Targeting cancer-derived extracellular vesicles by combining CD147 inhibition with tissue factor pathway inhibitor for the management of urothelial cancer cells.

Background: Extracellular vesicles (EVs), including microvesicles, hold promise for the management of bladder urothelial carcinoma (BLCA), particularly because of their utility in identifying therapeutic targets and their diagnostic potential using easily accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer-derived EVs, tissue factor (TF) and CD147 have been implicated in promoting tumor progression. In this in vitro study, we explored a novel approach to impede cancer cell migration and metastasis by simultaneously targeting these molecules on urothelial cancer-derived EVs.

An update on the secretory functions of brown, white, and beige adipose tissue: Towards therapeutic applications.

Adipose tissue, including white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, is vital in modulating whole-body energy metabolism. While WAT primarily stores energy, BAT dissipates energy as heat for thermoregulation. Beige adipose tissue is a hybrid form of adipose tissue that shares characteristics with WAT and BAT.

Contributing and limiting factors to guideline-adherent therapy in senior and elderly breast cancer patients: a questionnaire-based cross-sectional study using clinical and cancer registry data in Germany.

Purpose: Elderly cancer patients are less likely to be treated in accordance with evidence-based guideline recommendations. This study examines patient-related factors associated with deviations from guideline recommendations.

Methods: Using medical documentation and cancer registry data, we investigated the treatment courses of female breast cancer patients aged 50 and older in Germany regarding compliance with German guidelines.

Three-month life expectancy as inclusion criterion for clinical trials in advanced pancreatic cancer: is it really a valid tool for patient selection?

Purpose: To analyze the 3-month life expectancy rate in pancreatic cancer (PC) patients treated within prospective trials from the German AIO study group.

Patients And Methods: A pooled analysis was conducted for patients with advanced PC that were treated within five phase II/III studies conducted between 1997 and 2017 (Gem/Cis, Ro96, RC57, ACCEPT, RASH). The primary goal for the current report was to identify the actual 3-month survival rate, a standard inclusion criterion in oncology trials.

Physicians' perspectives on family caregivers' roles in elderly cancer patients' therapies: a qualitative, interview-based study.

Purpose: Clinical communication and facilitating informed and sound medical decisions become challenging as patients age and suffer from age-associated impairments. Family caregivers are perceived as essential actors in addressing these challenges. Here, we explore physicians' perspectives on family caregivers' roles and their involvement in consultations and therapy decision-making situations of elderly cancer patients.

The role of family confidants and caregivers in the care of older cancer patients: Extending the concept of "shared decision-making".

Background And Aims: Family caregivers play an important role in assisting their family members with cancer, but their influence on the treatment decision-making process has not yet been adequately investigated. This exploratory study approached this topic via reconstructive methodology, focusing on assessing patient-caregiver relationships.

Methods: We conducted semi-structured interviews with 37 mostly elderly cancer patients (median age: 74 years) about the context of their diagnosis, treatment decision, and family support.

Biologically Active Tissue Factor-Bearing Larger Ectosome-Like Extracellular Vesicles in Malignant Effusions from Ovarian Cancer Patients: Correlation with Incidence of Thrombosis.

The development of malignant effusions such as ascites reflects a massive progression of a malignant disease. In patients with ovarian carcinoma, a high amount of ascites (>500 mL) is an independent negative prognostic marker. The composition and constituents of ascites reflect the inflammatory environment of the underlying tumor.

Ambrisentan, an endothelin receptor type A-selective antagonist, inhibits cancer cell migration, invasion, and metastasis.

Several studies reported a central role of the endothelin type A receptor (ETAR) in tumor progression leading to the formation of metastasis. Here, we investigated the in vitro and in vivo anti-tumor effects of the FDA-approved ETAR antagonist, Ambrisentan, which is currently used to treat patients with pulmonary arterial hypertension. In vitro, Ambrisentan inhibited both spontaneous and induced migration/invasion capacity of different tumor cells (COLO-357 metastatic pancreatic adenocarcinoma, OvCar3 ovarian carcinoma, MDA-MB-231 breast adenocarcinoma, and HL-60 promyelocytic leukemia).

Extracellular Vesicles and Cell-Cell Communication: New Insights and New Therapeutic Strategies Not Only in Oncology.

The discovery that tumors are not separated from systemic regulatory mechanisms of the body but are rather integrated into them, and even use these mechanisms for their own purposes, was one of the most important findings in tumor biology of the last few years [...

Detection and Quantification of Extracellular Vesicles via FACS: Membrane Labeling Matters!

The field of extracellular vesicle (EV) research is challenged by the lack of standardized protocols to identify and specifically distinguish between exosomes and ectosomes, which are released via exocytosis or plasma membrane shedding, respectively. Using sequential centrifugation, we separated EV subpopulations from supernatants of COLO 357 pancreas carcinoma cells based on size and mass. After 10,000× centrifugation, we reconstituted high-speed (hs) EVs from the pellet, directly labeled them with the membrane dye carboxyfluorescein diacetate succinimidyl ester (CFSE), and performed flow cytometry based analysis.

Tissue factor activity on microvesicles from cancer patients.

Purpose: The expression of active tissue factor (TF) on the surface of microvesicles (MVs) is essential for the activation of the coagulation system and transduction of the signaling pathways in cancer cells. In its use as a biomarker for cancer-associated venous thromboembolism (VTE), TF has shown high expression variability. As a contribution to this discussion, we present a study investigating plasma samples from patients with various progressive tumors at high risk for VTE.

