Occurrence Of Liver Metastases Research Articles

Single-Cell RNA Sequencing Revealing that MMP12+ Macrophages are Associated with Cancer Liver Metastasis.

We aimed to explore the MMP12+ macrophages function in liver metastasis of Colorectal cancer [CRC]. CRC has a high incidence, and a great many patients develop liver metastases. Some studies have found that macrophages may participate in the liver metastasis of CRC. This study aimed to determine the factors and major signaling pathways of MMP12+ macrophages affecting liver metastasis of CRC. The single-cell RNA sequencing [scRNA-seq] data of CRC and bulk transcriptome data were downloaded. After filtering scRNA-seq data, dimensionality reduction and clustering were performed to identify different cell subgroups. The FindAll- Markers function was used to calculate the differentially expressed genes in each cell subgroup, and the genes in the promising set were uploaded to the DAVID database to analyze the biological processes to which these genes were enriched. Differentially expressed genes among macrophage subgroups were selected by the AverageExpression function. Then, the CIBERSORT algorithm was used to compute the proportion of each macrophage subgroup in each bulk tissue and determine the most significant macrophage subgroup. The dynamic changes of gene expression in macrophage subgroup were computed by Pseudotime. Finally, CellChat was applied to investigate the effect of the macrophage subgroup on epithelial cells and the ligand-receptor effect of B cells and T cells. Clustering scRNA-seq data showed a larger proportion of macrophages in liver metastases. The proportion of MMP12+ macrophage subtypes increased gradually among normal, tumor, and liver metastasis groups, and MMP12+ macrophages were associated with angiogenesis, cell migration, and inhibited T cell proliferation. The Pseudotime showed higher expression levels of genes related to angiogenesis and enhanced TGF-β signaling pathway and the negative regulation of T cell proliferation with the occurrence of liver metastasis in MMP12+ macrophages. MMP12+ macrophages can promote the proliferation of epithelial cells and inhibit the activation of T cells and B cells. MMP12+ macrophages promoted liver metastasis of CRC by influencing angiogenesis, TGF-β signaling pathway expression, and regulation of T cells and B cells.

Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating epithelial-mesenchymal transition.

Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunotherapy. However, there is currently a lack of comprehensive investigation into how senescent and exhausted immune cells contribute to LM. We gathered single-cell sequencing data from primary colorectal cancer (pCRC) and their corresponding matched LM tissues from 16 mCRC patients. In this study, we identified senescent and exhausted immune cells, performed enrichment analysis, cell communication, cell trajectory, and cell-based in vitro experiments to validate the results of single-cell multi-omics. This process allowed us to construct a regulatory network explaining the occurrence of LM. Finally, we utilized weighted gene co-expression network analysis (WGCNA) and 12 machine learning algorithms to create prognostic risk model. We identified senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) as the primary senescent and exhausted immune cells. Our findings indicate that SMCs and TEXs can potentially activate transcription factors downstream via ANGPTL4-SDC1/SDC4, this activation plays a role in regulating the epithelial-mesenchymal transition (EMT) program and facilitates the development of LM, the results of cell-based in vitro experiments have provided confirmation of this conclusion. We also developed and validated a prognostic risk model composed of 12 machine learning algorithms. This study elucidates the potential molecular mechanisms underlying the occurrence of LM from various angles through single-cell multi-omics analysis in CRC. It also constructs a network illustrating the role of senescent or exhausted immune cells in regulating EMT.

Immune function status of postoperative patients with colon cancer for predicting liver metastasis.

