CD206 modulates the role of M2 macrophages in the origin of metastatic tumors.

Tumor metastasis is a key factor affecting the life of patients with malignant tumors. For the past hundred years, scientists have focused on how to kill cancer cells and inhibit their metastasis in vivo, but few breakthroughs have been made. Here we hypothesized a novel mode for cancer metastasis. We show that the phagocytosis of apoptotic tumor cells by macrophages leads to their polarization into the M2 phenotype, and that the expression of stem cell related as well as drug resistance related genes was induced. Therefore, it appears that M2 macrophages have "defected" and have been transformed into the initial "metastatic cancer cells", and thus are the source, at least in part, of the distal tissue tumor metastasis. This assumption is supported by the presence of fused cells with characteristics of both macrophage and tumor cell observed in the peripheral blood and ascites of patients with ovarian cancer. By eliminating the expression of CD206 in M2 macrophages using siRNA, we show that the growth and metastasis of tumors was suppressed using both in vitro cell line and with experimental in vivo mouse models. In summary, we show that M2 macrophages in the blood circulation underwent a "change of loyalty" to become "cancer cells" that transformed into distal tissue metastasis, which could be suppressed by the knockdown of CD206 expression.

Neoadjuvant chemotherapy-induced remodeling of human hormonal receptor-positive breast cancer revealed by single-cell RNA sequencing.

Hormone receptor-positive breast cancer (HR+ BC) is known to be relatively insensitive to chemotherapy, and since chemotherapy has remained the major neoadjuvant therapy for HR+ BC, the undetermined mechanism of chemoresistance and how chemotherapy reshapes the immune microenvironment need to be explored by high-throughput technology. By using single-cell RNA sequencing and multiplexed immunofluorescence staining analysis of HR+ BC samples (paired pre- and post-neoadjuvant chemotherapy (NAC)), the levels of previously unrecognized immune cell subsets, including CD8+ T cells with pronounced expression of T-cell development (LMNA) and cytotoxicity (FGFBP2) markers, CD4+ T cells characterized by proliferation marker (ATP1B3) expression and macrophages characterized by CD52 expression, were found to be increased post-NAC, which were predictive of chemosensitivity and their antitumor function was also validated with in vitro experiments. In terms of immune checkpoint expression of CD8+ T cells, we found their changes were inconsistent post-NAC, that LAG3, VSIR were decreased, and PDCD1, HAVCR2, CTLA4, KLRC1 and BTLA were increased. In addition, we have identified novel genomic and transcriptional patterns of chemoresistant cancer cells, both innate and acquired, and have confirmed their prognostic value with TCGA cohorts. By shedding light on the ecosystem of HR+ BC reshaped by chemotherapy, our results uncover valuable candidates for predicting chemosensitivity and overcoming chemoresistance in HR+ BC.

CD95 promotes stemness of colorectal cancer cells by lncRNA MALAT1.

Colorectal cancer (CRC) is the second most fatal cancer. Many studies have shown that cancer stemness contributes to resistance to conventional chemotherapy and poor prognosis. However, the mechanisms involved in maintaining cancer stemness in CRC are still obscure and few clinical drugs were used to target cancer stemness. Previous studies had reported CD95 increases the stemness of cancer cells with long-term stimulation of exogenous agonist CD95 ligand (CD95L). However, the expression of CD95L is relative low in certain human tumor tissues. In this study, we found that CD95 was highly expressed in CRC cells, and in vitro it promoted the tumorsphere formation, chemotherapy resistance and in vivo tumor growth without stimulation of exogenous CD95L. Mechanistically, the bulk and single-cell RNA-sequencing results suggested that CD95 promotes stemness of CRC cells through upregulation of long non-coding RNAs metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1). MALAT1 knockdown inhibited CD95-induced tumorsphere formation and chemotherapy resistance. In summary, our findings reveal that CD95 has the capability to modulate cancer stemness via the action of the lncRNA MALAT1. Targeting CD95 may be a promising strategy to inhibit cancer stemness in CRC.

Integrated transcriptomics, proteomics, and functional analysis to characterize the tissue-specific small extracellular vesicle network of breast cancer.

