• Chemotherapeutics
• Exosomes
• Extracellular vesicles
• Mesenchymal stroma cells
• Stroma cell-derived factor
• Tumor plasticity
• Tumor tropism
• microRNAs

• Humans
• Paclitaxel/pharmacology
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/drug effects
• Exosomes/metabolism
• Chemokine CXCL12/metabolism
• Chemokine CXCL12/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Cell Line, Tumor
• Tropism
• Extracellular Vesicles/metabolism
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/genetics
• Neoplasms/drug therapy
• Antineoplastic Agents, Phytogenic/pharmacology

• 'Hand in Hand für Norddeutschland 2019' NDR charity campaign
• Medizinische Hochschule Hannover (MHH) (3118)

• Receptors, CXCR4/antagonists & inhibitors
• Receptors, CXCR4/metabolism
• Humans
• Binding Sites/drug effects
• Peptides/chemistry
• Peptides/pharmacology
• Peptides/chemical synthesis
• Disulfides/chemistry
• Disulfides/pharmacology
• Structure-Activity Relationship
• Molecular Structure
• Dose-Response Relationship, Drug
• Lactams/chemistry
• Lactams/pharmacology
• Lactams/chemical synthesis
• Cell Movement/drug effects
• Models, Molecular
• Cell Line, Tumor

• CAR-T-cell antigen
• chimeric antigen receptor (CAR)-T cell
• differentially expressed gene (DEG)
• ovarian cancer
• protein-protein interaction (PPI) network

• Female
• Humans
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/immunology
• Computational Biology
• Immunotherapy, Adoptive/methods
• Receptors, Chimeric Antigen/genetics
• Receptors, Chimeric Antigen/immunology
• Receptors, Chimeric Antigen/metabolism
• Gene Expression Regulation, Neoplastic
• Gene Expression Profiling

• Endometriosis
• Endometriosis-associated ovarian cancers
• Immune response
• Immunotherapy
• Ovarian neoplasms

• Immune-related genes
• Ovarian cancer
• Prognosis prediction
• Prognostic risk model
• Risk score

• Female
• Humans
• Ovarian Neoplasms/genetics
• Prognosis
• Carcinogenesis
• Risk Assessment
• Tumor Microenvironment/genetics

• No.20204Y0230 clinical research special projects from Shanghai Municipal Health Commission

• Chimeric antigen receptor (CAR)
• Pancreatic cancer
• Pancreatic ductal adenocarcinoma (PDAC)
• Protease-activated receptor 1 (PAR1)
• TGF-β

• Humans
• Animals
• Mice
• Receptor, PAR-1/genetics
• Matrix Metalloproteinase 1
• Receptors, Chimeric Antigen
• Pancreatic Neoplasms/therapy
• Tumor Microenvironment

• Ministry of Science and Technology, Taiwan

• CD39
• CD73
• P1 receptors
• P2X receptors
• P2Y receptors
• blood-brain barrier
• endothelial cells
• purinergic signaling

• immunotherapy
• next-generation sequencing
• ovarian cancer

• AMD3100
• CXCR4
• hepatocellular carcinoma
• transcatheter arterial chemoembolization

Despite rapid progress in the research on epithelial ovarian cancer (EOC), it is usually diagnosed during the advanced stage with only 30% of patients surviving longer than 5 years. This is the first study in which the whole CXCR4-CXCL12-CXCR7 axis was systematically evaluated in tumor and stromal cells, through rigorous statistical methods in a prospective clinical trial. CXCL12 expression in cancer cells is associated with worse progression-free survival in stage III EOC patients, and deserves further attention as a potential prognostic and therapeutic target.