Colon cancer (CC) has a high incidence rate. Radical resection is the main treatment method for CC; however, liver metastasis (LM) often occurs post-surgery. The liver contains both innate and adaptive immune cells that monitor and remove abnormal cells and pathogens. Before LM, tumor cells secrete cytokines and exosomes to adjust the immune microenvironment of the liver, thus forming an inhibitory immune microenvironment for colonization by circulating tumor cells. This indicates that the immune state of patients with CC plays a crucial role in the occurrence and progression of LM. To observe and analyze the relationship between immune status and expression of tumor factors in patients with LM of CC, and to provide a scientific intervention method for promoting the patient prognosis. A retrospective analysis was performed. The baseline data of 100 patients with CC and 100 patients with CC who suffered from postoperative LM and were admitted to our hospital from May 2021 to May 2023 were included in the non-occurrence and occurrence groups, respectively. The immune status of the patients and the expression of tumor factor-related indicators in the two groups were compared, and the predictive value of the indicators for postoperative LM in patients with CC was analyzed. Compared with the non-occurrence group, the expression of serum carcinoembryonic antigen (CEA), CA19-9, CA242, CA72-4 and CA50 in patients in the occurrence group were significantly higher, while the expression of CD3+, CD4+, CD8+, natural killer (NK) and CD4+/CD25 in patients in the occurrence group were significantly lower (P < 0.05). No significant difference was observed in other baseline data between groups (P > 0.05). Multivariate logistic regression model analysis revealed that the expressions of CEA, CA19-9, CA242, CA72-4, CA50, CD3+, CD4+, CD8+, NK, and CD4+/CD25 were associated with the LM in patients with CC. High expressions of serum CEA, CA19-9, CA242, CA72-4 and CA50, and low expressions of CD3+, CD4+, CD8+, NK, and CD4+/CD25 in patients with CC were risk factors for LM (OR > 1, P < 0.05). The receiver operating characteristic curve showed that the area under curve for CEA, CA19-9, CA242, CA72-4, CA50, CD3+, CD4+, CD8+, NK, and CD4+/CD25 in the prediction of LM in patients with CC were all > 0.80, with a high predictive value. The expression of tumor factors and immune state-related indices in patients with CC is closely associated with the occurrence of LM.

The Influence of Alpha Kinase 2 Expression on Prognosis in Serous Ovarian Cancer Liver Metastasis

Background. Globally, ovarian cancer is a leading contributor to cancer-related fatalities among women, with a notable concern being the occurrence of liver metastasis as a prevalent clinical complication. This study aims to investigate the potential impact of alpha kinase 2 (ALPK2) on ovarian cancer liver metastasis (OCLM), assessing its implications for patient prognosis and tumor advancement. Our research seeks to examine the prognostic significance of ALPK2 in individuals with OCLM and unravel the consequences of ALPK2 knockdown on the proliferation and invasion of ovarian cancer cells. Methods. A retrospective analysis of 49 OCLM cases from our medical center was conducted to evaluate the prognostic significance of ALPK2 through survival analyses. Experimental investigations involved the use of shRNA to knock down ALPK2 in ovarian cancer cell lines, with subsequent scrutiny of cellular changes. Results. Survival analyses revealed that ALPK2 functions as an independent adverse prognostic factor in OCLM (HR = 3.74, 95% CI: 1.34–10.42, and P=0.012). Knockdown experiments indicated a reduction in cell proliferation and invasion capacities, potentially associated with the epithelial-mesenchymal transition process. Conclusions. ALPK2 emerges as a crucial oncogene promoting tumors in OCLM. Its knockdown exhibits significant therapeutic potential by hindering cancer progression. Further investigations could solidify the role and therapeutic possibilities of ALPK2 in the treatment of ovarian cancer, particularly in cases involving liver metastasis.

Analysis of Related Risk Factors and Prognostic Factors of Gastric Cancer with Liver Metastasis: A SEER and External Validation Based Study.

Gastric cancer (GC) has a poor prognosis, particularly in patients with liver metastasis (LM). This study aims to identify relevant factors associated with the occurrence of LM in GC patients and factors influencing the prognosis of gastric cancer with liver metastasis (GCLM) patients, in addition to developing diagnostic and prognostic nomograms specifically. Overall, 6184 training data were from the Surveillance, Epidemiology, and End Results (SEER) database from 2011 to 2015. 1527 validation data were from our hospital between January 2018 and December 2022. Logistic regression was used to identify the risk factors associated with the occurrence of LM in GC patients, Cox regression was used to confirm the prognostic factors of GCLM patients. Two nomogram models were established to predict the risk and overall survival (OS) of patients with GCLM. The performance of the two models was evaluated using the area under the curve (AUC), concordance index (C-index), and calibration curves. A nomogram included five independent factors from multivariate logistic regression: sex, lymph node removal, chemotherapy, T stage and N stage were constructed to calculate the possibility of LM. Internal and external verifications of AUC were 0.786 and 0.885, respectively. The other nomogram included four independent factors from multivariate Cox regression: surgery at primary site, surgery at other site, chemotherapy, and N stage were constructed to predict OS. C-index for internal and external validations were 0.714 and 0.702, respectively, and the calibration curves demonstrated the robust discriminative ability of the models. Based on the SEER database and validation data, we defined effective nomogram models to predict risk and OS in patients with GCLM. They have important value in clinical decision-making and personalized treatment.