Small extracellular vesicles (sEVs) are essential mediators of intercellular communication within the tumor microenvironment (TME). Although the biological features of sEVs have been characterized based on in vitro culture models, recent evidence indicates significant differences between sEVs derived from tissue and those derived from in vitro models in terms of both content and biological function. However, comprehensive comparisons and functional analyses are still limited. Here, we collected sEVs from breast cancer tissues (T-sEVs), paired normal tissues (N-sEVs), corresponding plasma (B-sEVs), and tumor organoids (O-sEVs) to characterize their transcriptomic and proteomic profiles. We identified the actual cancer-specific sEV signatures characterized by enriched cell adhesion and immunomodulatory molecules. Furthermore, we revealed the significant contribution of cancer-associated fibroblasts in the sEV network within the TME. In vitro model-derived sEVs did not entirely inherit the extracellular matrix- and immunity regulation-related features of T-sEVs. Also, we demonstrated the greater immunostimulatory ability of T-sEVs on macrophages and CD8+ T cells compared to O-sEVs. Moreover, certain sEV biomarkers derived from noncancer cells in the circulation exhibited promising diagnostic potential. This study provides valuable insights into the functional characteristics of tumor tissue-derived sEVs, highlighting their potential as diagnostic markers and therapeutic agents for breast cancer.

CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer.

PURPOSE: Axillary lymph nodes (LN) are the primary and dominant metastatic sites in breast cancer. However, the interaction between tumor cells and immune cells within metastatic LNs (mLN) remains poorly understood. In our study, we explored the effect of CD24hiCD27+ regulatory B cells (Breg) within mLNs on orchestrating drug resistance of breast cancer cells. EXPERIMENTAL DESIGN: We collected mLN samples from patients with breast cancer who had received standard neoadjuvant therapy (NAT) and analyzed the spatial features of CD24hiCD27+ Bregs through multicolor immunofluorescence staining. The effect of CD24hiCD27+ Bregs on drug resistance of breast cancer cells was evaluated via in vitro experiments. A mouse model with mLNs was used to evaluate the strategies with blocking the interactions between Bregs and breast cancer for improving tumor regression within mLNs. RESULTS: In patients with breast cancer who had received NAT, there is a close spatial correlation between activated CD24hiCD27+ Bregs and residual tumor cells within mLNs. Mechanistically, CD24hiCD27+ Bregs greatly enhance the acquisition of multidrug resistance and stem-like features of breast cancer cells by secreting IL6 and TNFα. More importantly, breast cancer cells further promote the activation of CD24hiCD27+ Bregs via CD40L-dependent and PD-L1-dependent proximal signals, forming a positive feedback pattern. PD-L1 blockade significantly attenuates the drug resistance of breast cancer cells induced by CD24hiCD27+ Bregs, and addition of anti-PD-L1 antibody to chemotherapy improves tumor cell remission in mLNs. CONCLUSIONS: Our study reveals the pivotal role of CD24hiCD27+ Bregs in promoting drug resistance by interacting with breast cancer cells in mLNs, providing novel evidence for an improved strategy of chemoimmunotherapy combination for patients with breast cancer with mLNs.

Development of a novel machine learning model based on laboratory and imaging indices to predict acute cardiac injury in cancer patients with COVID-19 infection: a retrospective observational study.

PURPOSE: Due to the increased risk of acute cardiac injury (ACI) and poor prognosis in cancer patients with COVID-19 infection, our aim was to develop a novel and interpretable model for predicting ACI occurrence in cancer patients with COVID-19 infection. METHODS: This retrospective observational study screened 740 cancer patients with COVID-19 infection from December 2022 to April 2023. The least absolute shrinkage and selection operator (LASSO) regression was used for the preliminary screening of the indices. To enhance the model accuracy, we introduced an alpha index to further screen and rank the indices based on their significance. Random forest (RF) was used to construct the prediction model. The Shapley Additive Explanation (SHAP) and Local Interpretable Model-Agnostic Explanation (LIME) methods were utilized to explain the model. RESULTS: According to the inclusion criteria, 201 cancer patients with COVID-19, including 36 variables indices, were included in the analysis. The top eight indices (albumin, lactate dehydrogenase, cystatin C, neutrophil count, creatine kinase isoenzyme, red blood cell distribution width, D-dimer and chest computed tomography) for predicting the occurrence of ACI in cancer patients with COVID-19 infection were included in the RF model. The model achieved an area under curve (AUC) of 0.940, an accuracy of 0.866, a sensitivity of 0.750 and a specificity of 0.900. The calibration curve and decision curve analysis showed good calibration and clinical practicability. SHAP results demonstrated that albumin was the most important index for predicting the occurrence of ACI. LIME results showed that the model could predict the probability of ACI in each cancer patient infected with COVID-19 individually. CONCLUSION: We developed a novel machine-learning model that demonstrates high explainability and accuracy in predicting the occurrence of ACI in cancer patients with COVID-19 infection, using laboratory and imaging indices.

