• Humans
• Lymphatic Vessels/immunology
• Lymphatic Vessels/pathology
• Neoplasms/immunology
• Neoplasms/pathology
• Animals
• Tumor Microenvironment/immunology
• Neoplasm Metastasis
• Immunity
• Lymphatic Metastasis

• gastrointestinal carcinomas
• lymph node metastasis
• micrometastasis
• proteomics
• sentinel lymph node

• Humans
• Proteomics/methods
• Gastrointestinal Neoplasms/pathology
• Lymphatic Metastasis

• Axon guidance molecule
• Cancer neuroscience
• Nerves
• Neural invasion
• Pancreatic cancer
• Placental growth factor (PlGF)

• Humans
• Placenta Growth Factor/metabolism
• Pancreatic Neoplasms/surgery
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/metabolism
• Female
• Prognosis
• Male
• Aged
• Cell Line, Tumor
• Neoplasm Invasiveness
• Middle Aged
• Carcinoma, Pancreatic Ductal/surgery
• Carcinoma, Pancreatic Ductal/pathology
• Carcinoma, Pancreatic Ductal/metabolism
• Biomarkers, Tumor/metabolism

• ECRC Grant Max-Delbrück Center & Charité-Universitätsmedizin Berlin
• Scholarship Clinician Scientist Program Berlin Institute of Health
• Max-Delbrück Center & Charité–Universitätsmedizin Berlin
• Charité - Universitätsmedizin Berlin (3093)

• Blood endothelial cells
• Hepatocellular carcinoma
• Lymphatic endothelial cells
• Tumor microenvironment

• prognostic markers
• pancreatic cancer

• Humans
• Angiopoietin-2
• Carcinoma, Pancreatic Ductal/metabolism
• Pancreatic Neoplasms/pathology
• Prognosis
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factors

• Sigrid Juséliuksen Säätiö
• Mary och Georg C. Ehrnrooths Stiftelse
• Vatsatautien tutkimussäätiö
• Suomen Lääketieteen Säätiö
• Syöpäsäätiö
• HORIZON EUROPE European Research Council
• Academy of Finland
• Finska Läkaresällskapet
• Finnish Goverment subsidised funding

• PDAC
• metastasis
• pancreas
• signaling
• tumor microenvironment

• Humans
• Pancreatic Neoplasms
• Neuropilins
• Semaphorins
• Adenocarcinoma
• Tumor Microenvironment

• Cancer Osaka thyroid
• Chronic liver disease
• Inflammation
• MAPK
• Tumor progression locus 2
• cancer

• Angiopoietins
• Heart failure
• Heart failure with preserved ejection fraction
• Heart failure with reduced ejection fraction
• IHF
• Low-grade inflammation
• VEGFs
• sPLA(2)

• Humans
• Stroke Volume
• Heart Failure
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor D
• Vascular Endothelial Growth Factor C
• Angiopoietins
• Endothelial Cells
• Prognosis
• Phospholipases A2, Secretory
• Phospholipases

• Angiopoietin-2/metabolism
• Extracellular Traps
• Human Umbilical Vein Endothelial Cells/metabolism
• Humans
• Immunity
• Neutrophils
• Reproducibility of Results
• Stomach Neoplasms/pathology
• Tumor Microenvironment

• Lymphatic system
• cancer lymphangiogenesis
• lymph node
• lymphatic endothelial cells
• lymphatic metastasis

Fasting blood glucose and glycated hemoglobin (HbA1c) levels are associated with the risk of pancreatic cancer.

To examine the relationship between perioperative glucose and HbA1c levels and prognosis in patients with pancreatic cancer.

PubMed, Embase, and the Cochrane Library were queried for potentially eligible studies published up to May 2021. The exposures were perioperative fasting glucose and HbA1c levels. The primary outcome was survival. The secondary outcome was complications. All analyses were performed using the random-effects model.

