• cancer
• chronic inflammation
• tumor microenvironment

• Humans
• Inflammation/pathology
• Inflammation/immunology
• Inflammation/complications
• Neoplasms/pathology
• Neoplasms/immunology
• Disease Progression
• Neoplasm Metastasis
• Tumor Microenvironment/immunology
• Animals
• Carcinogenesis/pathology

• JP23K07435 Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan

• cancer associated fibroblasts
• fibroblast activation protein
• molecular imaging
• nuclear medicine
• radiopharmaceuticals
• tumor microenvironment

• anesthesia
• cancer recurrence
• lung cancer
• metastasis
• perioperative care

• No. 2021R1G1A1014702 National Research Foundation of Korea (NRF)

• Age-related macular degeneration
• Angiogenesis
• Diabetic retinopathy
• Inflammation
• Prostaglandins
• Prostanoids
• Retina
• Retinal artery occlusion
• Retinal occlusive disease
• Retinal vein occlusion
• Retinopathy of prematurity
• Uveitis

• Humans
• Prostaglandins/metabolism
• Signal Transduction
• Retinal Diseases/metabolism
• Retinal Diseases/drug therapy
• Animals
• Retinal Vessels/metabolism
• Retinal Vessels/pathology

• F31 EY034386 NEI NIH HHS

• amniotic membrane transplantation
• angiogenic factors
• anti-VEGF drugs
• antiangiogenic factors
• cornea
• fine needle diathermy
• immunosuppressive drugs
• keratoplasty
• neovascularization
• nonsteroidal anti-inflammatory drugs
• steroids

• Humans
• Corneal Neovascularization/drug therapy
• Corneal Neovascularization/therapy
• Corneal Neovascularization/metabolism
• Animals
• Genetic Therapy/methods
• Angiogenesis Inhibitors/therapeutic use
• Transforming Growth Factor beta/metabolism

• Humans
• Dinoprostone/metabolism
• Tumor Microenvironment
• Animals
• Receptors, Prostaglandin E, EP2 Subtype/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/immunology
• Neoplasms/pathology
• Receptors, Prostaglandin E, EP4 Subtype/metabolism
• Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors
• Signal Transduction

• Humans
• Animals
• Neovascularization, Pathologic
• Transient Receptor Potential Channels/metabolism
• Transient Receptor Potential Channels/physiology
• Signal Transduction

• R15 CA202847 NCI NIH HHS
• T32 HL134625 NHLBI NIH HHS
• R01 AI144115 NIAID NIH HHS
• R01 HL148585 NHLBI NIH HHS
• R01 HL119705 NHLBI NIH HHS

• Humans
• Drug Delivery Systems
• Pharmaceutical Preparations
• Lymphatic System
• Lupus Erythematosus, Systemic/drug therapy

• R01 AI155908 NIAID NIH HHS

• Mammalian evolution
• Mammary gland
• Marsupials
• Organoids
• ROCK protein

• Humans
• Female
• Animals
• Marsupialia/genetics
• Organoids/metabolism
• Lactation
• Eutheria
• Mammary Glands, Animal/metabolism
• Mammary Glands, Human

• R01 GM124491 NIGMS NIH HHS
• 7R01GM124491 NIGMS NIH HHS
• National Institute of General Medical Sciences
• Department of Defense Breast Cancer Research Program

• analgesia
• anesthesia
• anesthetics
• cancer recurrence
• metastasis
• opioids
• prostate cancer
• statins
• surgery and inflammatory response

• cancer microenvironment
• hepatocellular carcinoma
• liver cancer

• Animals
• Male
• Mice
• beta Catenin/metabolism
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Carcinoma, Hepatocellular/metabolism
• Fatty Acid Desaturases
• Hepatic Stellate Cells/metabolism
• Liver Neoplasms/metabolism
• Receptors, Leukotriene B4/genetics
• Receptors, Leukotriene B4/metabolism
• Tumor Microenvironment