The combination of phosphoinositol with inositol suppresses colorectal cancer growth and metastasis by regulating CLDN23/ RhoA /ROCK1 pathway

Colorectalcancerisa prevalentmalignanttumor, with liver metastases being the primary cause of death. The combination of inositol hexaphosphate (IP6) and inositol (INS) has been shown to inhibit colorectal cancer metastasis.We identified a correlation between CLDN23 expression and the occurrence of liver metastases in colorectal cancer patients. Following the transfection with the lentiviral vector (LV-CLDN23-RNAi), proteomic analysis of SW620 revealed significant alterations in the occludin, ZO-1, RhoA, and ROCK-1 genes expression by western blotting. We found that both SW620 and SW480 cells showed inhibited proliferation, invasion, and migration ability after the treatment with IP6 and INS. Additionally, this combination upregulated occludin and ZO-1, while downregulated CLDN23, RhoA, ROCK-1, and p-MLC2. In conclusion, the combination of IP6 and INS suppressed the proliferation, invasion, and migration of colorectal cancer cells and regulated CLDN23 expression by enhancing tightjunction proteins, such as occludin and ZO1, via the RhoA /ROCK1 pathway.

Effect of liver metastasis on the efficacy of immune checkpoint inhibitors in cancer patients: a systemic review and meta-analysis.

Liver metastasis is a frequent phenomenon in advanced tumor disease. Immune checkpoint inhibitors (ICIs) are a new class of therapeutics that can improve the prognosis of cancer patients. The purpose of this study is to elucidate the relationship between liver metastasis and survival outcomes of patients receiving ICIs treatment. We searched four main databases, including PubMed, EMBASE, Cochrane Library, and Web of Science. Overall survival (OS) and progression-free survival (PFS) were the survival outcomes of our concern. Hazard ratio (HR) with 95% confidence interval (CI) were used to evaluate the relationship between liver metastasis and OS/ PFS. Finally, 163 articles were included in the study. The pooled results showed that patients with liver metastasis receiving ICIs treatment had worse OS (HR=1.82, 95%CI:1.59-2.08) and PFS (HR=1.68, 95%CI:1.49-1.89) than patients without liver metastasis. The effect of liver metastasis on ICIs efficacy differed in different tumor types, and patients with urinary system tumors (renal cell carcinoma OS: HR=2.47, 95%CI:1.76-3.45; urothelial carcinoma OS: HR=2.37, 95%CI:2.03-2.76) had the worst prognosis, followed by patients with melanoma (OS: HR=2.04, 95%CI:1.68-2.49) or non-small cell lung cancer (OS: HR=1.81, 95%CI:1.72-1.91). ICIs efficacy in digestive system tumors (colorectal cancer OS: HR=1.35, 95%CI:1.07-1.71; gastric cancer/ esophagogastric cancer OS: HR=1.17, 95%CI:0.90-1.52) was less affected, and peritoneal metastasis and the number of metastases have a greater clinical significance than liver metastasis based on univariate data. For cancer patients receiving ICIs treatment, the occurrence of liver metastasis is associated with poor prognosis. Different cancer types and metastatic sites may hold a different prognostic effect on the efficacy of ICIs treatment in cancer patients.

