Modeling the Role of Immune Cell Conversion in the Tumor-Immune Microenvironment.

Tumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell-cell interactions in the TIME has led researchers to apply concepts from ecology to describe the dynamics. However, while tumor cells are known to induce immune cells to switch from anti-tumor to pro-tumor phenotypes, this type of ecological interaction has been largely overlooked. To address this gap in cancer modeling, we develop a minimal, ecological model of the TIME with immune cell conversion, to highlight this important interaction and explore its consequences. A key finding is that immune conversion increases the range of parameters supporting a co-existence phase in which the immune system and the tumor reach a stalemate. Our results suggest that further investigation of the consequences of immune cell conversion, using detailed, data-driven models, will be critical for greater understanding of TIME dynamics.

Identifying hepatocellular carcinoma patients with survival benefits from surgery combined with chemotherapy: based on machine learning model.

BACKGROUND: Hepatocellular carcinoma (HCC) is still fatal even after surgical resection. The purpose of this study was to analyze the prognostic factors of 5-year survival rate and to establish a model to identify HCC patients with gain of surgery combined with chemotherapy. METHODS: All patients with HCC after surgery from January 2010 to December 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic analysis were used to analyze the prognostic factors of patients, and the risk prediction model of 5-year survival rate of HCC patients was established by classical decision tree method. Propensity score matching was used to eliminate the confounding factors of whether to receive chemotherapy in high-risk group or low-risk group. RESULTS: One-thousand six-hundred twenty-five eligible HCC patients were included in the study. Marital status, α-fetoprotein (AFP), vascular infiltration, tumor size, number of lesions, and grade were independent prognostic factors affecting the 5-year survival rate of HCC patients. The area under the curve of the 5-year survival risk prediction model constructed from the above variables was 0.76, and the classification accuracy, precision, recall, and F1 scores were 0.752, 0.83, 0.842, and 0.836, respectively. High-risk patients classified according to the prediction model had better 5-year survival rate after chemotherapy, while there was no difference in 5-year survival rate between patients receiving chemotherapy and patients not receiving chemotherapy in the low-risk group. CONCLUSIONS: The 5-year survival risk prediction model constructed in this study provides accurate survival prediction information. The high-risk patients determined according to the prediction model may benefit from the 5-year survival rate after combined chemotherapy.

Exploration of the immune microenvironment of breast cancer in large population cohorts.

Tumor immune microenvironment is associated with tumor progression. However, previous studies have not fully explored the breast cancer (BC) immune microenvironment. All the data analyzed in this study were obtained from the open-access database, including The Cancer Genome Atlas, Gene Expression Omnibus (TCGA), and cBioPortal databases. R software v4.0 and SPSS 13.0 were used to perform all the statistical analysis. Firstly, the clinical and expression profile information of TCGA, GSE20685, GSE20711, GSE48390, GSE58812, and METABRIC cohorts was collected. Then, 53 immune terms were quantified using the single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm. A prognosis model based on HER2_Immune_PCA, IL12_score, IL13_score, IL4_score, and IR7_score was established, which showed great prognosis prediction efficiency in both training group and validation group. A nomogram was then established for a better clinical application. Clinical correlation showed that elderly BC patients might have a higher riskscore. Pathway enrichment analysis showed that the pathway of oxidative phosphorylation, E2F targets, hedgehog signaling, adipogenesis, DNA repair, glycolysis, heme metabolism, and mTORC1 signaling was activated in the high-risk group. Moreover, Tumor Immune Dysfunction and Exclusion and Genomics of Drug Sensitivity in Cancer analysis showed that low-risk patients might be more sensitive to PD-1 therapy, cisplatin, gemcitabine, paclitaxel, and sunitinib. Finally, four genes, XCL1, XCL2, TNFRSF17, and IRF4, were identified for risk group classification. In summary, our signature is a useful tool for the prognosis and prediction of the drug sensitivity of BC.

Diagnostic and Prognostic Nomograms for Lung Metastasis in Triple-Negative Breast Cancer.