Ten studies (48,424 patients) were included. The pre-operative (HR=1.10, 95%CI: 0.89-1.35; I² = 45.1%, P_{heterogeneity}=0.078) and postoperative (HR=1.19, 95%CI: 0.92-1.54; I² = 67.9%, P_{heterogeneity}=0.001) blood glucose levels were not associated with the survival to pancreatic cancer. Similar results were observed for HbA1c (HR=1.09, 95%CI: 0.75-1.58; I² = 64.2%, P_{heterogeneity}=0.039), fasting blood glucose (FBG)/HbA1c (HR=1.16, 95%CI: 0.67-1.68; I² = 0.0%, P_{heterogeneity}=0.928), and FBG (HR=1.75, 95%CI: 0.81-3.75; I² = 79.4%, P_{heterogeneity}=0.008). Pre-operative blood glucose levels were not associated with postoperative complications (OR=0.90, 95%CI: 0.52-1.56), but postoperative glucose levels were associated with postoperative complications (OR=3.06, 95%CI: 1.88-4.97; I² = 0.0%, P_{heterogeneity}=0.619).

Blood glucose, FBG, and HbA1c levels are not associated with the survival of patients with pancreatic cancer. Postoperative blood glucose levels could predict postoperative complications.

• complications
• glycemia
• meta-analysis
• pancreatic neoplasms
• prognosis

• annexin A3
• biomarkers
• drug resistance
• neoplasm
• signal transduction
• tumorigenesis

Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSA^{KIT WT} and ROSA ^{KIT D816V} and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSA^{KIT WT}, ROSA^{KIT D816V} and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.

• Angiopoietins
• Mast cells
• Mastocytosis
• Stem cell factor
• Tryptase
• Vascular endothelial growth factors

The lymphatic system plays key roles in the bodies’ defence against disease, including cancer. The expansion of this system is termed lymphangiogenesis and it is orchestrated by factors and conditions within the microenvironment. One approach to prevent cancer progression is by interfering with these microenvironment factors that promote this process and that facilitate the spread of cancer cells to distant organs. One of these factors are non-coding RNAs. This review will summarize recent findings of the distinct roles played by non-coding RNAs in the lymphatic system within normal tissues and tumours. Understanding the mechanisms involved in this process can provide new avenues for therapeutic intervention for inhibiting the spread of cancer.

Lymphatic vessels are regarded as the ”forgotten” circulation. Despite this, growing evidence has shown significant roles for the lymphatic circulation in normal and pathological conditions in humans, including cancers. The dissemination of tumor cells to other organs is often mediated by lymphatic vessels that serve as a conduit and is often referred to as tumor-associated lymphangiogenesis. Some of the most well-studied lymphangiogenic factors that govern tumor lymphangiogenesis are the vascular endothelial growth factor (VEGF-C/D and VEGFR-2/3), neuroplilin-2 (NRP2), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), to name a few. However, recent findings have illustrated that non-coding RNAs are significantly involved in regulating gene expression in most biological processes, including lymphangiogenesis. In this review, we focus on the regulation of growth factors and non-coding RNAs (ncRNAs) in the lymphatic development in normal and cancer physiology. Then, we discuss the lymphangiogenic factors that necessitate tumor-associated lymphangiogenesis, with regards to ncRNAs in various types of cancer. Understanding the different roles of ncRNAs in regulating lymphatic vasculature in normal and cancer conditions may pave the way towards the development of ncRNA-based anti-lymphangiogenic therapy.

• LEC
• lncRNA
• lymphatic
• miRNA
• ncRNA
• tumor-associated lymphangiogenesis

• PI3K/Akt signaling pathway
• annexin A3
• epithelial mesenchymal transition
• lymph node metastasis
• microRNA-382
• pancreatic cancer