This study investigated the prognostic role of the CXCR4-CXCL12-CXCR7 axis in advanced epithelial ovarian cancer (EOC) patients receiving first-line treatment within the MITO16A/MaNGO-OV2 phase-IV trial. CXCR4-CXCL12-CXCR7 expression was evaluated in the epithelial and stromal component of 308 EOC IHC-stained tumor samples. The statistical analysis focused on biomarkers’ expression, their association with other variables and prognostic value. Zero-inflated tests, shrinkage, bootstrap procedures, and multivariable models were applied. The majority of EOC (75.0%) expressed CXCR4 and CXCR7, 56.5% expressed the entire CXCR4-CXCL12-CXCR7 axis, while only 4.6% were negative for CXCL12 and its cognate receptors, in regard to the epithelial component. Stromal CXCL12 and CXCR7, expressed in 11.2% and 65.5%, respectively, were associated with the FIGO stage. High CXCL12 in epithelial cancer cells was associated with shorter progression-free and overall survival. However, after adjusting for overfitting due to best cut-off multiplicity testing, the significance was lost. This is a wide-ranging, prospective study in which CXCR4-CXCL12-CXCR7 were systematically evaluated in epithelial and stromal components, in selected stage III-IV EOC. Although CXCL12 was not prognostic, epithelial expression identified high-risk FIGO stage III patients for PFS. These data suggest that it might be worth studying the CXCL12 axis as a therapeutic target to improve treatment efficacy in EOC patients.

• CXCR4-CXCL12-CXCR7 axis
• chemokine
• ovarian cancer
• prognosis
• tumor microenvironment

• CXCL12
• CXCR7
• Esophageal cancer
• epithelial-mesenchymal transition
• tumor metastasis

• Cell Line, Tumor
• Chemokine CXCL12/genetics
• Chemokine CXCL12/metabolism
• Chemokine CXCL12/pharmacology
• Epithelial-Mesenchymal Transition/genetics
• Esophageal Neoplasms/genetics
• Humans
• Ligands
• Receptors, CXCR/genetics
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism

• PD-L1
• immunosuppression
• immunotherapy
• ovarian cancer
• tumor microenvironment

• Cancer
• Chemokine receptor antagonist
• Oncology

• Chemokine
• diffuse large B-cell lymphoma
• systemic lymphoma
• testicular lymphoma

Microarray profiles of hepatocellular carcinoma (HCC) identified that long intergenic noncoding RNA 00221 (LINC00221) was upregulated. Herein, we aimed to identify the functional significance and underlying mechanisms of LINC00221 in HCC.

Human HCC samples had increased expression of LINC00221. Effects of LINC00221 on HCC cellular functions were analyzed using gain- and loss-function approaches. LINC00221 knockdown repressed HCC cell growth, migration, and invasion and enhanced their apoptosis. This anti-tumor effect was validated in vivo. Online prediction showed the potential binding relationship between LINC00221 and let-7a-5p, as well as that between let-7a-5p and matrix metalloproteinase 11 (MMP11). The results of luciferase, RNA immunoprecipitation, and RNA pull-down assays identified that LINC00221 interacted with let-7a-5p to increase expression of MMP11. Furthermore, we demonstrated that LINC00221 silencing increased let-7a-5p and inhibited MMP11 expression, thereby delaying the progression of HCC in vitro.

Silencing of LINC00221 could prevent HCC progression via upregulating let-7a-5p and downregulating MMP11. As such, LINC00221 inhibition presents a promising antitumor strategy for the treatment of HCC.

• Cell cycle
• Cell migration
• Hepatocellular carcinoma
• Let-7a-5p
• Long noncoding RNA LINC00221
• Matrix metalloproteinase-11

• C-X-C motif chemokine ligand 12
• CXC chemokine receptor 4
• Esophageal squamous cell carcinoma
• antagonists
• imaging agent

• 81772619 National Natural Science Foundation of China
• 81702405 National Natural Science Foundation of China
• 320.6750.17519 Wu Jieping Medical Foundation
• HZB-20190528-18 Bethune Charitable Foundation
• 19JCQNJC10800 Tianjin Natural Science Foundation for Youth

Existing clinical methods for prognosis evaluating for Epithelial Ovarian Cancer (EOC) patients had defects of invasive, unsystematic and subjective and little data are available for individualizing treatment, therefore, to identify potential prognostic markers and new therapeutic targets for EOC is urgently required.