Disulfiram reduces the severity of mouse acute pancreatitis by inhibiting RIPK1-dependent acinar cell necrosis.

Acute pancreatitis (AP) is a frequent abdominal inflammatory disease. Despite the high morbidity and mortality, the management of AP remains unsatisfactory. Disulfiram (DSF) is an FDA-proved drug with potential therapeutic effects on inflammatory diseases. In this study, we aim to investigate the effect of DSF on pancreatic acinar cell necrosis, and to explore the underlying mechanisms. Cell necrosis was induced by sodium taurocholate or caerulein, AP mice model was induced by nine hourly injections of caerulein. Network pharmacology, molecular docking, and molecular dynamics simulation were used to explore the potential targets of DSF in protecting against cell necrosis. The results indicated that DSF significantly inhibited acinar cell necrosis as evidenced by a decreased ratio of necrotic cells in the pancreas. Network pharmacology, molecular docking, and molecular dynamics simulation identified RIPK1 as a potent target of DSF in protecting against acinar cell necrosis. qRT-PCR analysis revealed that DSF decreased the mRNA levels of RIPK1 in freshly isolated pancreatic acinar cells and the pancreas of AP mice. Western blot showed that DSF treatment decreased the expressions of RIPK1 and MLKL proteins. Moreover, DSF inhibited NF-κB activation in acini. It also decreased the protein expression of TLR4 and the formation of neutrophils extracellular traps (NETs) induced by damage-associated molecular patterns released by necrotic acinar cells. Collectively, DSF could ameliorate the severity of mouse acute pancreatitis by inhibiting RIPK-dependent acinar cell necrosis and the following formation of NETs.

Ruthenium red attenuates acute pancreatitis by inhibiting MCU and improving mitochondrial function.

Acute pancreatitis (AP) is a common inflammatory disease of the digestive system. Mitochondrial calcium uniporter (MCU) mediates mitochondrial uptake of Ca2+ and plays an important role in calcium homeostasis. However, it is undefined whether AP can be relieved by inhibiting MCU. This study aimed to study the therapeutic potential of Ruthenium red (RuR), a MCU inhibitor, in AP mice model and primary acinar cells. Cell injury and AP mice model was induced by caerulein. RuR alleviated CER-AP evidenced by reduced serum lipase, TNF-α, and pancreatic MPO levels, less severe pancreatic pathology damage, and decreased inflammatory cell infiltration. In freshly isolated pancreatic acinar cells, RuR diminished cell necrosis with effect on suppressing the expression of MCU. RuR also decreased levels of cytosolic calcium and ROS, preventing mitochondrial membrane potential loss, ATP depletion and MPTP opening. The present findings indicate that inhibit MCU by RuR has a beneficial effect in AP by preventing calcium overload, mitochondrial dysfunction, and cell necrosis.

Changes of gut microbiota in colorectal cancer patients with Pentatrichomonas hominis infection.