Background: The lungs are one of the common sites of metastasis of triple-negative breast cancer (TNBC). Patients with lung metastases (LM) have a shorter duration of survival. This study is aimed at determining the prognostic factors of patients with TNBC with LM and constructing two nomograms to assess the risk of LM and the prognosis of patients with TNBC with LM. Methods: Clinicopathological and follow-up data of patients with TNBC between 2010 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression analyses were used to screen for independent predictors of LM in patients with TNBC and identify the independent prognostic factors of patients with TNBC with LM. The two nomograms were appraised using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Results: A total of 27,048 patients with TNBC were included in this study. Age, tumour size, T stage, and N stage were identified as independent risk factors for LM in patients with TNBC. Histological type, marital status, prior surgery, chemotherapy, bone metastases, brain metastases, and LM were confirmed as independent prognostic factors for patients with TNBC with LM. The area under the ROC curve (AUC) of the diagnostic nomogram was 0.838 (95% confidence interval 0.817-0.860) in the training cohort and 0.894 (95% confidence interval 0.875-0.917) in the verification cohort. The AUC values of the 6-, 12-, and 18-month prognostic nomograms in the training cohort were 0.809 (95% confidence interval 0.771-0.868), 0.779 (95% confidence interval 0.737-0.834), and 0.735 (95% confidence interval 0.699-0.811), respectively, and the corresponding AUC values in the validation cohort were 0.735(95% confidence interval 0.642-0.820), 0.672 (95% confidence interval 0.575-0.758), and 0.705 (95% confidence interval 0.598-0.782), respectively. According to the calibration curves and data analysis, both nomograms exhibited good performance. Conclusion: We successfully constructed and verified two valuable nomograms for predicting the incidence of LM and prognosis of patients TNBC with LM.

Collective motility and mechanical waves in cell clusters.

Epithelial cell clusters often move collectively on a substrate. Mechanical signals play a major role in organizing this behavior. There are a number of experimental observations in these systems which await a comprehensive explanation. These include: the internal strains are tensile even for clusters that expand by proliferation; the tractions on the substrate are often confined to the edges of the cluster; there can exist density waves within the cluster; and for cells in an annulus, there is a transition between expanding clusters with proliferation and the case where cells fill the annulus and rotate around it. We formulate a mechanical model to examine these effects. We use a molecular clutch picture which allows "stalling"-inhibition of cell contraction by external forces. Stalled cells are passive from a physical point of view and the un-stalled cells are active. By attaching cells to the substrate and to each other, and taking into account contact inhibition of locomotion, we get a simple picture for many of these findings as well as predictions that could be tested.

Correlations Between the Characteristics of Alternative Splicing Events, Prognosis, and the Immune Microenvironment in Breast Cancer.

OBJECTIVE: Alternative splicing (AS) is the mechanism by which a few genes encode numerous proteins, and it redefines the concept of gene expression regulation. Recent studies showed that dysregulation of AS was an important cause of tumorigenesis and microenvironment formation. Therefore, we performed a systematic analysis to examine the role of AS in breast cancer (Breast Cancer, BrCa) progression. METHODS: The present study included 993 BrCa patients from The Cancer Genome Atlas (TCGA) database in the genome-wide analysis of AS events. We used differential and prognostic analyses and found differentially expressed alternative splicing (DEAS) events and independent prognostic factors related to patients' overall survival (OS) and disease-free survival (DFS). We divided the patients into two groups based on these AS events and analyzed their clinical features, molecular subtyping and immune characteristics. We also constructed a splicing factor (SF) regulation network for key AS events and verified the existence of AS events in tissue samples using real-time quantitative PCR. RESULTS: A total of 678 AS events were identified as differentially expressed, of which 13 and 10 AS events were independent prognostic factors of patients' OS and DFS, respectively. Unsupervised clustering analysis based on these prognostic factors indicated that the Cluster 1 group had a better prognosis and more immune cell infiltration. SFs were significantly related to the expression of AS events, and AA-RPS21 was significantly upregulated in tumors. CONCLUSION: Alternative splicing expands the mechanism of breast cancer progression from a new perspective. Notably, alternative splicing may affect the patient's prognosis by affecting the infiltration of immune cells. Our research provides important guidance for subsequent studies of AS in breast cancer.

A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2.

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-ß or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor.

lncRNA FGD5­AS1 promotes breast cancer progression by regulating the hsa­miR­195­5p/NUAK2 axis.

Breast cancer is the second most prevalent cancer in women worldwide. Long non­coding RNAs (lncRNAs) have been identified as important regulators of tumorigenesis and tumor metastasis. lncRNA FGD5­AS1 has been previously reported as a carcinogenic gene, however its role in breast cancer has yet to be investigated. The present study aimed to understand the function of lncRNA FGD5­AS1 in breast cancer and examine the underlying molecular mechanisms. Sample tissues for downstream gene expression profiling were collected from patients with breast cancer (n=23). The effect of FGD5­AS1 overexpression on cell viability, invasion and migration has been studied in breast cancer cells (MDA­MB­231). Changes in glycolysis were monitored by comparing glucose consumption, lactate production and ATP levels. Using StarBase and TargetScan databases a putative interaction between FGD5­AS1, miR­195­5p and SNF1­like kinase 2 (NUAK2) was predicted in silico. Expression levels of FGD5­AS1, has­miR­195­5p and NUAK2 were validated by reverse transcription­quantitative PCR and interactions were validated using dual­luciferase reporter assays and RNA pull­down. High expression of lncRNA FGD5­AS1 was detected in breast cancer tissue samples and disease model cell lines. Silencing of FGD5­AS1 led to decreased cell proliferation, migration and invasion. It was identified that at a molecular level FGD5­AS1 serves as a sponge of miR­195­5p and alters the expression of its downstream target gene NUAK2. In breast cancer lncRNA FGD5­AS1 serve a key role in glycolysis and tumor progression via the miR­195­5p/NUAK2 axis. The findings of the present study indicated FGD5­AS1 as a candidate target for intervention in patients with breast cancer.