Heart failure (HF) is a growing public health burden, with high prevalence and mortality rates. In contrast to ischemic heart failure (IHF), the diagnosis of non-ischemic heart failure (NIHF) is established in the absence of coronary artery disease. Angiopoietins (ANGPTs), vascular endothelial growth factors (VEGFs) and secretory phospholipases A₂ (sPLA₂s) are proinflammatory mediators and key regulators of endothelial cells. In the present manuscript, we analyze the plasma concentrations of angiogenic (ANGPT1, ANGPT2, VEGF-A) and lymphangiogenic (VEGF-C, VEGF-D) factors and the plasma activity of sPLA₂ in patients with IHF and NIHF compared to healthy controls. The concentrations of ANGPT1, ANGPT2 and their ratio significantly differed between HF patients and healthy controls. Similarly, plasma levels of VEGF-D and sPLA₂ activity were higher in HF as compared to controls. Concentrations of ANGPT2 and the ANGPT2/ANGPT1 ratio (an index of vascular permeability) were increased in NIHF patients. VEGF-A and VEGF-C concentrations did not differ among the three examined groups. Interestingly, VEGF-D was selectively increased in IFH patients compared to controls. Plasma activity of sPLA₂ was increased in IHF and NIHF patients compared to controls. Our results indicate that several regulators of vascular permeability and smoldering inflammation are specifically altered in IHF and NIHF patients. Studies involving larger cohorts of these patients will be necessary to demonstrate the clinical implications of our findings.

• IHF
• NIHF
• VEGFs
• angiopoietins
• heart failure
• sPLA2

Accurate evaluation of microcirculation perfusion in tumor tissue is of great significance for clinical treatment and prognosis evaluation. Contrast-enhanced ultrasonography (CEUS) is a highly sensitive means of monitoring microcirculation perfusion, which can objectively reflect the microcirculation perfusion state of tumor tissue and provide reliable hemodynamic information for clinical diagnosis and treatment.

To evaluate the perfusion status of gastric cancer (GC) by CEUS, and to explore the correlation between the perfusion status and the indexes of angiogenesis.

Sixty-six patients with GC were selected as study subjects (GC group). All patients were examined by CEUS 3 d before operation. The enhanced intensity (EI) and time to peak (TTP) of GC and tumor-adjacent normal tissues were measured by time-intensity curve analysis. The levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay (ELISA), and the microvessel density (MVD) was measured after operation. Seventy-two healthy volunteers were selected as a control group for comparative analysis.

The EI and MVD were significantly higher and the TTP was significantly shorter in GC tissue than in normal tissue (P < 0.05). VEGF and Ang-2 levels were significantly higher in the GC group than in the control group (P < 0.05). EI had a positive correlation with VEGF, Ang-2, and MVD (r = 0.85, 0.81, and 0.88, respectively; P < 0.05), and TTP had a negative correlation with VEGF, Ang-2, and MVD (r = -0.72, -0.73, and -0.86, respectively; P < 0.05).

CEUS can dynamically evaluate the perfusion status of GC, and CEUS blood flow parameters have a good correlation with VEGF, Ang-2, and MVD. CEUS can provide a noninvasive imaging method for clinical evaluation of the angiogenesis status of GC.

• Contrast-enhanced ultrasound
• Gastric cancer
• Enhanced intensity
• Time to peak
• Vascular endothelial growth factor
• Angiopoietin-2
• Microvessel density

• abnormal blood vessels
• anti-angiogenesis
• immune checkpoint blockers
• tumor microenvironment
• tumor vessels normalization

• Angiogenesis Inhibitors/pharmacology
• Angiogenesis Inhibitors/therapeutic use
• Biomarkers, Tumor
• Clinical Decision-Making
• Clinical Trials as Topic
• Disease Management
• Humans
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy
• Molecular Targeted Therapy
• Neoplasms/etiology
• Neoplasms/pathology
• Neoplasms/therapy
• Neovascularization, Pathologic/therapy
• Treatment Outcome
• Tumor Microenvironment/immunology

• the Medical Science & Technology Program of Zhejiang Province, China

Tumor escape mechanisms mediated in the tumor microenvironment can significantly reduce the capacity of the anti-tumor function of the immune system. TIE2-expressing monocytes (TEMs), related angiopoietins, and tumor necrosis are considered to have a key role in this process. We aimed to investigate the abundance and clinical significance of these biomarkers in hepatocellular carcinoma (HCC).

In this retrospective study, 58 HCC patients received surgery with a curative intent. The abundance of TEMs, angiopoietin-1 and -2 were detected in tumor specimens of the HCC patients (n = 58), and together with the occurrence of histologic tumor necrosis, were associated with established clinicopathological characteristics and survival.

Patients with HCC characterized by necrosis and TEMs revealed reduced both overall survival and recurrence-free survival (all p < 0.05). Angiopoietins and TEMs were associated with metastatic and recurrent HCC. Furthermore, the formation of histologic tumor necrosis was associated with advanced tumor stage and density of TEMs (all p < 0.05).