Pentatrichomonas hominis is a parasitic trichomonads protozoa that parasitizes in the colon and cecum of humans and other animals. Our previous studies have demonstrated that infection with P. hominis is associated with the incidence of colon cancer (37.93%). However, the mechanism by which P. hominis infections increase the incidence of colon cancer remains unclear. Previous studies have suggested that certain parasites promote colon cancer by regulating gut microbiota. This study aimed to elucidate whether the association between P. hominis infections and the increased incidence of colon cancer is related to changes in gut microbiota. Therefore, the gut microbiota patients with colon cancer who were infected with P. hominis and uninfected patients with colon cancer were analyzed by 16S rRNA high-throughput sequencing. The results demonstrated that patients with colon cancer who were not infected with P. hominis showed increased gut bacterial diversity, a higher relative abundance of Alcaligenes sp., Leucobacter sp., Paraprevotella sp., Ruminococcaceae UCG-002, and a significant reduction in the abundance of Veillonella sp., compared to individuals without colon cancer. Additionally, the relative abundance of the Ruminococcaceae UCG-002 and the Eubacterium eligens groups was reduced, while the relative abundance of bacteria associated with colon cancer, including Flavonifractor sp., Lachnoclostridium sp., and the Ruminococcus gnavus group, increased significantly in patients with colon cancer who were infected with P. hominis, compared to those of uninfected patients with colon cancer. In conclusion, these results suggested that P. hominis infections may aggravate the development of colon cancer and the findings provide new insights for subsequent in-depth studies on the pathogenesis, diagnosis, and prevention of colon cancer.

A comprehensive comparison of circulating tumor cells and breast imaging modalities as screening tools for breast cancer in Chinese women.

Background: Circulating tumor cells (CTCs) have been recognized as a sensitive biomarker for breast cancer (BC). This study aimed to comprehensively compare CTC with imaging modalities, including ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging (MRI) in screening for BC in Chinese women. Methods: Three hundred forty-three participants were enrolled in this study, including 102 treatment-naive BC patients, 177 with breast benign diseases (BBD) and 64 healthy female patients. All participants underwent CTC testing and at least one of the following examinations, ultrasonography, mammography, and MRI at the Second Affiliated Hospital of Zhejiang University between December 2017 and November 2020. CTCs were quantitatively assessed using cell counting (CTC detection rate/counts) and categorically examined using a cutoff value (CTC classification). The diagnostic power of CTC tests and imaging modalities, including accuracy and capability to predict clinicopathological characteristics of BC, were evaluated and compared. Results: CTC classification with a cutoff value of 2 showed a "good" diagnostic accuracy of 0.889 for early- to mid-stage BC comparable to breast imaging modalities using Breast Imaging-Reporting and Data System (BI-RADS). MRI demonstrated the highest sensitivity of 0.872 for BC, and CTC classification had the highest specificity of 0.938. A relatively low sensitivity was found for mammography in this cohort of patients. Successful detection of BC by CTC detection rate/counts, but not CTC classification, correlated with two important clinicopathological features, American Joint Committee on Cancer (AJCC) stage and tumor-node-metastasis (TNM) stage. The detection power of certain imaging modalities was also associated with AJCC stage (ultrasonography, p = 0.0438 and MRI, p = 0.0422) and lymph node metastasis (ultrasonography, 0.0157). There were clear correlations between CTC tests (counts or classification) and imaging BI-RADS scoring system in detecting positive BC cases (p < 0.05). Further correlation analysis suggested that CTC quantity, but not CTC classification, had the capability to predict clinicopathological traits of BC that were identified by ultrasonography. Conclusions: CTC tests have a diagnostic potency comparable to breast imaging modalities, and may be used as an alternative screening tool for BC.

Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis.

BACKGROUND: Neutrophils-linked premetastatic niche plays a key role in tumor metastasis, but not much is known about the heterogeneity and diverse role of neutrophils in niche formation. Our study focuses on the existence and biological function of a rarely delved subset of neutrophils, named as tumor-associated aged neutrophils (Naged, CXCR4+CD62Llow), involved in premetastatic niche formation during breast cancer metastasis. METHODS: We explored the distributions of Naged in 206 patients and mice models (4T1 and MMTV-PyMT) by flow cytometry. The ability of Naged to form neutrophil extracellular traps (NETs) and promote tumor metastasis in patients and mice was determined by polychromatic immunohistochemistry, scanning electron microscopy and real-time video detection. Furthermore, the differences among tumor-associated Naged, Non-Naged and inflammation-associated aged neutrophils were compared by transcriptome, the biological characteristics of Naged were comprehensively analyzed from the perspectives of morphology, the metabolic capacity and mitochondrial function were investigated by Seahorse, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) and transmission electron microscopy (TEM). Finally, 120 patients' sample were applied to confirm the acceleration of Naged formation through secreted NAMPT, and the importance of blocking this pathway in mice was evaluated. RESULTS: We find that Naged accumulate in the lung premetastatic niche at early stage of breast tumorigenesis in multiple mice models and also exist in peripheral blood and metastatic lung of patients with breast cancer. Naged exhibit distinct cell marker and morphological feature of oversegmented nuclei. Further transcriptome reveals that Naged are completely different from those of Non-Aged or inflammation-associated aged neutrophils and illustrates that the key transcription factor SIRT1 in Naged is the core to maintain their lifespan via mitophagy for their function. The responsible mechanism is that SIRT1 can induce the opening of mitochondrial permeability transition pore channels to release mitochondrial DNA and lead to the mitochondria-dependent vital NETs formation, rather than traditional Cit-Histone H3 dependent fatal-NETs. Further mechanically investigation found tumor derived NAMPT could induce Naged formation. Additionally, therapeutic interventions of Naged and its formation-linked pathways could effectively decrease breast cancer lung metastasis. CONCLUSIONS: Naged exerts a vital role in breast cancer lung metastasis, and strategies targeting SIRT1-Naged-NETs axis show promise for translational application.