• R01 CA249204 NCI NIH HHS
• K99 CA273538 NCI NIH HHS
• F32 CA247414 NCI NIH HHS
• I01 BX001991 BLRD VA
• P30 GM118247 NIGMS NIH HHS
• P30 CA014089 NCI NIH HHS
• P50 AA011999 NIAAA NIH HHS
• IK6 BX004205 BLRD VA
• R01 CA248984 NCI NIH HHS
• R24 AA012885 NIAAA NIH HHS
• P30 DK048522 NIDDK NIH HHS
• U01 AA027681 NIAAA NIH HHS
• P20 GM103549 NIGMS NIH HHS
• R01 CA256480 NCI NIH HHS
• P30 CA196521 NCI NIH HHS
• R01 CA234128 NCI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• U.S. Department of Veterans Affairs (Department of Veterans Affairs)

• HuR
• breast cancer
• eltrombopag (ELB)
• lung metastasis
• lymph node metastasis
• macrophage

• Animals
• Female
• Humans
• Breast Neoplasms/metabolism
• Cell Line, Tumor
• Cyclooxygenase 2/metabolism
• ELAV-Like Protein 1
• Vascular Endothelial Growth Factor C/genetics

• COX-2
• COX-2 inhibitors
• EP
• PGE2
• tumor immune escape

• cancer
• cyclooxygenase
• inflammation
• non-steroidal anti-inflammatory drugs
• pharmacogenomics

• Cancer
• Competing endogenous RNA
• Diagnosis
• Drug resistance
• LINC00461
• Prognosis

While surgical resection is the gold standard treatment for solid tumors, cancer recurrence after surgery is common. Immunosurveillance of remnant tumor cells is an important protective mechanism. Therefore, maintenance of anti-tumor cell activity and proper levels of inflammatory mediators is crucial. An increasing body of evidence suggests that surgery itself and perioperative interventions could affect these pathophysiological responses. Various factors, such as the extent of tissue injury, perioperative medications such as anesthetics and analgesics, and perioperative management including transfusions and methods of mechanical ventilation, modulate the inflammatory response in lung cancer surgery. This narrative review summarizes the pathophysiological mechanisms involved in cancer recurrence after surgery and perioperative management related to cancer recurrence after lung cancer surgery.

• cancer pain
• immunotherapy
• neuroinflammation
• opioid-induced hyperalgesia
• tumor microenvironment

• cancer
• cancer survivor
• cardiovascular risk reduction
• cholesterol
• dyslipidemia

Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair of DNA double-strand breaks. Loss of BRCA1 is lethal to embryos due to extreme genomic instability and the activation of p53-dependent apoptosis. However, the apoptosis is resisted in BRCA1-deficient cancer cells even though their p53 is proficient. In this study, by analysis of transcriptome data of ovarian cancer patients bearing BRCA1 defects in TCGA database, we found that cAMP signaling pathway was significantly activated. Experimentally, we found that BRCA1 deficiency caused an increased expression of ADRB1, a transmembrane receptor that can promote the generation of cAMP. The elevated cAMP not only inhibited DNA damage-induced apoptosis through abrogating p53 accumulation, but also suppressed the proliferation of cytotoxic T lymphocytes by enhancing the expression of immunosuppressive factors DKK1. Inhibition of ADRB1 effectively killed cancer cells by abolishing the apoptotic resistance. These findings uncover a novel mechanism of apoptotic resistance in BRCA1-deficient ovarian cancer cells and point to a potentially new strategy for treating BRCA1-mutated tumors.