Histologic tumor necrosis, TEMs, and related angiopoietins were associated with multiple HCC parameters and patient survival. The tumor necrosis–TEM–angiopoietin axis may offer a novel diagnostic modality to predict patient outcome after surgery for HCC.

• Angiogenesis
• Angiopoietins
• Hepatocellular carcinoma
• Prognosis
• TIE2-expressing monocytes
• Tumor necrosis
• Tumor-infiltrating macrophages

Tumor blood vessel formation (angiogenesis) is essential for tumor growth and metastasis. Two main endothelial ligand–receptor pathways regulating angiogenesis are vascular endothelial growth factor (VEGF) receptor and angiopoietin-TIE receptor pathways. The angiopoietin-TIE pathway is required for the remodeling and maturation of the blood and lymphatic vessels during embryonic development after VEGF and VEGF-C mediated development of the primary vascular plexus. Angiopoietin-1 (ANGPT1) stabilizes the vasculature after angiogenic processes, via tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) activation. In contrast, ANGPT2 is upregulated at sites of vascular remodeling. ANGPT2 is secreted by activated endothelial cells in inflammation, promoting vascular destabilization. ANGPT2 has been found to be expressed in many human cancers. Intriguingly, in preclinical models inhibition of ANGPT2 has provided promising results in preventing tumor angiogenesis, tumor growth, and metastasis, making it an attractive candidate to target in tumors. However, until now the first ANGPT2 targeting therapies have been less effective in clinical trials than in experimental models. Additionally, in preclinical models combined therapy against ANGPT2 and VEGF or immune checkpoint inhibitors has been superior to monotherapies, and these pathways are also targeted in early clinical trials. In order to improve current anti-angiogenic therapies and successfully exploit ANGPT2 as a target for cancer treatment, the biology of the angiopoietin-TIE pathway needs to be profoundly clarified.

Tumour angiogenesis is modulated on both an epigenetic and protein level and has potential implications for immune cell responses. However, the importance of related angiogenic biomarkers in cholangiocarcinoma (CCA) is unknown. This study assessed human CCA samples for the expression of angiogenesis-associated microRNAs, angiopoietins (Angs) and monocytes expressing the Ang-receptor, TIE2, with regards to prognostic significance after liver resection.

Angiogenic miRNAs were analysed in frozen samples of intrahepatic CCA (iCC; n = 43) and hilar CCA (HC; n = 45). Ang-1 and Ang-2, as well as TIE2-expressing monocytes (TEMs), were detected in paraffin-embedded iCC sections (n = 88). MiRNA expression and the abundance of TEMs and Angs were correlated with clinicopathological characteristics and survival.

MiR-126 was downregulated in 76.7% of all CCA samples, with high relative expression associated with smaller tumours and reduced lymph node metastasis. High Ang-1 expression was associated with less lymphangiosis carcinomatosa and better histological grading (all p < 0.05). The absence of TEMs in iCC correlated with elevated CA19-9 levels. High relative miR-126 and low miR-128 levels were associated with improved survival in iCC and HC, respectively (all p < 0.05). High miR-126, low miR-128 and TEMs were independent prognostic factors for recurrence-free and overall survival (all p < 0.05).

These results suggest that angiogenic miRNAs, Angs and TEMs are of prognostic value in CCA. In addition to the possible functional links between angiogenic miRNA expression profiles, Angs and immune-cell responses by TEMs, these data have clinical implications as novel diagnostic tools.

• TIE2-expressing monocytes
• angiopoietins
• cholangiocarcinoma
• miR-126
• microRNAs

M2-polarized tumor-associated macrophages (TAMs) and TIE2-expressing monocytes (TEMs) are associated with angiogenesis and have been identified as a potential prognostic marker in several solid tumors, including hepatobiliary malignancies. However, little is known regarding their influence on tumor progression and patient survival in pancreatic ductal adenocarcinoma (PDAC).

