III). No significant differences were observed in operative time, postoperative hospital stay, postoperative complications, total adjuvant chemotherapy cycles, and low anterior resection syndrome scores among the three groups. There was no significant difference in disease-free survival (p = 0.834) and overall survival (p = 0.462) between the three groups. CONCLUSION: Temporary ileostomy closure before adjuvant chemotherapy following curative rectal cancer resection can achieve a clinical and oncological safety level equal to stoma closure during or after chemotherapy in selected patients.
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Anastomotic leakage is a life-threatening complication in patients with gastric adenocarcinoma who received total or proximal gastrectomy, and there is still no model accurately predicting anastomotic leakage. In this study, we aim to develop a high-performance machine learning tool to predict anastomotic leakage in patients with gastric adenocarcinoma received total or proximal gastrectomy. A total of 1660 cases of gastric adenocarcinoma patients who received total or proximal gastrectomy in a large academic hospital from 1 January 2010 to 31 December 2019 were investigated, and these patients were randomly divided into training and testing sets at a ratio of 8:2. Four machine learning models, such as logistic regression, random forest, support vector machine, and XGBoost, were employed, and 24 clinical preoperative and intraoperative variables were included to develop the predictive model. Regarding the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, random forest had a favorable performance with an AUC of 0.89, a sensitivity of 81.8% and specificity of 82.2% in the testing set. Moreover, we built a web app based on random forest model to achieve real-time predictions for guiding surgeons' intraoperative decision making.
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Implementation of complete mesogastric excision in gastric cancer surgery, named D2 lymphadenectomy plus complete mesogastric excision (D2+CME), has recently been proposed as an optimal procedure. However, the safety and efficacy of D2+CME remain uncertain. In this randomized controlled trial, patients receiving D2+CME exhibit less intraoperative blood loss, more lymph node harvesting, and earlier postoperative flatus than patients receiving conventional D2 radical surgery. Univariate Cox regression analysis reveals that the risk ratio for postoperative flatus in D2+CME group is 1.247 (p = 0.044). Overall postoperative complications are comparable between the two groups, but complications are significantly less severe in the D2+CME group than the D2 group (Clavien-Dindo classification grade ≥ IIIa: 4 D2+CME patients [11.8%] versus 9 D2 patients [33.3%]; p = 0.041). In conclusion, our work shows that D2+CME is associated with better short-term outcomes and surgical safety than conventional D2 dissection for patients with advanced gastric cancer.
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Gastrectomia/métodos , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Mesentério/cirurgia , Neoplasias Gástricas/cirurgia , Estômago/cirurgia , Adulto , Perda Sanguínea Cirúrgica/fisiopatologia , Perda Sanguínea Cirúrgica/prevenção & controle , Progressão da Doença , Feminino , Flatulência/diagnóstico , Flatulência/etiologia , Flatulência/fisiopatologia , Humanos , Linfonodos/patologia , Masculino , Mesentério/patologia , Pessoa de Meia-Idade , Razão de Chances , Segurança do Paciente , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/fisiopatologia , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Introduction. Shigella sonnei, the cause of bacillary dysentery, belongs to Gram-negative enteropathogenic bacteria. S. sonnei contains a 210 kb virulence plasmid that encodes an O-antigen gene cluster of LPSs. However, this virulence plasmid is frequently lost during replication. It is well-documented that after losing the O-antigen and becoming rough strains, the Gram-negative bacteria may express an LPS core on its surface. Previous studies have suggested that by using the LPS core, Gram-negative bacteria can interact with several C-type lectin receptors that are expressed on antigen-presenting cells (APCs).Hypothesis/Gap Statement. S. sonnei by losing the virulence plasmid may hijack APCs via the interactions of LPS-CD209/CD207.Aim. This study aimed to investigate if the S. sonnei rough strain, by losing the virulence plasmid, interacted with APCs that express C-type lectins of human CD207, human CD209a and mouse CD209b.Methodology. SDS-PAGE silver staining was used to examine the O-antigen expression of S. sonnei WT and its rough strain. Invasion assays and inhibition assays were used to examine the ability of S. sonnei WT and its rough strain to invade APCs and investigate whether CD209 and CD207 are receptors for phagocytosis of rough S. sonnei. Animal assays were used to observe the dissemination of S. sonnei.Results. S. sonnei did not express O-antigens after losing the virulence plasmid. The S. sonnei rough strain invades with APCs, including human dendritic cells (DCs) and mouse macrophages. CD209 and CD207 are receptors for phagocytosis of rough S. sonnei. Expression of the O-antigen reduces the ability of the S. sonnei rough strain to be disseminated to mesenteric lymph nodes and spleens.Conclusion. This work demonstrated that S. sonnei rough strains - by losing the virulence plasmid - invaded APCs through interactions with CD209 and CD207 receptors.