Two machine learning-based nomogram to predict risk and prognostic factors for liver metastasis from pancreatic neuroendocrine tumors: a multicenter study

BackgroundPancreatic neuroendocrine tumors (PNETs) are one of the most common endocrine tumors, and liver metastasis (LMs) are the most common location of metastasis from PNETS; However, there is no valid nomogram to predict the diagnosis and prognosis of liver metastasis (LMs) from PNETs. Therefore, we aimed to develop a valid predictive model to aid physicians in making better clinical decisions.MethodsWe screened patients in the Surveillance, Epidemiology, and End Results (SEER) database from 2010–2016. Feature selection was performed by machine learning algorithms and then models were constructed. Two nomograms were constructed based on the feature selection algorithm to predict the prognosis and risk of LMs from PNETs. We then used the area under the curve (AUC), receiver operating characteristic (ROC) curve, calibration plot and consistency index (C-index) to evaluate the discrimination and accuracy of the nomograms. Kaplan-Meier (K-M) survival curves and decision curve analysis (DCA) were also used further to validate the clinical efficacy of the nomograms. In the external validation set, the same validation is performed.ResultsOf the 1998 patients screened from the SEER database with a pathological diagnosis of PNET, 343 (17.2%) had LMs at the time of diagnosis. The independent risk factors for the occurrence of LMs in PNET patients included histological grade, N stage, surgery, chemotherapy, tumor size and bone metastasis. According to Cox regression analysis, we found that histological subtype, histological grade, surgery, age, and brain metastasis were independent prognostic factors for PNET patients with LMs. Based on these factors, the two nomograms demonstrated good performance in model evaluation.ConclusionWe developed two clinically significant predictive models to aid physicians in personalized clinical decision-makings.

Molecular mechanism and potential therapeutic targets of liver metastasis from gastric cancer.

Gastric cancer (GC) is characterized by high invasion and poor prognosis. The occurrence of liver metastasis seriously affects advanced GC prognosis. In recent years, great progress has been made in the field of GC liver metastasis. The abnormal expression of related genes leads to the occurrence of GC liver metastasis through metastasis cascades. The changes in the liver microenvironment provide a pre-metastasis condition for GC cells to colonize and grow. The development of several potential therapeutic targets might provide new therapeutic strategies for its treatment. Therefore, we reviewed the regulatory mechanism of abnormal genes mediating liver metastasis, the effect of liver resident cells on liver metastasis, and potential therapeutic targets, hoping to provide a novel therapeutic option to improve the quality of life and prognosis of GC patients with liver metastasis.

Evaluating the outcomes of liver‐first approach for liver metastases due to colorectal cancer: A systematic review and meta‐analysis

AbstractPurposeSurgery is the mainstay treatment for colorectal cancer and offers a long‐term survival benefit for patients with liver metastases; however, the appropriate approach remains debatable. We aimed to systematically review and perform a meta‐analysis of liver‐first and classical (colon‐first) approaches.MethodsThe following electronic databases were searched for systematic literature: PubMed and the Cochrane Library. Studies that compared patients with liver metastases due to colorectal cancer and who underwent liver‐first and classical resections were selected. Primary outcomes were long‐term overall survival and disease‐free survival, and secondary outcomes were perioperative morbidity and mortality.ResultsOver 12 studies with 6344 patients were analysed; of the total patients, 1141 and 4552 underwent liver‐first resection and classical resection, respectively. The meta‐analysis showed no significant difference between the liver‐first resection group and classical resection group in terms of overall morbidity (risk ratio [RR] 1.26, 95% confidence interval [CI] 0.91‐1.74) and 90‐day mortality (RR 1.26, 95% CI 0.52‐3.04, P = .23). The classical resection group showed favourable overall survival and disease‐free survival than the liver‐first resection group in the nonpropensity score‐matched studies (RR 1.19, 95% CI 1.09‐1.3) but showed comparable results in the propensity score‐matched studies (RR 1.07, 95% CI 0.97‐1.18).ConclusionsThe perioperative and long‐term outcomes of the liver‐first and classical approaches were comparable. Selection of the appropriate approach that will be used for a patient depends on the characteristics of the primary colorectal tumour and the occurrence of liver metastases.

Identification of DNA methylation biomarkers for risk of liver metastasis in early-stage colorectal cancer