Patients with tumors characterized by the presence of CD163⁺ TAMs or TEMs in TCA or TIF, respectively, showed a significantly decreased 1-, 3- and 5-year overall and recurrence-free survival compared to patients without CD163⁺ TAMs or TEMs (all ρ < 0.05). Patients with TEMs in TCA showed a higher incidence of tumor recurrence (ρ < 0.05). Furthermore, the presence of CD163⁺ TAMs was associated with a higher tumor MVD (ρ < 0.05).

Presence of M2-polarized TAMs and TEMs is associated with a decreased overall and recurrence-free survival of patients with PDAC.

The localization and density of CD163⁺ M2-polarized TAMs and TEMs were quantified in the tumor central area (TCA) and tumor-infiltrating front (TIF) in human PDAC tissue (n = 106) and correlated to clinicopathological characteristics, tumor recurrence rates and patient survival. In parallel, tumor microvascular density (MVD) and the density of angiopoietin-positive tumor cells were quantified. Statistical analysis was performed using SPSS software.

• M2-macrophages
• TIE2-expressing monocytes
• angiogenesis
• pancreatic adenocarcinoma
• tumor-associated macrophages

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease. Numerous studies have been conducted to seek molecular targets to treat TNBC effectively, but chemotherapy is still the main choice for patients with TNBC. We have previously presented evidence of the important roles of interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL5) in TNBC tumor growth and metastasis. These experiments highlighted the importance of the crosstalk between cancer cells and stromal lymphatic endothelial cells (LECs) in tumor growth and metastasis.

We examined the viability and migration of MDA-MB-231-LN, SUM149, and SUM159 cells co-cultured with LECs when treated with maraviroc (CCR5 inhibitor) and tocilizumab (anti-IL-6 receptor antibody). To assess the anti-tumor effects of the combination of these two drugs in an athymic nude mouse model, MDA-MB-231-LN cells were implanted in the mammary fat pad and maraviroc (8 mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10 mg/kg, IP, 3 days a week) were administrated for 5 weeks and effects on tumor growth and thoracic metastasis were measured.

In this study, we used maraviroc and tocilizumab to confirm that IL-6 and CCL5 signaling are key pathways promoting TNBC cell proliferation and migration. Further, in a xenograft mouse model, we showed that tumor growth was dramatically inhibited by cMR16-1, the mouse version of the anti-IL6R antibody. The combination of maraviroc and cMR16-1 caused significant reduction of TNBC tumor growth compared to the single agents. Significantly, the combination of maraviroc and cMR16-1 abrogated thoracic metastasis.

Taken together, these findings show that IL-6 and CCL5 signaling, which promote crosstalk between TNBC and lymphatic vessels, are key enhancers of TNBC tumor growth and metastasis. Furthermore, these results demonstrate that a drug combination inhibiting these pathways may be a promising therapy for TNBC patients.

The online version of this article (10.1186/s13058-018-0981-3) contains supplementary material, which is available to authorized users.

• Drug repurposing
• Maraviroc
• Secretome
• Tocilizumab
• Triple negative breast cancer
• Tumor microenvironment

• Angiogenesis
• Apoptosis
• Brassinosteroid analog
• Cancer cell lines
• HUVEC

• Angiogenesis Inhibitors/chemistry
• Angiogenesis Inhibitors/pharmacology
• Apoptosis/drug effects
• Brassinosteroids/chemistry
• Brassinosteroids/pharmacology
• Cell Cycle Checkpoints/drug effects
• Cell Proliferation/drug effects
• Human Umbilical Vein Endothelial Cells/drug effects
• Human Umbilical Vein Endothelial Cells/pathology
• Humans
• In Vitro Techniques
• Neoplasms/blood supply
• Neoplasms/drug therapy
• Neoplasms/pathology
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/prevention & control
• Phosphorylation
• Signal Transduction
• Tumor Cells, Cultured

Angiopoietins have been found to play essential roles in tumor angiogenesis. The present study was aimed at investigating the diagnostic and prognostic values of serum angiopoietin 1 and 2 (sAng-1 and sAng-2) in cervical cancer.