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Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Disenteria Bacilar/microbiologia , Lectinas Tipo C/imunologia , Lectinas de Ligação a Manose/imunologia , Antígenos O , Plasmídeos , Receptores de Superfície Celular/imunologia , Shigella sonnei/patogenicidade , Virulência/genética , Animais , Células CHO , Cricetulus , Células Dendríticas/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/microbiologia , Camundongos , Antígenos O/genética , Antígenos O/metabolismo , Shigella sonnei/genéticaRESUMO
Tumors harbor diverse compartments of cells with distinct metabolic properties and phenotypes, but the mechanism by which metabolic commensalism among distinct subsets of cancer cells affects tumor progression remains unclear. Colorectal cancer (CRC) has been reported to consist of cancer stem cells (CSCs) and differentiated cancer cells (non-CSCs). In the present study, organoid models were employed to show that CSCs and non-CSCs in CRC were characterized by distinct metabolic phenotypes. Treatment with either non-CSC-derived conditioned medium or exogenous lactate enhanced organoid-forming and tumor-initiating capacity of CSCs. In tumor regeneration assays with co-implanted CSCs and non-CSCs, the tumor-initiating activity was reduced when either monocarboxylate transporter (MCT)4 in non-CSCs or MCT1 in CSCs was silenced or inhibited. Mechanistically, oxiadative phosphorylation-derived reactive oxygen species in CSCs activated AKT-Wnt/ß-catenin signaling, which could be induced by lactate from non-CSCs. Overall, these results suggest that CSCs and non-CSCs possess distinct metabolic profiles and, unexpectedly, non-CSC-originated lactate promotes self-renewal of CSCs and thus contributes to CRC progression. Our findings establish a rationale for developing novel therapies targeting the metabolic commensalism between different cell populations in CRC.
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Neoplasias Colorretais/patologia , Ácido Láctico/metabolismo , Células-Tronco Neoplásicas/patologia , Organoides/transplante , Animais , Diferenciação Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Organoides/citologia , Organoides/metabolismo , Fosforilação Oxidativa , Células Tumorais Cultivadas , Via de Sinalização WntRESUMO
Tumor heterogeneity is an important feature of malignant tumors, and cell subpopulations may positively interact to facilitate tumor progression. Studies have shown that hypoxic cancer cells possess enhanced metastatic capacity. However, it is still unclear whether hypoxic cancer cells may promote the metastasis of normoxic cells, which have greater access to the blood circulation. When cocultured with hypoxic CRC cells or treated with hypoxic CRC cell-derived CM, normoxic CRC cells possessed increased metastatic capacity. Furthermore, hypoxic CRC cell-derived CM was enriched in interleukin 8. Hypoxic CRC cell-derived CM and recombinant human IL-8 both enhanced the metastatic capacity of normoxic cells by increasing the phosphorylation of p65 and then by inducing epithelial-mesenchymal transition. Knockdown of IL-8 in hypoxic CRC cells or the use of an anti-IL-8 antibody attenuated the CM- or rhIL-8-induced prometastatic capacity of normoxic CRC cells. Inhibition or knockdown of p65 abrogated IL-8-induced prometastatic effects. Most importantly, hypoxia-treated xenograft tumors enhanced the metastasis of normoxic CRC cells. Hypoxic CRC cell-derived IL-8 promotes the metastatic capacity of normoxic cells, and novel therapies targeting the positive interactions between hypoxic and normoxic cells should be developed.
Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Interleucina-8/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Hipóxia Tumoral , Hipóxia Celular , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Comunicação ParácrinaRESUMO
Salmonella enterica serovar Typhimurium, a Gram-negative bacterium, can cause infectious diseases ranging from gastroenteritis to systemic dissemination and infection. However, the molecular mechanisms underlying this bacterial dissemination have yet to be elucidated. A study indicated that using the lipopolysaccharide (LPS) core as a ligand, S Typhimurium was able to bind human dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (hCD209a), an HIV receptor that promotes viral dissemination by hijacking antigen-presenting cells (APCs). In this study, we showed that S Typhimurium interacted with CD209s, leading to the invasion of APCs and potentially the dissemination to regional lymph nodes, spleen, and liver in mice. Shielding of the exposed LPS core through the expression of O-antigen reduces dissemination and infection. Thus, we propose that similar to HIV, S Typhimurium may also utilize APCs via interactions with CD209s as a way to disseminate to the lymph nodes, spleen, and liver to initiate host infection.