Towards decoding the coupled decision-making of metabolism and epithelial-to-mesenchymal transition in cancer.

Cancer cells have the plasticity to adjust their metabolic phenotypes for survival and metastasis. A developmental programme known as epithelial-to-mesenchymal transition (EMT) plays a critical role during metastasis, promoting the loss of polarity and cell-cell adhesion and the acquisition of motile, stem-cell characteristics. Cells undergoing EMT or the reverse mesenchymal-to-epithelial transition (MET) are often associated with metabolic changes, as the change in phenotype often correlates with a different balance of proliferation versus energy-intensive migration. Extensive crosstalk occurs between metabolism and EMT, but how this crosstalk leads to coordinated physiological changes is still uncertain. The elusive connection between metabolism and EMT compromises the efficacy of metabolic therapies targeting metastasis. In this review, we aim to clarify the causation between metabolism and EMT on the basis of experimental studies, and propose integrated theoretical-experimental efforts to better understand the coupled decision-making of metabolism and EMT.

The mechanics and dynamics of cancer cells sensing noisy 3D contact guidance.

Contact guidance is a major physical cue that modulates cancer cell morphology and motility, and is directly linked to the prognosis of cancer patients. Under physiological conditions, particularly in the three-dimensional (3D) extracellular matrix (ECM), the disordered assembly of fibers presents a complex directional bias to the cells. It is unclear how cancer cells respond to these noncoherent contact guidance cues. Here we combine quantitative experiments, theoretical analysis, and computational modeling to study the morphological and migrational responses of breast cancer cells to 3D collagen ECM with varying degrees of fiber alignment. We quantify the strength of contact guidance using directional coherence of ECM fibers, and find that stronger contact guidance causes cells to polarize more strongly along the principal direction of the fibers. Interestingly, sensitivity to contact guidance is positively correlated with cell aspect ratio, with elongated cells responding more strongly to ECM alignment than rounded cells. Both experiments and simulations show that cell-ECM adhesions and actomyosin contractility modulate cell responses to contact guidance by inducing a population shift between rounded and elongated cells. We also find that cells rapidly change their morphology when navigating the ECM, and that ECM fiber coherence modulates cell transition rates between different morphological phenotypes. Taken together, we find that subcellular processes that integrate conflicting mechanical cues determine cell morphology, which predicts the polarization and migration dynamics of cancer cells in 3D ECM.

Incidence, Risk Factors and Prognosis of T4a Gastric Cancer: A Population-Based Study.

Background: T4a gastric cancer (GC) is a subtype of advanced GC (AGC), which urgently needs a comprehensive grade method for better treatment strategy choosing. The purpose of this study was to develop two nomograms for predicting the prognosis of patients with T4a GC. Methods: A total of 1,129 patients diagnosed as T4a GC between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Result (SEER) program database. Univariate and multivariate Cox analyses were performed to explore the independent predictors and to establish nomogram for overall survival (OS) of the patients, whereas competing risk analyses were performed to find the independent predictors and to establish nomogram for cancer-specific survival (CSS) of the patients. The area under the curve (AUC), calibration curve, decision curve analysis (DCA), and Kaplan-Meier analysis were performed to evaluate the nomograms. Results: Older age, larger tumor size, black race, signet ring cell carcinoma (SRCC), more lymph node involvement, the absence of surgery, the absence of radiotherapy, and the absence of chemotherapy were identified as independent prognostic factors for both OS and CSS. In the training cohort, the AUCs of the OS nomogram were 0.760, 0.743, and 0.723 for 1-, 3-, and 5-year OS, whereas the AUCs of the CSS nomogram were 0.724, 0.703, and 0.713 for 1-, 3-, and 5-year CSS, respectively. The calibration curve and DCA indicated that both nomograms can effectively predict OS and CSS, respectively. The abovementioned results were also confirmed in the validation cohort. Stratification of the patients into high- and low-risk groups highlighted the differences in prognosis between the two groups both in training and in validation cohorts. Conclusions: Age, tumor size, race, histologic type, N stage, surgery status, radiotherapy, and chemotherapy were confirmed as independent prognostic factors for both OS and CSS in patients with T4a GC. Two nomograms based on the abovementioned variables were constructed to provide more accurate individual survival predictions for them.