• China Postdoctoral Science Foundation
• National Natural Science Foundation of China

Culprits of cancer development, metastasis, and drug resistance, cancer stem cells (CSCs) are characterized by specific markers, active developmental signaling pathways, metabolic plasticity, increased motility, invasiveness, and epithelial-mesenchymal transition. In breast cancer, these cells are often more prominent in aggressive disease, are amplified in drug-resistant tumors, and contribute to recurrence. For breast cancer, two distinct CSC populations exist and are typically defined by CD44+/CD24- cell surface marker expression or increased aldehyde dehydrogenase (ALDH) activity. These CSC populations share many of the same properties but also exhibit signaling pathways that are more active in CD44+/CD24- or ALDH+ populations. Understanding these CSC populations and their shared or specific signaling pathways may lead to the development of novel therapeutic strategies that will improve breast cancer patient outcomes. Herein, we review the current evidence and assess published patient tumor datasets of sorted breast CSC populations for evidence of heightened prostaglandin E2 (PGE₂) signaling and activity in these breast CSC populations. PGE₂ is a biologically active lipid mediator and in cancer PGE₂ promotes tumor progression and poor patient prognosis. Overall, the data suggests that PGE₂ signaling is important in propagating breast CSCs by enhancing inherent tumor-initiating capacities. Development of anti-PGE₂ signaling therapeutics may be beneficial in inhibiting tumor growth and limiting breast CSC populations.

• Canadian Institutes of Health Research

• Blood–brain barrier
• Brain metastasis
• Breast cancer
• COX-2
• miR-101
• miR-26b

Loss of function of the lipid kinase diacylglycerol kinase ε (DGKε), encoded by the gene DGKE, causes a form of atypical hemolytic uremic syndrome that is not related to abnormalities of the alternative pathway of the complement, by mechanisms that are not understood. By generating a potentially novel endothelial specific Dgke-knockout mouse, we demonstrate that loss of Dgke in the endothelium results in impaired signaling downstream of VEGFR2 due to cellular shortage of phosphatidylinositol 4,5-biphosphate. Mechanistically, we found that, in the absence of DGKε in the endothelium, Akt fails to be activated upon VEGFR2 stimulation, resulting in defective induction of the enzyme cyclooxygenase 2 and production of prostaglandin E₂ (PGE₂). Treating the endothelial specific Dgke-knockout mice with a stable PGE₂ analog was sufficient to reverse the clinical manifestations of thrombotic microangiopathy and proteinuria, possibly by suppressing the expression of matrix metalloproteinase 2 through PGE₂-dependent upregulation of the chemokine receptor CXCR4. Our study reveals a complex array of autocrine signaling events downstream of VEGFR2 that are mediated by PGE₂, that control endothelial activation and thrombogenic state, and that result in abnormalities of the glomerular filtration barrier.

• Inositol phosphates
• Microcirculation
• Nephrology

The aim of this study was to investigate the effects of artesunate (ART) on breast epithelial cell proliferation in vitro and in vivo.

Immortalized human non-cancer mammary epithelial (MCF-10A) cells were used to determine the effect of ART on estrogen-induced mammary hyperplasia cells. We investigated the effect of ART on the synthesis of cyclooxygenase-2 (COX-2) and proliferating cell nuclear antigen (PCNA) in MCF-10A by treating MCF-10A 36 h with different concentrations of ART (0, 100, 200, 400 µm, n=12/group). We then investigated the effect of ART on estrogen induced COX-2, PCNA, nuclear factor-kappa B (NF-κB), and pNF-κB synthesis by treating MCF-10A with both estrogen and ART (0, 50, 100, 200 µm, n=12/group). A mammary hyperplasia model (MGH) was established in rats. All rats (n=12) were divided into 4 groups [group A: negative control (NC) + Art −; group B: NC + Art +; group C: MGH + Art −; group D: MGH + Art +] by the random number table method and the effects of ART on estradiol-induced mammary hyperplasia, fibrosis, and phosphorylation of AKT and NF-κB were studied by histopathological staining, Masson trichrome staining, immunohistochemistry (IHC), and western blotting.