Extracellular Vesicles: Subcellular Organelles With the Potential to Spread Cancer Resistance.

Although modern anticancer drugs have made great progress in disease treatment, the occurrence of drug resistance often leads to treatment failure. Understanding the molecular basis of resistance mechanisms is important to determine prognosis and develop strategies for circumvention. In this context, subcellular vesicles released by cancer cells have been identified to mediate cellular resistance by various mechanisms.

RAC1B Suppresses TGF-β1-Dependent Cell Migration in Pancreatic Carcinoma Cells through Inhibition of the TGF-β Type I Receptor ALK5.

The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown previously by RNA interference-mediated knockdown (KD) to function as a powerful inhibitor of transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition in epithelial cells, but the underlying mechanism has remained enigmatic. Using pancreatic carcinoma cells, we show that both KD and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated knockout (KO) of RAC1B increased the expression of the TGF-β type I receptor ALK5 (activin receptor-like kinase 5), but this effect was more pronounced in CRISPR-KO cells. Of note, in KO, but not KD cells, ALK5 upregulation was associated with resensitization of to induction by TGF-β1 stimulation.

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis.

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer's disease, and ovarian cancer.

Heterogeneity of microvesicles from cancer cell lines under inflammatory stimulation with TNF-α.

Microvesicles (MVs) represent a subgroup of extracellular vesicles (EVs) emerging from various cells by blebbing of their outer membrane. Therefore, they share features such as membrane composition and antigenicity with their parental cells. Released by many immune and tumor cells, MVs act as intercellular messengers, account for horizontal gene transfer and can activate the coagulation system.

Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer.

Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described.

Cancer Diagnosis: A Trauma for Patients and Doctors Alike.

The quality of communication between oncologists and patients can have a direct effect on each individual's coping mechanisms for dealing with stress, especially when dealing with the stress of a cancer diagnosis. This report applies the findings of trauma research to this aspect of oncological care.

The Role of PAR2 in TGF-β1-Induced ERK Activation and Cell Motility.

Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell migration by transforming growth factor (TGF)-β1. However, it is not known whether activation of non-SMAD TGF-β signaling (e.g.

Proteinase-Activated Receptor 2 May Drive Cancer Progression by Facilitating TGF-β Signaling.

The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer, it usually acts as a driver of cancer progression in various tumor types by promoting invasion and metastasis in response to activation by serine proteinases. Recently, we discovered another mode through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor-β (TGF-β) signaling to promote TGF-β1-induced cell migration/invasion and invasion-associated gene expression in ductal pancreatic adenocarcinoma (PDAC) cells.

Transforming Growth Factor-1/Activin Receptor-like Kinase 5-Mediated Cell Migration is Dependent on the Protein Proteinase-Activated Receptor 2 but not on Proteinase-Activated Receptor 2-Stimulated G-Calcium Signaling.

Transforming growth factor- (TGF-), serine proteinases such as trypsin, and proteinase-activated receptor 2 (PAR2) promote tumor development by stimulating invasion and metastasis. Previously, we found that in cancer cells derived from pancreatic ductal adenocarcinoma (PDAC) PAR2 protein is necessary for TGF-1-dependent cell motility. Here, we show in the same cells that, conversely, the type I TGF- receptor activin receptor-like kinase 5 is dispensable for trypsin and PAR2 activating peptide (PAR2-AP)-induced migration.

Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer.

TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes. Serine proteinases mediate their cellular effects via activation of proteinase-activated receptors (PARs), a subclass of G protein-coupled receptors that are activated by proteolytic cleavage.

Extracellular vesicles from malignant effusions induce tumor cell migration: inhibitory effect of LMWH tinzaparin.

Elevated levels of extracellular vesicles (EVs) have been correlated with inflammatory diseases as well as progressive and metastatic cancer. By presenting tissue factor (TF) on their membrane surface, cellular microparticles (MPs) activate both the coagulation system and cell-signaling pathways such as the PAR/ERK pathway. We have shown before that malignant effusions are a rich source of tumor cell-derived EVs.

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.

Dasatinib blocks transcriptional and promigratory responses to transforming growth factor-beta in pancreatic adenocarcinoma cells through inhibition of Smad signalling: implications for in vivo mode of action.

Background: We have previously shown in pancreatic ductal adenocarcinoma (PDAC) cells that the SRC inhibitors PP2 and PP1 effectively inhibited TGF-β1-mediated cellular responses by blocking the kinase function of the TGF-β type I receptor ALK5 rather than SRC. Here, we investigated the ability of the clinically utilised SRC/ABL inhibitor dasatinib to mimic the PP2/PP1 effect.

Methods: The effect of dasatinib on TGF-β1-dependent Smad2/3 phosphorylation, general transcriptional activity, gene expression, cell motility, and the generation of tumour stem cells was measured in Panc-1 and Colo-357 cells using immunoblotting, reporter gene assays, RT-PCR, impedance-based real-time measurement of cell migration, and colony formation assays, respectively.

Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway.

Radiotherapy, a major treatment modality against cancer, can lead to secondary malignancies but it is uncertain as to whether tumor cells that survive ionizing radiation (IR) treatment undergo epithelial-mesenchymal transition (EMT) and eventually become invasive or metastatic. Here, we have tested the hypothesis that the application of IR (10 MeV photon beams, 2-20 Gy) to lung and pancreatic carcinoma cells induces a migratory/invasive phenotype in these cells by hyperactivation of TGF-β and/or activin signaling. In accordance with this assumption, IR induced gene expression patterns and migratory responses consistent with an EMT phenotype.