ERα is an RNA-binding protein sustaining tumor cell survival and drug resistance.

Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor. Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism. In particular, we demonstrate that ERα RNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 and MCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifen resistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, and this activity transforms our knowledge of post-transcriptional regulation underlying cancer development and drug response.

The role of postmastectomy radiation in patients with ypN0 breast cancer after neoadjuvant chemotherapy: a meta-analysis.

BACKGROUND: It has been demonstrated that postmastectomy radiation therapy (PMRT) was beneficial for breast cancer patients who are axillary lymph node-positive. However, the effectiveness of radiotherapy in pathological negative nodes (ypN0) after neoadjuvant chemotherapy (NAC) remains open to considerable debate. Here, we aim to evaluate whether PMRT improves loco-regional control and survival for such patients. METHODS: The literature from January 2004 to June 2019 was searched. The effects of PMRT on local-regional recurrence (LRR) and survival was evaluated in a meta-analysis. Pooled relative risk (RR) values with 95% confidence intervals (CIs) were computed using random and fixed-effect model. Subgroup and heterogeneity analyses were also conducted. RESULTS: Twelve studies that included 17,747 patients met the inclusion criteria. Pooled results showed that PMRT was associated with reduced LRR (RR, 0.38; 95% CI, 0.19-0.77, P = 0.007), particularly in patients with stage III breast cancer (RR, 0.16; 95% CI, 0.07-0.37, P < 0.001). However, no significant difference in disease-free survival were observed with the addition of PMRT for ypN0 patients (RR, 0.70; 95% CI, 0.21-2.27, P = 0.55). Also, there was no statistically significant association between radiotherapy with overall survival (RR, 0.81; 95% CI, 0.64-1.04, P = 0.10). CONCLUSIONS: Our meta-analysis indicated that PMRT might reduce local-regional recurrence for ypN0 patients after NAC, but lack of benefit for survival outcomes. Prospective randomized clinical trial data will be needed to confirm our results.

Breast-specific gamma imaging or ultrasonography as adjunct imaging diagnostics in women with mammographically dense breasts.

BACKGROUND: Mammography (MMG) shows decreased diagnostic accuracy in dense breast tissue, and thus, ultrasonography (US) and breast-specific gamma imaging (BSGI) have gradually been adopted for women with mammographically dense breasts. However, these two adjunct modalities have not been directly compared in previous studies. Hence, we investigated the adjunctive efficacy of US and BSGI in mammographically dense breasts. METHODS: This retrospective, comparative study recruited women with mammographically dense breasts. All enrolled women underwent US and BSGI as adjunctive imaging, and the comparative sensitivity, specificity, and diagnostic accuracy of combined MMG plus BSGI versus MMG plus US were evaluated. McNemar's test was used for paired binary data in this comparative analysis. RESULTS: From April 2013 to April 2016, 364 women with mammographically dense breasts and a final surgical or biopsy pathological diagnosis were recruited, comprising 218 cases of malignant disease (59.9%) and 146 cases of benign disease (40.1%). There was no difference between BSGI and US in enhancing the sensitivity of MMG diagnosis (Se-Difference 3.2%, p = 0.23), but the diagnostic specificity of MMG plus BSGI was superior to that of MMG plus US (Sp-Difference 10.3%, p = 0.003). The area under the ROC curve showed that MMG plus BSGI had better diagnostic accuracy than MMG plus US (0.90 vs. 0.83, p = 0.0019). CONCLUSIONS: For women with mammographically dense breasts, MMG plus BSGI or US can improve the diagnostic accuracy. In addition, BSGI has high specificity and could reduce invasive biopsies and thus may represent a viable diagnostic imaging alternative for mammographically dense breasts. KEY POINTS: • Both BSGI and US can be applied as adjunct imaging diagnostics in women with mammographically dense breasts. • The diagnostic accuracy of MMG plus BSGI was higher than that of MMG plus US. • BSGI has the potential to be used as an adjunct diagnostic modality in women with mammographically dense breasts.