High interleukin-8 and/or extracellular signal-regulated kinase 2 expression predicts poor prognosis in patients with hepatocellular carcinoma.

Interleukin (IL)-8 and extracellular signal-regulated kinase (ERK) 2 play key roles in tumor progression, but the relationship between IL-8 and/or ERK2 expression in hepatocellular carcinoma (HCC) tissues and postoperative recurrence or survival is unclear. The expression levels of IL-8 and ERK2 in both HCC tissues and non-tumor liver tissues were analyzed using the Oncomine™ database and immunohistochemistry assay. Reverse transcription-quantitative PCR was then used to evaluate the expression levels of IL-8 and ERK2 in the tumor tissues of 67 patients with HCC undergoing radical hepatectomy. Pearson's correlation, Kaplan-Meier, Cox univariate and multivariate survival analyses were utilized to determine the correlation between IL-8 and ERK2 expression in HCC tissues, and their potential prognostic significance. As indicated by the data from the Oncomine™ database, and the patient samples, IL-8 and ERK2 were expressed at significantly higher levels in HCC tissues than in non-tumor liver tissues (P<0.05). The rates of high IL-8 and ERK2 expression in HCC tissues were 43.28 (29/67) and 34.33% (23/67), respectively, and the IL-8 and ERK2 expression levels were positively correlated (r=0.764; P<0.001). Both ERK2 expression and IL-8/ERK2 co-expression were significantly associated with tumor size and differentiation (P<0.05). Additionally, high expression levels of IL-8, ERK2 and IL-8/ERK2 co-expression were all significantly associated with poor overall survival (OS; P<0.05) and disease-free survival (DFS; P<0.05). Multivariate Cox regression analysis also showed that high expression levels of IL-8, ERK2, and IL-8 and ERK2 were independent prognostic factors for OS and DFS (P<0.05). The results of the present study indicate a significant increase in the risk of recurrence and mortality in HCC patients with high expression levels of IL-8 and/or ERK2, compared with patients with low expression. Therefore, IL-8 and ERK2 may be predictors of postoperative prognosis in patients with HCC.

Quantifying Cancer Epithelial-Mesenchymal Plasticity and its Association with Stemness and Immune Response.

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial-mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor. Moreover, cancer cells in hybrid E/M phenotypes tend to be more associated with stemness which endows them with tumor-initiation ability and therapy resistance. Most recently, cells undergoing EMT have been shown to promote immune suppression for better survival. A systematic understanding of the emergence of hybrid E/M phenotypes and the connection of EMT with stemness and immune suppression would contribute to more effective therapeutic strategies. In this review, we first discuss recent efforts combining theoretical and experimental approaches to elucidate mechanisms underlying EMT multi-stability (i.e., the existence of multiple stable phenotypes during EMT) and the properties of hybrid E/M phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell cooperation and extracellular matrix. Afterwards, we discuss various metrics that can be used to quantify EMT spectrum. We further describe possible mechanisms underlying the formation of clusters of circulating tumor cells. Last but not least, we summarize recent systems biology analysis of the role of EMT in the acquisition of stemness and immune suppression.

Isolated retroperitoneal enteric duplication cyst associated with an accessory pancreatic lobe.

INTRODUCTION: Enteric duplication cysts are rare congenital anomalies. They are lined by gastrointestinal mucosa, connected to the digestive tract, and share smooth muscle layers and a common blood supply. In rare cases, duplication cysts are isolated from the digestive tract and have a unique blood supply. No patient with isolated duplication cysts that are located in the retroperitoneum and associated with an accessory pancreatic lobe at the onset have been reported to date. MATERIALS AND METHODS: A 10-year-old Asian boy complained of left upper abdominal pain for more than 3 months. Contrast-enhanced computed tomography showed that the main pancreatic duct in the tail of the pancreas was dilated. A soft tissue density shadow was observed around the tail of the pancreas. The lesion was connected to the main pancreatic duct and the blood was supplied from a branch of the splenic artery. Surgical exploration and pathologic specimens resulted in the diagnosis of an isolated retroperitoneal enteric duplication cyst associated with an accessory pancreatic lobe. The patient received treatments of rehydration, antibiotics, and protease inhibitors. Due to the poor conservative treatment effect in internal medicine, a surgical resection of abnormal tissue was performed. RESULTS: The boy did not have abdominal pain again in the first year after leaving the hospital. DISCUSSION: For repeated abdominal pain in young people, especially in children, an enteric duplication cyst needs to be ruled out. This case was difficult to diagnose and imaging examination was not able to determine whether it is located in the anterior peritoneum or the retroperitoneum. For such cases, surgical exploration is necessary, and surgical resection can achieve more satisfactory results.