The sAng-1 and sAng-2 concentrations were analyzed in 77 women with cervical cancer, 44 women with cervical intraepithelial neoplasia (CIN) and 43 women without cervical lesions by enzyme-linked immunosorbent assay. The diagnostic values of sAng-1, sAng-2 and sAng-1/sAng-2 were evaluated by receiver operating characteristic (ROC) curves. The Ang-1 and Ang-2 expression in cervical cancer tissues as well as microvessel density (MVD), were assessed by immunohistochemistry.

The concentration of sAng-2 gradually increased and the sAng-1/Ang-2 ratio was gradually decreased from normal control to CIN, then to squamous cell cancer, and the sAng-1/sAng-2 ratio was also significantly decreased in adenocarcinoma. The area under ROC curves of sAng-2 and sAng-1/sAng-2 ratio for discriminating cervical cancer from normal were 0.744 and 0.705, respectively. Decreased sAng-1/sAng-2 was significantly associated with advanced tumor stage, poor differentiation, lymph-vascular space invasion and high MVD. sAng-2 was positively correlated with the Ang-2 expression in cervix epithelia. A high sAng-1/sAng-2 ratio was associated with a longer progression-free survival and a longer overall survival in cervical cancer patients.

These findings suggest that sAng-2 and the sAng-1/sAng-2 ratio may be valuable diagnostic and prognostic biomarkers for cervical cancer.

• Angiogenesis
• Cervical cancer
• Diagnostic biomarker
• Serum angiopoietin
• Survival

• Angiogenesis
• Anti-angiogenesis therapy
• Breast cancer
• VEGF

• Animals
• Carcinoma, Pancreatic Ductal/pathology
• Cell Proliferation/drug effects
• Disease Models, Animal
• Disease Progression
• Humans
• Mice
• Neovascularization, Pathologic/pathology
• Pancreatic Neoplasms/pathology
• Peptides/pharmacology
• Phosphoproteins/antagonists & inhibitors
• RNA-Binding Proteins/antagonists & inhibitors
• Tissue Array Analysis
• Nucleolin

• bone
• breast
• cell signaling
• endocrine therapy resistance
• metastasis

• Angiopoietin-1/metabolism
• Angiopoietin-2/genetics
• Angiopoietin-2/metabolism
• Antineoplastic Agents, Hormonal/therapeutic use
• Bone Marrow/metabolism
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Survival
• Cells, Cultured
• Coculture Techniques
• Estrogen Antagonists/therapeutic use
• Estrogens/deficiency
• Estrogens/metabolism
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Integrin beta1/metabolism
• Kaplan-Meier Estimate
• Mesenchymal Stem Cells
• Receptor, TIE-2/metabolism
• Receptors, Estrogen/metabolism

• Anti-lymphangiogenic drug
• Clinical trial
• Lymph node
• Lymphatic endothelial cell
• Metastasis
• Tumor-associated inflammation

In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker.

Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n=387) or placebo (n=387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis.

Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml⁻¹) vs non-Asian patients (3193 pg ml⁻¹), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml⁻¹ increase: 1.19; 95% CI 1.10–1.29; P<0.0001 (non-Asians) and 1.37; 95% CI 1.13–1.64; P=0.0010 (Asians).

Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer.

Angiopoietin-1 (Ang1) activation of Tie2 receptors on endothelial cells (ECs) reduces adhesion by tumor cells (TCs) and limits junctional permeability to TC diapedesis. We hypothesized that systemic therapy with Vasculotide (VT)—a purported Ang1 mimetic, Tie2 agonist—can reduce the extravasation of potentially metastatic circulating TCs by similarly stabilizing the host vasculature. In vitro, VT and Ang1 treatments impeded endothelial hypermeability and the transendothelial migration of MDA-MB-231•LM2-4 (breast), HT29 (colon), or SN12 (renal) cancer cells to varying degrees. In mice, VT treatment inhibited the transit of TCs through the pulmonary endothelium, but not the hepatic or lymphatic endothelium. In the in vivo LM2-4 model, VT monotherapy had no effect on primary tumors, but significantly delayed distant metastatic dissemination to the lungs. In the post-surgical adjuvant treatment setting, VT therapeutically complemented sunitinib therapy, an anti-angiogenic tyrosine kinase inhibitor which limited the local growth of residual disease. Unexpectedly, detailed investigations into the putative mechanism of action of VT revealed no evidence of Tie2 agonism or Tie2 binding; alternative mechanisms have yet to be determined.