BackgroundLiver metastases can occur even in CRC patients who underwent curative surgery. While evidence suggested that adjuvant chemotherapy can help to reduce the occurrence of liver metastases for certain patients, it is not a recommended routine as the side effects outweigh the potential benefits, especially in Stage II CRC patients. This study aims to construct a model for predicting liver metastasis risk using differential methylation signals in primary CRC tumors, which can facilitate the decision for adjuvant chemotherapy.MethodsFifty-nine stage I/II and IV CRC patients were enrolled. Primary tumor, adjacent normal tissue, and metastatic tumor tissues were subject to targeted bisulfite sequencing for DNA methylation. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was used to identify potential DMRs for predicting liver metastasis of CRC.ResultsWe identified a total of 241,573 DMRs by comparing the DNA methylation profile of primary tumors of stage II patients who developed metastasis to those who were metastasis-free during the follow up period. 213 DMRs were associated with poor prognosis, among which 182 DMRS were found to be hypermethylated in the primary tumor of patients with metastases. Furthermore, by using the LASSO regression model, we identified 23 DMRs that contributed to a high probability of liver metastasis of CRC. The leave-one-out cross validation (LOOCV) was used to evaluate model predictive performance at an AUC of 0.701. In particular, 7 out of those 23 DMRs were found to be in the promoter region of genes that were previously reported prognostic biomarkers in diverse tumor types, including TNNI2, PAX8, GUF1, KLF4, EVI2B, CEP112, and long non-coding RNA AC011298. In addition, the model was also able to distinguish metastases of different sites (liver or lung) at an AUC of 0.933.ConclusionWe have identified DNA methylation biomarkers associated with the risk of cancer liver metastasis in early-stage CRC patients. A risk prediction model based on those epigenetic markers was proposed for outcome assessment.

The Effect of Diffuse Liver Diseases on the Occurrence of Liver Metastases in Cancer Patients: A Systematic Review and Meta-Analysis.

Simple SummaryDiffuse liver diseases have a high incidence among the general population and even higher in patients with a solid cancer. Since many patients with a solid tumor die of liver metastases, the aim of this systematic review of the literature was to explore the correlation between diffuse liver diseases and the risk of having liver metastases at diagnosis or during follow-up. To summarize the results of included studies, a meta-analysis was also conducted. The results of our systematic review should encourage the research community to further investigate the complex relationship between the liver’s microscopic environment and metastases, which may also affect prognosis and response to therapy.This systematic review with meta-analysis aimed to assess the effect of diffuse liver diseases (DLD) on the risk of synchronous (S-) or metachronous (M-) liver metastases (LMs) in patients with solid neoplasms. Relevant databases were searched for systematic reviews and cross-sectional or cohort studies published since 1990 comparing the risk of LMs in patients with and without DLD (steatosis, viral hepatitis, cirrhosis, fibrosis) in non-liver solid cancer patients. Outcomes were prevalence of S-LMs, cumulative risk of M-LMs and LM-free survival. Risk of bias (ROB) was assessed using the Newcastle-Ottawa Scale. We report the pooled relative risks (RR) for S-LMs and hazard ratios (HR) for M-LMs. Subgroup analyses included DLD, primary site and continent. Nineteen studies were included (n = 37,591 patients), the majority on colorectal cancer. ROB appraisal results were mixed. Patients with DLD had a lower risk of S-LMs (RR 0.50, 95% CI 0.34–0.76), with a higher effect for cirrhosis and a slightly higher risk of M-LMs (HR 1.11 95% CI, 1.03–1.19), despite a lower risk of M-LMs in patients with vs without viral hepatitis (HR 0.57, 95% CI 0.40–0.82). There may have been a publication bias in favor of studies reporting a lower risk for patients with DLD. DLD are protective against S-LMs and slightly protective against M-LMs for viral hepatitis only.

Abstract 2443: miR-146a methylation regulates proliferation and metastasis by targeted activation of VASN/TGF-beta signaling pathway in colorectal cancer