Prevalence and Genotyping of Cryptosporidium parvum in Gastrointestinal Cancer Patients.

Gastrointestinal cancers are the most commonly occurring malignancies which contributing to over 1/5 of cancer incidences worldwide. Increasing evidences have shown that Cryptosporidium spp., an apicomplexan protozoan, is highly associated with gastrointestinal cancers. However, the prevalence of Cryptosporidium spp. infections among gastrointestinal cancer patients in China has not been estimated yet. We here performed a case-control study to evaluate the occurrences of Cryptosporidium spp. in patients with digestive malignancies before chemotherapy and in control population. Nested PCR amplifying 18S rRNA gene was used to detect the presence of Cryptosporidium spp. in each fecal sample. The results herein confirmed the correlation of Cryptosporidium spp. infection with colorectal and liver cancers, while first identified the high frequencies of Cryptosporidium spp. in esophageal cancer and small intestine cancer. The infection rates of Cryptosporidium spp. in colorectal, esophageal, liver and small intestine cancers were 17.24% (20/116, P<0.001), 6.25% (1/16, P=0.029), 14.29% (1/7, P<0.001) and 40% (2/5, P<0.001), respectively. In addition, molecular characterization indicated that all the Cryptosporidium spp. obtained were Cryptosporidium parvum (C. parvum), and the 18S rRNA sequences were identical to the reference sequences isolated from cattle, suggesting potential zoonotic transmission. Furthermore, subtyping analyses revealed that IIaA15G2R1 and IIaA15G2R2 were the predominant subtypes in colorectal cancer, while IIaA13G2R2 subtype was first named and identified in colorectal and liver cancers. Taken together, for the first time, the prevalence of Cryptosporidium spp. infections in digestive cancer patients has been estimated among Chinese. Our results indicated that C. parvum were highly associated with gastrointestinal cancers, supporting that cryptosporidiosis could be a potential risk factor for these diseases.

In silico analysis of the prognostic value of FAS mRNA in malignancies.

Background: FAS is a classical death receptor involved in the FAS/FAS ligand (FASL) apoptosis pathway and plays a role in anti-tumor activity. Some studies have recently reported that FAS can serve as an oncogene that promotes tumor proliferation and maintains the stemness of tumor cells. Hence, its prognostic value in malignancies remains controversial. Methods: we assessed the prognostic value of FAS mRNA in several types of tumors by online platforms including Kaplan-Meier Plotter and SurvExpress. Results: FAS mRNA was associated with better overall survival (OS) in breast cancer (Hazard ratio (HR): 0.59 [0.47, 0.73]; p=1.5e-06), gastric cancer (HR: 0.65 [0.54, 0.77]; p=8e-07) and non-small-cell lung cancer (NSCLC) (HR: 0.78 [0.69, 0.89]; p=0.00016), especially in lung adenocarcinoma (HR: 0.64 [0.51, 0.81], p=1.7e-04), female lung cancer (HR:0.72 [0.57, 0.9], p=0.0049) and patients who have never smoked (HR: 0.39 [0.21, 0.7], p=0.0012). However, a high level of FAS mRNA expression indicated poorer OS in pancreatic cancer (HR: 1.33 [1.06, 1.66]; p=0.01) and acute myeloid leukemia (AML) (HR: 1.57 [1.02, 2.41], p=0.04). Additionally, FAS showed no prognostic value in renal carcinoma, head and neck carcinoma, hepatic cancer, ovarian cancer, colorectal cancer or glioblastoma. The results from the Cell Miner tool revealed that FAS expression was associated with the sensitivity of tumor cells to cabozantinib and erlotinib. Conclusions: In summary, the dominant function of FAS may vary in different malignancies. FAS mRNA expression was correlated with better OS in breast cancer, gastric cancer and lung cancer, but worse OS in pancreatic cancer and AML. We also suggested that FAS mRNA expression could be a potential biomarker for cabozantinib and erlotinib.