The proliferation and inflammation of mammary epithelial cells were blocked by ART (P<0.05). The phosphorylation of NF-κB induced by estradiol in MCF-10A was attenuated by ART (P<0.05). In the rat MGH, ART reduced cell proliferation and fibrosis (P<0.05) and inhibited the phosphorylation of AKT and NF-κB (P<0.05).

The drug ART inhibits estrogen-induced breast hyperplasia by blocking AKT and NFkB phosphorylation.

• Artesunate (ART)
• benign mammary gland hyperplasia
• nuclear factor-kappa B (NF-κB)
• traditional Chinese medicine

• COX-2 inhibitor
• Cisplatin
• Drug-drug conjugate
• Nanoprodrug
• Synergistic therapy

G protein-coupled receptors (GPCRs) represent a large family of transmembrane proteins that transduce an external stimulus into a variety of cellular responses. They play a critical role in various pathological conditions in humans, including cancer, by regulating a number of key processes involved in tumor formation and progression. The epithelial-mesenchymal transition (EMT) is a fundamental process in promoting cancer cell invasion and tumor dissemination leading to metastasis, an often intractable state of the disease. Uncontrolled proliferation and persistent metabolism of cancer cells also induce oxidative stress, hypoxia, and depletion of growth factors and nutrients. These disturbances lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and induce a cellular condition called ER stress (ERS) which is counteracted by activation of the unfolded protein response (UPR). Many GPCRs modulate ERS and UPR signaling via ERS sensors, IRE1α, PERK, and ATF6, to support cancer cell survival and inhibit cell death. By regulating downstream signaling pathways such as NF-κB, MAPK/ERK, PI3K/AKT, TGF-β, and Wnt/β-catenin, GPCRs also upregulate mesenchymal transcription factors including Snail, ZEB, and Twist superfamilies which regulate cell polarity, cytoskeleton remodeling, migration, and invasion. Likewise, ERS-induced UPR upregulates gene transcription and expression of proteins related to EMT enhancing tumor aggressiveness. Though GPCRs are attractive therapeutic targets in cancer biology, much less is known about their roles in regulating ERS and EMT. Here, we will discuss the interplay in GPCR-ERS linked to the EMT process of cancer cells, with a particular focus on oncogenes and molecular signaling pathways.

• COX-2
• LINC00461
• endometrial carcinoma
• metastasis
• miR-219-5p
• tumor growth

• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cyclooxygenase 2/metabolism
• Endometrial Neoplasms/genetics
• Endometrial Neoplasms/metabolism
• Female
• Humans
• MicroRNAs/metabolism
• Middle Aged
• RNA, Long Noncoding/metabolism
• Signal Transduction

• Cancer therapy
• Immune regulation
• Lipid metabolism
• Stress response
• Tumor microenvironment

• HPRG
• ROS
• cell migration
• confocal microscopy
• human prostate cancer cells
• nanomaterials
• nanomedicine
• peptides
• prostaglandins
• theranostics

A close association between pericytes and endothelial cells (ECs) is crucial to the stability and function of capillary blood vessels and microvessels. The loss or dysfunction of pericytes results in significant disruption of these blood vessels as observed in pathological conditions, including cancer, diabetes, stroke, and Alzheimer’s disease. Prostaglandin E2 (PGE2) is a lipid mediator of inflammation, and its tissue concentration is elevated in cancer and neurological disorders. Here, we show that the exposure to PGE2 switches pericytes to a fast-migrating, loosely adhered phenotype that fails to intimately interact with ECs. N-cadherin and connexin-43 in adherens junction and gap junction between pericytes and ECs are downregulated by EP-4 and EP-1-dependent mechanisms, leading to breakdown of the pericyte–EC interaction. Furthermore, R-Ras, a small GTPase important for vascular normalization and vessel stability, is transcriptionally repressed by PGE2 in an EP4-dependent manner. Mouse dermal capillary vessels lose pericyte coverage substantially upon PGE2 injection into the skin. Our results suggest that EP-mediated direct disruption of pericytes by PGE2 is a key process for vascular destabilization. Restoring pericyte–EC interaction using inhibitors of PGE2 signaling may offer a therapeutic strategy in cancer and neurological disorders, in which pericyte dysfunction contributes to the disease progression.