Abstract Tumor specific alterations in miRNA provide ideal biomarkers for early diagnosis of colorectal cancer(CRC). Methylation changes play an important role in the miRNA regulation mechanism involved in tumorigenesis. Therefore, it is important to find miRNA methylation markers related to tumor proliferation and metastasis, and to explore its key regulatory mechanisms. Previous integrated bioinformatics analysis suggested that reduced expression and hypermethation of miR-146a have detected in majority of CRC. However, its biological behavior in CRC remains unclear. This article aims to explore its epigenetic regulation and mechanism in the development of CRC. We collected peripheral blood and tissues from 60 patients with advanced primary CRC, analyzed their clinicopathological characteristics. The mRNA and methylation difference was detected by qPCR and MSP respectively, and the significance in the diagnosis of CRC was analyzed. The research was further confirmed in SW480, SW620, HCT116 and HT29 CRC cell lines, as well as CRC animal models treated with demethylated drugs–5-aza-miR2-oxyeytidineine(5-AZA) and various gene transfection, in order to explore the key downstream regulatory network of miR-146a methylation changes and the effect of methylation inhibitors in the development of CRC. We found that the percentage of down-regulated and methylation of miR-146a in both tissues and plasmas of CRC was significantly higher than that of normal samples, and the expression of miR-146a could be recovered after demethylation treatment in cancer, which was associated with clinical stage. miR-146a methylation was significantly correlated with grading, but not gender, tumor location, histological type or TNM, it may be used as a predictor of poor prognosis. Diagnostic evaluation of miR-146a methylation in tissue and plasma was evaluated using ROC curve, area under regional curve, which indicated that miR-146a methylation could be used as a biomarker for the diagnosis of CRC. Fluorescein report system showed that miR-146a targeted VASN protein, and while miR-146a was overexpressed after transfection into CRC cells, the expression levels of VASN, TGF-β, VEGF-C, MMP9, and Vimentin were significantly reduced, while the expression of TIMP1 and Ecadherin were up-regulated. Additionally, the miR-146a mRNA in CRC tissues was also negatively correlated with the expression of VASN. VASN Silencing down-regulated TGF-β expression, accompanied by a decrease of MMP9. At the same time, after 5-aza demethylation or siVASN, proliferation activity of CRC cells decreased, accompanied by varying degrees of decline in membrane penetrating and migration ability, suggesting that miR-146a may regulate the proliferation and metastasis by regulating VASN/TGF-β relatived pathway. In vivo animal models, it was further confirmed that overexpressed miR-146a was consistent with the effect of 5-aza intervention or siVASN, which could significantly inhibit the occurrence of liver metastasis of CRC. Demethylated drugs treatment or VASN knockdown also significantly inhibited tumor growth in nude mice with CRC. miR-146a was a potential epigenetic silencing tumor suppressor in CRC, and the methylation of miR-146a may play an important role in the diagnosis and prediction of tumor progression in CRC as a new tumor marker. Citation Format: Weiwei Tang, Dan Zhou, Hanxiang An, Jiapeng Kang, Mingquan Cai, Ru Zeng, Jing Song, Bin Hu, Jiabian Lian, Qin Lin, Lilin Chen, Feng Ye. miR-146a methylation regulates proliferation and metastasis by targeted activation of VASN/TGF-beta signaling pathway in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2443.

Circular RNA hsa_circRNA_102209 promotes the growth and metastasis of colorectal cancer through miR-761-mediated Ras and Rab interactor 1 signaling.

In our study, has_circRNA_102209 was the most elevated regulator in colorectal cancer (CRC) tissues according to circRNA array data. The levels of hsa_circRNA_102209 in CRC specimens and cells, as well as its effects on CRC cells were investigated. The expression of hsa_circRNA_102209 in CRC and paired non‐cancerous samples, human CRC, and normal colonic epithelial cells were examined using reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR). Cells with hsa_circRNA_102209 knockdown were established using lentiviral vectors. Cell proliferative ability was evaluated using CCK‐8 assay; cell migrative/invasive activities were determined using wound healing/Transwell assay. Cell cycle arrest and apoptosis were assessed by flow cytometry; apoptosis, and EMT markers were examined using RT‐qPCR and western blotting. Tumor development and levels of associated proteins were determined in hsa_circRNA_102209 knockdown mice. Our results revealed that expression of hsa_circRNA_102209 was remarkably increased in CRC tissues, where the levels of miR‐761 were notably reduced (P < .05). Additionally, the levels of hsa_circRNA_102209 were associated with histology grade and occurrence of liver metastasis in CRC patients, and the expression of hsa_circRNA_102209 and miR‐761 were negatively correlated (P < .05). Moreover, hsa_circRNA_102209 was upregulated in CRC cells compared with normal colonic epithelial cells. Knockdown of hsa_circRNA_102209 notably inhibited the proliferation, migration, invasion, and EMT of CRC cells (P < .05), whereas cell cycle arrest at G0/G1 phase and apoptosis were enhanced (P < .05). Furthermore, miR‐761/Ras and Rab interactor 1 (RIN1) axis was the putative target of hsa_circRNA_102209 in CRC and involved in hsa_circRNA_102209‐modulated growth and metastasis of CRC cells (P < .05). Knockdown of hsa_circRNA_102209 also remarkably suppressed tumor growth in vivo (P < .05). In summary, our data revealed that the expression of hsa_circRNA_102209 was elevated in CRC samples and cells. Furthermore, hsa_circRNA_102209 could promote the progression of CRC through miR‐761/RIN1 axis. More importantly, hsa_circRNA_102209/miR‐761/RIN1 signaling may be a novel therapeutic target for the treatment of CRC patients.