Expression of 232 autophagy-related genes (ARGs) in 354 EOC and 56 human ovarian surface epithelial specimens from 7 independent laboratories were analyzed, 31 mRNAs were identified as DEARGs. We did functional and pathway enrichment analysis and constructed protein–protein interaction network for all DEARGs. To screen out candidate DEARGs related to EOC patients’ survival and construct an autophagy-related prognostic risk signature, univariate and multivariate Cox proportional hazards models were established separately. Finally, 5 optimal independent prognostic DEARGs (PEX3, DNAJB9, RB1, HSP90AB1 and CXCR4) were confirmed and the autophagy-related risk model was established by the 5 prognostic DEARGs. The accuracy and robustness of the prognostic risk model for survival prediction were evaluated and verified by analyzing the correlation between EOC patients’ survival status, clinicopathological features and risk scores.

The autophagy-related prognostic risk model can be independently used to predict overall survival in EOC patients, it can also potentially assist in individualizing treatment and biomarker development.

• Autophagy-related genes
• Epithelial ovarian Cancer
• Prognostic risk model
• Survival prediction
• Targeted therapeutic intervention

Objective: This study aimed to explore ferroptosis-related mRNAs as potential therapeutic targets for ovarian cancer treatment.

Methods: Molecular subtypes were classified based on ferroptosis-related mRNAs via ConsensusClusterPlus package. The differences in prognosis, stromal score, immune score, immune function, and immune checkpoints were assessed between subtypes. Small molecular drugs were predicted via the CMap database. The sensitivity to chemotherapy drugs was estimated through the GDSC. A LASSO Cox regression model was conducted via the glmnet package, followed by a nomogram model.

Results: Based on ferroptosis mRNA expression profile, two molecular subtypes (C1 and C2) were classified, with distinct clinical outcomes. C1 subtype exhibited higher stromal score, immune cell score (T helper, Treg, neutrophil) and immune function (APC co-inhibition, parainflammation and Type II IFN response). Higher mRNA expression levels of immune checkpoints (like PDCD1) were found in C1 than C2. Potential small molecular drugs (PI3K and mTOR inhibitors) were found for treatment of ovarian cancer. C1 was more sensitive to eight chemotherapy drugs (A.443654, AZD.0530, AZD6482, AZD7762, AZD8055, BAY.61.3606, Bicalutamide, and CGP.60474). A 15-ferroptosis-related mRNA signature was developed, which could robustly and independently predict the outcomes. Moreover, a nomogram was established combining the signature and age, which could intuitively and accurately predict the 5-year overall survival probability.

Conclusion: Our study characterized two ferroptosis-related subtypes with distinct prognosis and tumor immune features, which could assist clinicians make decisions and individual therapy. Moreover, 15 ferroptosis-related mRNAs were identified, which could become potential therapeutic targets for ovarian cancer.

• ferroptosis
• mRNA
• ovarian carcinoma
• prognosis
• therapeutic targets
• tumor microenvironment

Traditional chemotherapy for ovarian cancer is limited due to drug resistance and systemic side effects. Although various targeted drug delivery strategies have been designed to enhance drug accumulation at the tumor site, simply improvement of targeting capability has not consistently led to satisfactory outcomes. Herein, AMD3100 was selected as the targeting ligand because of its high affinity to chemokine receptor 4 (CXCR4), which was highly expressed on ovarian cancer cells. Moreover, the AMD3100 has been proved having blockage capability of stromal cell-derived factor 1 (SDF-1 or CXCL12)/CXCR4 axis and to be a sensitizer of chemotherapeutic therapy. We designed a dual-functional targeting delivery system by modifying paclitaxel (PTX)-loaded PEGylation bovine serum albumin (BSA) nanoparticles (NPs) with AMD3100 (AMD-NP-PTX), which can not only achieve specific tumor-targeting efficiency but also enhance the therapeutic outcomes.

AMD3100 was chemically modified to Mal-PEG-NHS followed by reacting with BSA, then AMD-NP-PTX was synthesized and characterized. The targeting efficiency of AMD-NP was evaluated both in vitro and in vivo. The anticancer effect of AMD-NP-PTX was determined on Caov3 cells and ovarian cancer-bearing nude mice. Finally, the potential therapeutic mechanism was studied.