The aim of this study was to evaluate the prognostic impact of prostaglandin E2 receptor 3 (EP3) receptor expression might have on the two different breast cancer entities: multifocal/multicentric versus unifocal. As the prognosis determining aspects, we investigated the overall- and disease-free survival by uni-and multivariate analysis. To underline the study’s conclusion, we additionally considered the histopathological grading and the tumor node metastasis (TNM) staging system. A retrospective statistical analysis was performed on survival related events in a series of 289 sporadic breast cancer (BC) patients treated at the Department of Obstetrics and Gynecology at the Ludwig–Maximillian’s University in Munich between 2000 and 2002. The EP3 receptor expression was analyzed by immunohistochemistry and showed to have a significantly positive association with breast cancer prognosis for both entities, although with major differences. Patients with unifocal BC with EP3 receptor expression showed a significant improved overall survival, in contrast to the patient cohort with multifocal/multicentric BC. In this group, EP3 expression revealed its positive impact merely five years after initial diagnosis. Underlining the positive influence of EP3 as a positive prognosticator notably for unifocal breast cancer, only this patient cohort showed favorable outcomes in staging and grading. Especially EP3 expression in unifocal breast cancer was identified as an independent prognostic marker for the overall survival, when adjusted for age, grading, and staging. Altogether, our results strengthen the need to further investigate the behavior of EP3 in breast cancer and understand why markers linked to inflammation show different effects on prognosis and clinicopathological parameters on each focality type.

• breast cancer
• focality
• multifocal
• prognosis
• prostaglandin E2 receptor 3 (EP3)
• unifocal

• Biomarkers, Tumor/metabolism
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Breast Neoplasms/surgery
• Female
• Follow-Up Studies
• Humans
• Middle Aged
• Prognosis
• Receptors, Estrogen/metabolism
• Receptors, Progesterone/metabolism
• Receptors, Prostaglandin E, EP3 Subtype/metabolism
• Retrospective Studies
• Survival Rate

• communication in cancer
• oncology therapy
• therapeutic target
• tumor microenvironment

• Profile of selected factors secreted by fibroblasts at various cancer stages Medical University of Warsaw

• Breast cancer
• Chemoresistance
• EMT
• Inflammatory cytokine
• Metastasis
• Proliferation
• Stem cell
• Survival
• TNF-α

Lung cancer is the leading cause of cancer-related death worldwide, and the timely and serial assessment of low-dose computed tomography (LDCT) in high-risk populations remains a challenge. Furthermore, testing a single biomarker for the diagnosis of lung cancers is of relatively low effectiveness. Thus, a stronger diagnostic combination of blood biomarkers is needed to improve the diagnosis of non-small cell lung cancer (NSCLC).

The blood levels of individual biomarkers [IDH1, DNA methylation of short stature homeobox 2 gene (SHOX2), and prostaglandin E receptor 4 gene (PTGER4)] were measured and statistically analyzed in samples from healthy controls and patients with lung cancer. In total, 221 candidates were enrolled and randomly assigned into two groups for the training and validation of a diagnostic panel. Additionally, a subgroup analysis was performed in the whole cohort.

A newly combined 3-marker diagnostic model for lung cancers was established and validated with area under the receiver operating characteristic (ROC) curve (AUC) values ranging from 0.835 to 0.905 in independent groups showing significantly stronger diagnostic value compared with a single tested biomarker. The sensitivity of the diagnostic model was as high as 86.1% and 80.0% in the training and validation sets, respectively. Although no apparent differences were found between the 3-marker and 2-marker models, the high clinical T-stage and histological type specificity of IDH1 and two other methylated DNA biomarkers were demonstrated in the subgroup analysis.