Apoptotic SKOV3 cells stimulate M0 macrophages to differentiate into M2 macrophages and promote the proliferation and migration of ovarian cancer cells by activating the ERK signaling pathway.

Ovarian cancer has a high rate of recurrence, with M2 macrophages having been found to be involved in its progression and metastasis. To examine the relationship between macrophages and ovarian cancer in the present study, M0 macrophages were stimulated with apoptotic SKOV3 cells and it was found that these macrophages promoted tumor proliferation and migration. Subsequently, the mRNAs and proteins expressed at high levels in these M2 macrophages were examined by RNA­Seq and quantitative proteomics, respectively, which revealed that M0 macrophages stimulated by apoptotic SKOV3 cells also expressed M2 markers, including CD206, interleukin­10, C­C motif chemokine ligand 22, aminopeptidase­N, disabled homolog 2, matrix metalloproteinase 1 and 5'­nucleotidase. The abundance of phosphorylated Erk1/2 in these macrophages was increased. The results indicate that apoptotic SKOV3 cells stimulate M0 macrophages to differentiate into M2 macrophages by activating the ERK pathway. These results suggest possible treatments for patients with ovarian cancer who undergo chemotherapy; inhibiting M2 macrophage differentiation during chemotherapy may reduce the rate of tumor recurrence.

Endothelial cells in colorectal cancer.

The dependence of tumor growth on neovascularization has become an important aspect of cancer biology. Tumor angiogenesis is one of the key mechanisms of tumorigenesis, growth and metastasis. The key events involved in this process are endothelial cell proliferation, migration, and vascular formation. Recent studies have revealed the importance of tumor-associated endothelial cells (TECs) in the development and progression of colorectal cancer (CRC), including epithelial proliferation, stem cell maintenance, angiogenesis, and immune remodeling. Decades of research have identified that the molecular basis of tumor angiogenesis includes vascular endothelial growth factors (VEGFs) and their receptor family, which are the main targets of antiangiogenesis therapy. VEGFs and their receptors play key roles in the pathology of angiogenesis, and their overexpression indicates poor prognosis in CRC. This article reviews the characteristics of the tumor vasculature and the role of TECs in different stages of CRC and immune remodeling. We also discuss the biological effects of VEGFs and their receptor family as angiogenesis regulators and emphasize the clinical implications of TECs in clinical treatment.

Associations between miR-146a rs2910164 polymorphisms and risk of ischemic cardio-cerebrovascular diseases.

BACKGROUND: Many studies investigated the association between miR-146a rs2910164 polymorphisms and risk of ischemic cardio-cerebrovascular diseases. However, the results were inconsistent. METHODS: We searched the PubMed, EMBASE, Cochrane library, Web of Science, Chinese National Knowledge Infrastructure, VIP, and Wanfang databases for appropriate studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations. Heterogeneity, sensitivity, and publication bias were conducted to measure the robustness of our findings.All analyses were based on previous published studies, thus, no ethical approval and patient consent are required. RESULTS: We conducted a meta-analysis to evaluate the relationship between miR-146a rs2910164 polymorphisms and risk of ischemic cardio-cerebrovascular diseases. A total of 26 related studies involving 11,602 cases and 14,016 controls were identified and included in our meta-analysis. After considering the heterogeneity of the global analysis, we inferred that rs2910164 polymorphisms were associated with a lower risk of coronary heart disease (CHD) significantly in all genetic models. In addition, it was also found that the miR-146a rs2910164 polymorphisms were associated with the low risk of ischemic cardio-cerebrovascular diseases in large sample size subgroup analysis. CONCLUSION: These results indicate that miR-146a rs2910164 polymorphisms were significantly associated with a lower risk of ischemic cardio-cerebrovascular. The miR-146a rs29101164 might be recommended as a predictor for susceptibility of ischemic cardio-cerebrovascular diseases.