AMD-NP-PTX was synthesized successfully and well characterized. Cellular uptake assay and in vivo imaging experiments demonstrated that NPs could be internalized by Caov3 cells more efficiently after modification of AMD3100. Furthermore, the AMD-NP-PTX exhibited significantly enhanced inhibition effect on tumor growth and metastasis compared with PTX, NP-PTX and free AMD3100 plus NP-PTX both in vitro and in vivo, and demonstrated improved safety profile. We also confirmed that AMD-NP-PTX worked through targeting CXCL12/CXCR4 axis, thereby disturbing its downstream signaling pathways including epithelial–mesenchymal transition (EMT) processes and nuclear factor κB (NF-κB) pathway.

The AMD-NP-PTX we designed would open a new avenue for dual-functional NPs in ovarian cancer therapy.

• AMD3100
• CXCL12/CXCR4 axis
• nanoparticle
• ovarian cancer
• paclitaxel

• AKT
• EMT
• HIV-protease inhibitors
• MMP-9
• cancer
• integrins
• metastasis
• tumor cell invasion

• Cell Line, Tumor
• Extracellular Matrix/metabolism
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Matrix Metalloproteinase 9/metabolism
• Matrix Metalloproteinase 9/physiology
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases/metabolism
• Matrix Metalloproteinases/physiology
• Neoplasm Invasiveness/pathology
• Neoplasm Metastasis/genetics
• Neoplasm Metastasis/physiopathology
• Neoplasms/metabolism

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of 9%. Major obstacles to successful treatment of pancreatic cancer are the immunosuppressive tumor microenvironment (TME) and antigenic complexity or heterogeneity. Programmed death-ligand 1 (PD-L1) is expressed on PDAC and immunosuppressed cells within the TME, providing suitable immunotherapy targets. We applied a chimeric antigen receptor (CAR) strategy to target immune checkpoint programmed death-1 (PD-1)/PD-L1 interactions. Lentiviral vectors were used to express the extracellular domain of human PD-1 (PD-1-CD28-4-1BB activating chimeric receptor [PD1ACR]) or the single-chain variable fragment (scFv) region of anti-PD-L1 (PDL1CAR) that binds to PD-L1, and each was fused to intracellular signaling domains containing CD3 zeta, CD28, and 4-1BB (CD137). Both engineered CAR T cells recognized and eliminated PD-L1-overexpressing CFPAC1 cells efficiently at approximately 80% in vitro. Adoptive transfer of both CAR T cells enhanced T cell persistence and induced specific regression of established CFPAC1 cancer by >80% in both xenograft and orthotopic models. Ki67 expression in tumors decreased, whereas proinflammatory cytokines/chemokines increased in CAR T cell-treated mouse sera. PD1ACR and PDL1CAR obtained a similar therapeutic efficacy. Thus, these armed third-generation PD-L1-targeted CAR T cells confer antitumor activity and the ability to combat T cell exhaustion, providing a potentially new and innovative CAR T cell immunotherapy against pancreatic cancers.

• ACR
• CAR
• PD-1
• PD-L1
• PDAC

• R01 HL151077 NHLBI NIH HHS
• U54 HL142019 NHLBI NIH HHS

Prostate adenocarcinoma (PRAD) is a common malignant tumor in elderly men. Our research uses The Cancer Gene Atlas (TCGA) database to find potential related genes for predicting the prognosis of patients with PRAD.

We downloaded gene expression profiles and clinical sample information from TCGA for 490 patients with PRAD (patient age: 41-78 years). We calculated stromal and immune scores using the ESTIMATE algorithm to predict the level of stromal and immune cell infiltration. We categorized patients with PRAD in TCGA into high and low score arrays according to their median immune/stromal scores and identified differentially expressed genes (DEGs) that were significantly correlated with the prognosis of PRAD. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. The association between DEGs and overall survival was investigated by weighted Kaplan–Meier survival analysis and multivariate analysis. Furthermore, the protein-protein interaction network (PPI) of DEGs was constructed using the STRING tool. Finally, the hub genes were identified by analyzing the degree of association of PPI networks.