Clinical Features and Prognosis of Merkel Cell Carcinoma in Elderly Patients.

BackgroundMerkel cell carcinoma (MCC) occurs primarily among elderly patients over 70 years old, but the ability to predict the prognosis of these elderly patients is poor. This population-based study aimed to identify prognostic risk factors for elderly patients with MCC.Material/MethodsThe survival and disease information of MCC patients age 65 years or older was downloaded from the SEER database, and all data were split into 2 groups based on age 80 years, with overall survival and MCC-specific survival as the main outcome indicators.ResultsApplication of the inclusion criteria yielded 1973 patients with MCC, of whom 55.6% were age 65–80 years. Among them, 1258 were males, accounting for 63.8%. In survival analysis, factors that were significantly correlated with overall survival and MCC-specific survival were N stage, M stage, liver metastasis, and lymph node surgery.ConclusionsWe provide epidemiological insights into Merkel cell carcinoma in elderly patients and confirmed that patients receiving lymph node surgery have better outcomes. To the best of our knowledge, this is the first study to show that the occurrence of liver metastasis is associated with poor prognosis. Our results will help strengthen monitoring of the liver condition of elderly patients and to perform necessary lymph node surgery within the patient’s tolerance.

Prognostic meaning of tissue inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2 in patients with colorectal cancer

The aim of this study was to analyze TIMP-1 and TIMP-2 serum levels in patients with colorectal cancer (CRC) and to correlate the results with the pathological stage of the disease and outcome in order to evaluate the role of TIMP-1 and TIMP-2 serum levels as prognostic markers. The investigation has been made on 82 patients with operable CRC without distant metastases, who had undergone blood tests in order to determine the TIMP-1 and TIMP-2 serum levels in the following points of time: preoperatively, as well as 3, 6, 9 and 12 months postoperatively. Significant differences were found between serum levels of TIMP-1 and TIMP-2 obtained preoperatively and postoperatively, as well as significant association of serum TIMP-1 levels obtained preoperatively in CRC patients in stage I and III, in the 3th and in the 6th month (p&lt;0.001) postoperatively as defined points of time with the outcome of CRC patients. Serum TIMP-2 levels obtained preoperatively was significantly associated with the outcome of the CRC patients. Analysis of the obtained TIMP-1 and TIMP-2 serum levels in CRC patients showed statistically significant differences with: disease progression, occurrence of liver metastasis, prior to and post chemotherapy treatment. The results derived a conclusion that the serum levels of TIMP-1 and TIMP-2 could be indicators for occurrence and progression of CRC, as well as valuable and useful markers for following the effects of chemotherapy treatment. Keywords: colorectal cancer, TIMP-1, TIMP-2, prognosis

The Role of PEDF in Pancreatic Cancer.

Pigment epithelium-derived factor (PEDF) is an important antiangiogenic and antitumorigenic factor in a variety of cancer forms, including pancreatic cancer. PEDF is mainly secreted as a soluble monomeric glycoprotein. In human pancreatic cancer PEDF levels are decreased, both in the tissue and serum. The decrease is associated with increased tumor angiogenesis, fibrosis, inflammation, autophagy, occurrence of liver metastasis and worse prognosis. In murine models, loss of PEDF is sufficient to induce invasive carcinoma and this phenotype is associated with large lesions characterized by poor differentiation. Lentiviral gene transfer of PEDF has resulted in decreased microvessel density and has inhibited tumor growth. Herein we review the multifunctional role of PEDF in pancreatic cancer and its therapeutic potential.