The combination of single biomarkers with high stage-specificity and histological type specificity (SHOX2 and PTGER4 DNA methylation and IDH1) showed better diagnostic performance in the detection of lung cancers compared with single marker assessment. A greater clinical utility of the panel may be developed by adding demographic/epidemiologic characteristics.

• Circulating tumor DNA
• DNA methylation
• Diagnostic biomarker
• IDH1
• Lung cancer

• cancer
• circulating tumor cells (CTCs)
• coagulation system
• disseminated tumor cells (DTCs)
• immunosuppression
• inflammation
• ischemia/reperfusion injury (IRI)
• nervous system
• surgical stress

• Arachidonic acid
• Cancer
• EGFR
• Eicosanoids

• Animals
• Eicosanoids/metabolism
• ErbB Receptors/metabolism
• Heparin-binding EGF-like Growth Factor/metabolism
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Signal Transduction

• Cancer
• Eicosanoid
• Matrix metalloproteinase
• Metastasis

Ruyan Neixiao Cream (RYNXC), a patented Chinese herbal formula, was reported to have the effect of treating mammary precancerous disease. In this study, we predicted the potential targets, pathways, and diseases of the ingredients contained in each herbal of RYNXC and constructed an ingredients-targets-diseases network. Then, we analyzed molecular mechanisms of this Chinese herbal formula by MCF-10AT cells and model rats of breast precancerous lesions. BATMAN-TCM prediction showed that ESR1, PGR, PTGS2, EGFR, and Src were mRNA targets of RYNXC. Our results suggested that RYNXC transdermal fluid downregulated ESR1, PGR, PTGS2, EGFR, and Src expression at gene and protein level in MCF-10AT cells. In the rat breast precancerous lesions model, high and low dose RYNXC could also significantly reduce genes and proteins expression of ESR1, PGR, PTGS2, EGFR, and Src. Taken together these data indicate that RYNXC targets multiple molecules responsible for breast precancerous lesion and is an effective Chinese herbal formula. So RYNXC may be a promising external drug for breast precancerous lesions.

Female breast cancer (BrCa) is the most common noncutaneous cancer among women in the United States. Human epidemiological studies reveal that a p53 single-nucleotide polymorphism (SNP) at codon 72, encoding proline (P72) or arginine (R72), is associated with differential risk of several cancers, including BrCa. However, the molecular mechanisms by which these variants affect mammary tumorigenesis remain unresolved. To investigate the effects of this polymorphism on susceptibility to mammary cancer, we used a humanized p53 mouse model, homozygous for either P72 or R72. Our studies revealed that R72 mice had a significantly higher mammary tumor incidence and reduced latency in both DMBA-induced and MMTV-Erbb2/Neu mouse mammary tumor models compared to P72 mice. Analyses showed that susceptible mammary glands from E-R72 (R72 x MMTV-Erbb2/Neu) mice developed a senescence-associated secretory phenotype (SASP) with influx of proinflammatory macrophages, ultimately resulting in chronic, protumorigenic inflammation. Mammary tumors arising in E-R72 mice also had an increased influx of tumor-associated macrophages, contributing to angiogenesis and elevated tumor growth rates. These results demonstrate that the p53 R72 variant increased susceptibility to mammary tumorigenesis through chronic inflammation.

• COX-2
• breast cancer
• celecoxib
• inflammation

• Cancer
• In vivo
• Morphine
• Mu-opioid receptor

• Analgesics, Opioid/pharmacology
• Analgesics, Opioid/therapeutic use
• Animals
• Cancer Pain/drug therapy
• Cancer Pain/metabolism
• Cancer Pain/pathology
• Humans
• Morphine/pharmacology
• Morphine/therapeutic use
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Receptors, Opioid, mu/metabolism