We found that 8 individual DEGs, C6, S100A12, MLC1, PAX5, C7, FAM162B, CAMK1G, and TCEAL5, were significantly predictive of favorable overall survival and one DEG, EPYC, was associated with poor overall survival. GO and KEGG pathway analyses revealed that the DEGs were associated with immune responses. Moreover, 30 hub genes were obtained using the PPI network of DEGs: ITGAM, CD4, CD3E, IL-10, LCP2, ITGB2, ZAP-70, C3, CCL19, CXCL13, CXCL9, BTK, CCL21, CD247, CD28, CD3D, FCER1G, PTPRC, TYROBP, CCR5, ITK, CCL13, CCR1, CCR2, CD79B, CYBB, IL2RG, JAK3, PLCG2, and CD19. These prominent nodes had the most associations with other genes, indicating that they might play crucial roles in the prognosis of PRAD.

We extracted a list of genes associated with the prostate adenocarcinoma microenvironment, which might contribute to the prediction and interpretation of PRAD prognosis.

• CXCL12
• SCAMP1
• miR-137
• ovarian cancer

• C-X-C motif chemokine receptor 4 (CXCR4)
• adenosine A2A receptor
• metastasis
• stromal cell-derived factor-1 (SDF-1)

Previous studies have demonstrated that C-C motif chemokine 14 (CCL14) plays an important role in the occurrence and development of cancer. However, the significance of CCL14 in the progression and prognosis of epithelial ovarian cancer (EOC) has not yet been reported. The standard EnVision procedure for tissue microarrays was used to evaluate the immunohistochemical expression of CCL14 protein in 154 patients with EOC who underwent tumor-debulking operations at the Central Cancer Department of Sun Yat-Sen University (Guangzhou, China) or Jiangmen Central Hospital (Jiangmen, China). The association between CCL14 expression and clinicopathological variables was assessed using the χ² test. For survival status of patients with EOC, Kaplan-Meier survival analysis and a Cox multivariate regression model was used. Expression of CCL14 protein was significantly associated with International Federation of Gynecology and Obstetric stage (P=0.014) and pN status(P=0.005). Kaplan-Meier survival analysis revealed that the survival time of patients with high expression of CCL14 was 136.1 months and that of patients with low expression of CCL14 was 98.9 months (P=0.026). Multivariate analysis demonstrated that CCL14 upregulation was associated with overall survival time (HR, 0.48; 95% CI, 0.261–0.896; P=0.021) and progression-free survival time (HR,0.437; 95% CI, 0.228–0.839; P=0.013). In conclusion, CCL14 is an independent prognostic factor for EOC and upregulation of CCL14 is associated with a more favorable prognosis in patients with EOC.

• C-C motif chemokine 14
• epithelial ovarian cancer
• prognosis

G-coupled protein receptors (GCPR) involve several signaling pathways, some of them being coupled with intracellular calcium (Ca²⁺) mobilization. GPCRs were involved in migration, invasion and metastasis of different types of cancers, including ovarian cancer. Many studies have discussed the essential contribution of GPCRs activated by steroid hormones in ovarian cancer. However, ovarian cancer is also associated with altered signals coming from the nervous system, the immune system or the inflammatory environment, in which GPCRs are ‘sensing’ these molecular signals. Many studies have been oriented so far on ovarian cell lines (most of them being of human cell lines), and only few studies based on animal models or clinical studies have been devoted to the expression changes or functional role of GPCRs in ovarian cancer. In this paper, we review the alterations of GPCRs activated by neurotransmitters (muscarinic receptors, serotonin receptors, dopamine receptors, adrenoceptors) or inflammation-associated molecules (bradykinin receptors, histamine receptors, chemokine receptors) in ovarian cancer and we discuss their potential as histological biomarkers.