Cisplatin shows greater efficacy than gemcitabine when combined with nab-paclitaxel in metastatic triple-negative breast cancer

Our study aimed to compare the efficacy and safety of nab-paclitaxel plus cisplatin (AP) with nab-paclitaxel plus gemcitabine (AG) in patients with metastatic breast cancer (MBC). We collected data from two single-arm, phase II MBC studies. In NCT01149798, seventy-three MBC patients received 125 mg/m2 nab-paclitaxel on days 1, 8 and 15 followed by 75 mg/m2 cisplatin on day 1 of a 28-day cycle. In NCT01550848, eighty-four MBC patients received 125 mg/m2 nab-paclitaxel and 800 mg/m2 gemcitabine on days 1, 8, and 15 of a 28-day cycle. The endpoints were the overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety profiles of these regimens. Among the 157 patients included, the ORR were 67.1% and 52.4% for the AP and AG arms, respectively (odds ratio [OR] = 0.246; hazard ratio [HR] = 1.485; 95% confidence interval [CI], 0.762–2.985). After median follow-up periods of 26.3 and 23.3 months in the AP and AG arms, the median PFS were 9.8 months (95%CI, 8.1–11.6) and 8.1 months (95%CI, 6.8–9.4), respectively, while the median OS were 26.9 months (95%CI, 22.4–31.4) and 25.5 months (95%CI, 19.3–31.4), respectively. Neither PFS nor OS adjusted for the number of metastases, occurrence of liver metastasis and chemotherapeutic lines differed significantly between the two arms (PFS:HR = 0.769; 95%CI, 0.541–1.092; p = 0.142; OS:HR = 0.686; 95%CI, 0.426–1.104; p = 0.120). However, PFS was significantly better with AP than with AG in metastatic triple-negative breast cancer (mTNBC) patients (HR = 0.308; 95%CI, 0.129–0.732; p = 0.008). Adverse events were more common with AP than with AG, except for edema and myalgia. Both regimens showed substantial efficacy and were tolerated well in MBC patients. mTNBC who received AP rather than AG showed longer PFS. However, adverse events were more common with AP. Thus, AP may be worth recommending to mTNBC, while AG may be a better alternative for MBC patients with other subtypes.

Role and mechanism of macrophages modulating the liver microenvironment in digestive tract malignancies liver metastasis

Macrophagses are important components of the liver microenvironment, and play an essential role in the occurrence and development of liver metastasis of digestive system malignancies. Macrophages and liver sinusoidal endothelial cells constitute the first defense line of the liver, which can rapidly recognize and arrest the circulating tumor cells invading into the liver sinusoidal, by phagocytosis or promoting their apoptosis, thus play a cytotoxic effect to inhibit the occurrence of liver metastases. On the other hand, macrophages can combine to the circulating tumor cells and be activated. As a result, hepatocyte growth factor and other cytokines were released, which significantly promoted the proliferation of tumors cells, and thus promoting liver metastases. It may provide a new idea in preventing and treating liver metastasis of digestive system malignancies by targeting macrophages during tumor immunotherapy. Key words: Macrophages; Neoplasm metastasis; Tumor microenvironment

A Pathway to Personalizing Therapy for Metastases Using Liver-on-a-Chip Platforms.

Metastasis accounts for most cancer-related deaths. The majority of solid cancers, including those of the breast, colorectum, prostate and skin, metastasize at significant levels to the liver due to its hemodynamic as well as tumor permissive microenvironmental properties. As this occurs prior to detection and treatment of the primary tumor, we need to target liver metastases to improve patients' outcomes. Animal models, while proven to be useful in mechanistic studies, do not represent the heterogeneity of human population especially in drug metabolism lack proper human cell-cell interactions, and this gap between animals and humans results in costly and inefficient drug discovery. This underscores the need to accurately model the human liver for disease studies and drug development. Further, the occurrence of liver metastases is influenced by the primary tumor type, sex and race; thus, modeling these specific settings will facilitate the development of personalized/targeted medicine for each specific group. We have adapted such all-human 3D ex vivo hepatic microphysiological system (MPS) (a.k.a. liver-on-a-chip) to investigate human micrometastases. This review focuses on the sources of liver resident cells, especially the iPS cell-derived hepatocytes, and examines some of the advantages and disadvantages of these sources. In addition, this review also examines other potential challenges and limitations in modeling human liver.