• Tie2
• angiopoietin
• metastasis
• tumor cell extravasation
• vascular permeability

• Lymph node
• Lymphatics
• Pancreatic cancer

• Animals
• Carcinoma, Pancreatic Ductal/immunology
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/secondary
• Carcinoma, Pancreatic Ductal/surgery
• Cell Communication
• Humans
• Lymph Node Excision
• Lymphangiogenesis
• Lymphatic Metastasis
• Lymphatic System/immunology
• Lymphatic System/metabolism
• Lymphatic System/pathology
• Lymphatic System/surgery
• Neoplasm Invasiveness
• Pancreatectomy
• Pancreatic Neoplasms/immunology
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/surgery
• Treatment Outcome
• Tumor Microenvironment

• U54 CA163120 NCI NIH HHS
• U01 CA111294 NCI NIH HHS
• R01 CA057362 NCI NIH HHS
• P50 CA127297 NCI NIH HHS
• P30 CA036727 NCI NIH HHS
• T32 CA009476 NCI NIH HHS

• Animals
• Aorta/drug effects
• Aorta/pathology
• Calcium-Binding Proteins/genetics
• Cell Line, Tumor
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Female
• Humans
• Intercellular Signaling Peptides and Proteins/genetics
• Interleukin-6/genetics
• Interleukin-6/metabolism
• Interleukin-6/pharmacology
• Jagged-1 Protein
• Male
• Membrane Proteins/genetics
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Molecular Targeted Therapy/methods
• Neovascularization, Pathologic/chemically induced
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Organ Culture Techniques
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Pericytes/drug effects
• Pericytes/pathology
• Rats, Wistar
• Serrate-Jagged Proteins
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor A/pharmacology
• Vesicular Transport Proteins/genetics
• Xenograft Model Antitumor Assays

• 12007 Cancer Research UK
• G0901609 Medical Research Council
• 18673 Cancer Research UK
• A16354 Cancer Research UK
• 322566 European Research Council
• Arthritis Research UK
• G0501974 Medical Research Council
• 19207 Versus Arthritis
• 12-1068 Worldwide Cancer Research
• 16354 Cancer Research UK

Tumor progression locus 2 (Tpl2) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that conveys various intra- and extra-cellular stimuli to effector proteins of cells provoking adequate adoptive responses. Recent studies have elucidated that Tpl2 is an indispensable signal transducer as an MAP3K family member in diverse signaling pathways that regulate cell proliferation, survival, and death. Since tumorigenesis results from dysregulation of cellular proliferation, differentiation, and apoptosis, Tpl2 participates in many decisive molecular processes of tumor development and progression. Moreover, Tpl2 is closely associated with cytokine release of inflammatory cells, which has crucial effects on not only tumor cells but also tumor microenvironments. These critical roles of Tpl2 in human cancers make it an attractive anti-cancer therapeutic target. However, Tpl2 contradictorily works as a tumor suppressor in some cancers. The double-sided effects of Tpl2 originate from the specific upstream and downstream signaling environment of each tumor, since Tpl2 interacts with various signaling components. This review summarizes recent studies concerning the possible roles of Tpl2 in human cancers and considers its possibility as a therapeutic target, against which novel anti-cancer agents could be developed.

• Cytokines/metabolism
• Disease Progression
• Humans
• Immune System/immunology
• Immune System/metabolism
• Inflammation Mediators/metabolism
• MAP Kinase Kinase Kinases/metabolism
• Models, Biological
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/pathology
• Proto-Oncogene Proteins/metabolism
• Signal Transduction
• Tumor Microenvironment

• Angiogenesis
• Angiopoietin-2
• Cell Invasion
• Cell Migration
• Endothelial Cell
• Integrin
• Tie2

• Extracellular Matrix/metabolism
• Extracellular Matrix/pathology
• Humans
• Lymphangiogenesis/genetics
• Lymphatic Metastasis/genetics
• Lymphatic Metastasis/pathology
• Lymphatic Vessels/pathology
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/pathology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Signal Transduction
• Tumor Microenvironment/genetics