• G-coupled protein receptors
• GPCR cross-talk
• calcium mobilization
• inflammation-associated molecules
• neurotransmitters
• ovarian cancer

• Animals
• Biomarkers, Tumor/metabolism
• Calcium Signaling
• Female
• Humans
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation Mediators/metabolism
• Neoplasm Proteins/metabolism
• Neurotransmitter Agents/metabolism
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Receptors, G-Protein-Coupled/metabolism
• Tumor Microenvironment

• Androgen receptor (AR)
• Apoptosis
• C-X-C chemokine receptor type 4 (CXCR4)
• Cell cycle
• Dihydrotestosterone (DHT)
• Epithelial mesenchymal transition (EMT)
• Resveratrol (Res)

• Androgen Receptor Antagonists/pharmacology
• Androgens/pharmacology
• Antioxidants/pharmacology
• Apoptosis/drug effects
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Dihydrotestosterone/pharmacology
• Disease Progression
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Male
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• Receptors, Androgen/chemistry
• Receptors, CXCR4/antagonists & inhibitors
• Resveratrol/pharmacology
• Signal Transduction
• Tumor Cells, Cultured

Liver cancer (LC), which is one of the most common types of cancer worldwide, is notorious for its high morbidity and mortality rates. Interleukin-8 (IL-8), an important member of the CXC chemokine family that was originally classified as a potent neutrophil chemoattractant, has been shown to serve an important role in inflammation, tumor growth, invasion and metastasis through interactions with its receptors. However, the expression and functional roles of IL-8 and its receptors, CXC chemokine receptor (CXCR) 1 and CXCR2 in the progression of liver cancer remain to be fully elucidated. In the present study, it was shown that the mRNA levels of IL-8, CXCR1 and CXCR2 were increased in peripheral blood mononuclear cells from patients with liver cancer compared with those from patients with cirrhosis or normal controls (P<0.05). Higher levels of CXCR1, CXCR2 and IL-8 were associated with advanced tumor stage and increased risk of lymph node or distant metastasis. Immunohistochemistry showed that the IL-8, CXCR1 and CXCR2 proteins were expressed in the cytoplasm of hepatoma cells at higher intensities than those of normal controls (P<0.05). The semi-quantitative analysis revealed that the relative mean density of hepatic IL-8, CXCR1 and CXCR2 staining in liver cancer was significantly increased compared with that in normal liver tissues (P<0.05). The analysis revealed that the mRNA expression of IL-8 was positively associated with that of CXCR1 (r=0.618; P<0.05) and CXCR2 (r=0.569; P<0.05). The mRNA levels of CXCR1 and CXCR2 gradually increased with elevated expression of IL-8 in liver cancer. Experiments were performed using human Huh-7 and HepG2 cell lines, incubating cells with IL-8 and conducting in vitro migration and invasion assays. The results showed that the wound healing activity and migration of Huh-7 and HepG2 cells were increased by IL-8. Pretreatment of the cells with anti-CXCR1 or anti-CXCR2 (5 µM) for 30 min markedly inhibited IL-8-directed cell migration. Taken together, these results indicated that IL-8 promotes liver cancer cell migration via CXCR1 and CXCR2 and that targeting the CXCR1/2 may be a potential strategy for liver cancer treatment.

• CXC chemokine receptor 1
• CXC chemokine receptor 2
• interleukin-8
• invasion
• liver cancer
• metastasis

• acute myeloid leukemia
• disease-free survival
• overall survival
• prognosis
• relative fluorescence intensity of chemokine receptor 4
• relapse

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/metabolism
• Bone Marrow/metabolism
• Disease-Free Survival
• Female
• Flow Cytometry
• Humans
• Leukemia, Myeloid, Acute/metabolism
• Leukemia, Myeloid, Acute/mortality
• Male
• Middle Aged
• Prognosis
• Proportional Hazards Models
• Receptors, CXCR4/metabolism
• Recurrence
• Tumor Microenvironment
• Young Adult

AMD3100 (plerixafor, Mozobil®) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. Through interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), it also mobilized the CD34⁺stem cells from the bone marrow into the peripheral blood stream. In December 2008, AMD3100 was formally approved by the US FDA for autologous transplantation in patients with Non-Hodgkin’s Lymphoma or multiple myeloma. It may be beneficially used in various other malignant diseases as well as hereditary immunological disorders such as WHIM syndrome, and physiopathological processes such as hepatopulmonary syndrome.