Assuntos
Moléculas de Adesão Celular/fisiologia , Lectinas Tipo C/fisiologia , Receptores de Superfície Celular/fisiologia , Salmonella typhimurium/patogenicidade , Animais , Células Apresentadoras de Antígenos/microbiologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Lipopolissacarídeos/fisiologia , Mananas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Antígenos O/fisiologia , Nódulos Linfáticos Agregados/fisiologia , Fagocitose , Células RAW 264.7RESUMO
Threedimensional (3D) cultures are indispensable for capturing tumor heterogeneity in colorectal cancer (CRC) in vitro. Although 3D cultures (such as sphereforming assay and organoid culture) can partially preserve the morphological and molecular characteristics of primary CRC, whether these 3D cultures maintain the longterm stemness of cancer stem cells (CSCs) remains largely unknown. In the present study, spheres and organoids were generated side by side using individual primary CRC specimens, then respectively processed as serial passages. The results revealed that during serial passages, the percentage of CSCs (such as cluster of differentiation133+ and Wnt+ cells) in organoids and the tumorinitiating capacity of organoidderived cells were constant, while they gradually increased in the spherederived cells. Furthermore, during serial passages, resistance to chemotherapeutic agents (including 5fluorouracil and oxaliplatin) in sphere and organoidderived cells was evaluated. The results indicated that the percentage of chemoresistant cells was constant in serial organoid cultures; however, it gradually increased in the serial sphereforming assays. Taken together, the results of the present study comprehensively demonstrate that, with regard to longterm culture in vitro, organoid culture may be useful in maintaining tumor heterogeneity and the levels of chemoresistant cells, while the sphere formation assay enriches for CSCs and chemoresistant cells.
Assuntos
Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas/patologia , Organoides/patologia , Técnicas de Cultura de Tecidos/normas , Animais , Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Organoides/efeitos dos fármacos , Organoides/metabolismo , Células Tumorais Cultivadas , Proteínas Wnt/metabolismoRESUMO
BACKGROUND: Although radical gastrectomy with D2 lymph node dissection has become the standard surgical approach for locally advanced gastric cancer, patients still have a poor prognosis after operation. Previously, we proposed laparoscopic distal gastrectomy (D2 lymphadenectomy plus complete mesogastrium excision [D2 + CME]) as an optimized surgical procedure for locally advanced gastric cancer. By dissection along the boundary of the mesogastrium, D2 + CME resected proximal segments of the dorsal mesogastrium completely with less blood loss, and it improved the short-term surgical outcome. However, the oncologic therapeutic effect of D2 + CME has not yet been confirmed. METHODS/DESIGN: A single-center, prospective, parallel-group, randomized controlled trial of laparoscopic distal gastrectomy with D2 + CME versus conventional D2 was conducted for patients with locally advanced gastric cancer at Tongji Hospital, Wuhan, China. In total, 336 patients who met the following eligibly criteria were included and were randomized to receive either the D2 + CME or D2 procedure: (1) pathologically proven adenocarcinoma; (2) 18 to 75 years old; cT2-4, N0-3, M0 at preoperative evaluation; (3) expected curative resection via laparoscopic distal gastrectomy; (4) no history of other cancer, chemotherapy, or radiotherapy; (5) no history of upper abdominal operation; and (6) perioperative American Society of Anesthesiologists class I, II, or III. The primary endpoint is 3 years of disease-free survival. The secondary endpoints are overall survival, recurrence pattern, mortality, morbidity, postoperative recovery course, and other parameters. DISCUSSION: Previous studies have demonstrated the safety and feasibility of D2 + CME for locally advanced gastric cancer; however, there is still a lack of evidence to support its therapeutic effect. Thus, we performed this randomized trial to investigate whether D2 + CME can improve oncologic outcomes of patients with locally advanced gastric cancer. The findings from this trial may potentially optimize the surgical procedure and may improve the prognosis of patients with locally advanced gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01978444 . Registered on October 31, 2013.