• AMD3100
• CXCR4
• MM
• Mozobil®
• NHL
• WHIM
• stem cells

Immune and inflammatory cascades may play multiple roles in ovarian cancer. We aimed to identify relationships between expression of immune and inflammatory mediators and patient outcomes. We interrogated differential gene expression of 44 markers and marker combinations (n = 1,978) in 1,656 ovarian carcinoma patient tumors, alongside matched 5-year overall survival (OS) data in silico. Using machine learning methods, we investigated whether genomic expression of these 44 mediators can discriminate between malignant and non-malignant tissues in 839 ovarian cancer and 115 non-malignant ovary samples. We furthermore assessed inflammation markers in 289 ovarian cancer patients’ sera in the Swedish Apolipoprotein MOrtality-related RISk (AMORIS) cohort. Expression of the 44 mediators could discriminate between malignant and non-malignant tissues with at least 96% accuracy. Higher expression of classical Th1, Th2, Th17, anti-parasitic/infection and M1 macrophage mediator signatures were associated with better OS. Contrastingly, inflammatory and angiogenic mediators, CXCL-12, C-reactive protein (CRP) and platelet-derived growth factor subunit A (PDGFA) were negatively associated with OS. Of the serum inflammatory markers in the AMORIS cohort, women with ovarian cancer who had elevated levels of haptoglobin (≥1.4 g/L) had a higher risk of dying from ovarian cancer compared to those with haptoglobin levels <1.4 g/L (HR = 2.09, 95% CI:1.38–3.16). Our findings indicate that elevated “classical” immune mediators, associated with response to pathogen antigen challenge, may confer immunological advantage in ovarian cancer, while inflammatory markers appear to have negative prognostic value. These highlight associations between immune protection, inflammation and clinical outcomes, and offer opportunities for patient stratification based on secretome markers.

• Immune activation
• M1/M2
• Th1/Th2/Th17
• biomarkers
• immune mediators
• inflammation
• ovarian cancer

• Ovarian carcinoma
• RNA interference
• follicle-stimulating hormone
• growth-regulated oncogene α
• nanoparticle
• targeted therapy

• Animals
• Cell Line, Tumor
• Drug Delivery Systems/methods
• Female
• Follicle Stimulating Hormone/chemistry
• Follicle Stimulating Hormone/pharmacology
• Gene Transfer Techniques
• Genetic Therapy/methods
• HEK293 Cells
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles/chemistry
• Ovarian Neoplasms/drug therapy
• Peptides/chemistry
• Peptides/pharmacology
• Plasmids/genetics
• Polyethylene Glycols/chemistry
• Polyethyleneimine/chemistry
• RNA, Small Interfering/genetics
• Transfection/methods

The tumor microenvironment for epithelial ovarian cancer is complex and rich in bioactive molecules that modulate cell-cell interactions and stimulate numerous signal transduction cascades. These signals ultimately modulate all aspects of tumor behavior including progression, metastasis and therapeutic response. Many of the signaling pathways converge on the small GTPase Ras-related C3 botulinum toxin substrate (Rac)1. In addition to regulating actin cytoskeleton remodeling necessary for tumor cell adhesion, migration and invasion, Rac1 through its downstream effectors, regulates cancer cell survival, tumor angiogenesis, phenotypic plasticity, quiescence, and resistance to therapeutics. In this review we discuss evidence for Rac1 activation within the ovarian tumor microenvironment, mechanisms of Rac1 dysregulation as they apply to ovarian cancer, and the potential benefits of targeting aberrant Rac1 activity in this disease. The potential for Rac1 contribution to extraperitoneal dissemination of ovarian cancer is addressed.

• GTPase activating proteins (GAPs)
• Rac1
• Rho-GTPase
• bone niche
• guanine nucleotide exchange factors (GEFs)
• oncogene
• oncoprotein
• ovarian cancer
• therapeutic targeting
• tumor microenvironment

• P30 CA118100 NCI NIH HHS
• P50 GM085273 NIGMS NIH HHS
• R21 TR001731 NCATS NIH HHS

• AMD3100
• CXCL12-CXCR4 axis
• apoptosis
• invasion
• migration
• ovarian cancer
• proliferation

The CARMA–Bcl10–MALT1 (CBM) signalosome is an intracellular protein complex composed of a CARMA scaffolding protein, the Bcl10 linker protein, and the MALT1 protease. This complex was first recognized because the genes encoding its components are targeted by mutation and chromosomal translocation in lymphoid malignancy. We now know that the CBM signalosome plays a critical role in normal lymphocyte function by mediating antigen receptor-dependent activation of the pro-inflammatory, pro-survival NF-κB transcription factor, and that deregulation of this signaling complex promotes B-cell lymphomagenesis. More recently, we and others have demonstrated that a CBM signalosome also operates in cells outside of the immune system, including in several solid tumors. While CARMA1 (also referred to as CARD11) is expressed primarily within lymphoid tissues, the related scaffolding protein, CARMA3 (CARD10), is more widely expressed and participates in a CARMA3-containing CBM complex in a variety of cell types. The CARMA3-containing CBM complex operates downstream of specific G protein-coupled receptors (GPCRs) and/or growth factor receptor tyrosine kinases (RTKs). Since inappropriate expression and activation of GPCRs and/or RTKs underlies the pathogenesis of several solid tumors, there is now great interest in elucidating the contribution of CARMA3-mediated cellular signaling in these malignancies. Here, we summarize the key discoveries leading to our current understanding of the role of CARMA3 in solid tumor biology and highlight the current gaps in our knowledge.

• Bcl10
• CARMA3
• G protein-coupled receptor
• MALT1
• NF-κB
• cancer
• receptor tyrosine kinases

• AnnexinA7
• CXCR4
• Hepatocarcinoma
• SDF1
• VEGFC/D-VEGFR3/NRP2

• Animals
• Annexin A7/metabolism
• Carcinoma, Hepatocellular/pathology
• Chemokine CXCL12/genetics
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Liver Neoplasms/pathology
• Lymphatic Metastasis
• Mice
• Receptors, CXCR4/genetics
• Signal Transduction

• (No.81071725) National Natural Science Foundation of China
• (No. 20121203) Financial Department of Liaoning Province, PRC.
• Financial Department of Liaoning Province, PRC.

Colorectal cancer (CRC) is both a global and national burden, being the third most common malignancy in men and the second in women, worldwide. The prognosis of CRC is affected by various factors like the histological grade, angiolymphatic invasion, and distant metastases. Metastasis is an intricate process; one of the possible mechanisms is through the interaction of the chemokines CXCL12 and CXCR4. This study aims to reveal the expression patterns of CXCL12 and CXCR4 in CRC.

The quantitative expressions of CXCL12 and CXCR4 messenger RNA (mRNA) were evaluated in 32 patients with adenocarcinoma-type CRC. Real-time polymerase chain reaction (qRT-PCR) was performed on formalin-fixed tissues. CXCL12 and CXCR4's expressions, clinicopathologic features, and the treatment response to the CRC were analysed.

All tumour tissues showed higher levels of both chemokines compared to normal colonic tissue. The expression of CXCL12 mRNA was higher in rectal location (p = 0.04) with a tendency to be higher in later stages (p = 0.15), while the expression of CXCR4 was lower in tumours with a lymphatic invasion (p = 0.02), compared to their counterparts. There was no difference in the expression of CXCL12 and CXCR4 according to the patients' ages, gender, tumour differentiation, or response to chemotherapy.

Our study demonstrated that the mRNA expression of CXCL12 was significantly correlated with rectal location. CXCR4 mRNA expression was inversely correlated in tumours with a lymphatic invasion.