Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival.

Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane proteoglycan, is highly expressed in intestinal subtype gastric tumors and that this signature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

'What if it were like this?' Perception of mothers of children with cerebral palsy about the ankle-foot orthosis of their children: A qualitative study.

BACKGROUND: The family-centred approach is fundamental in the therapeutic process of children with cerebral palsy (CP), and the increased competence of parents about therapeutic devices, especially orthoses, can facilitate its implementation, thus intensifying the benefits that this device provides. The aim of this study was to understand the perception of mothers of children with CP in relation to their children's ankle-foot orthosis. METHODS: This is a qualitative study using thematic content analysis technique. Data were collected using semi-structured interviews from 24 mothers of children with Levels IV and V of CP according to the Gross Motor Function Classification System (GMFCS), who were attended at a philanthropic rehabilitation centre. RESULTS: Three categories were identified from analyzing the interviews: benefits of the orthosis, the orthosis in the child's daily life and 'What if it were like this?' CONCLUSIONS: According to the mothers' perceptions, the ankle-foot orthosis improved their child's mobility. The orthoses are used in different contexts in the child's daily life, and the mothers pointed out suggestions regarding personalizing the orthosis with different colors and patterns, increasing comfort and facilitating the way in which the device is placed.

MicroRNAs and Extracellular Vesicles as Distinctive Biomarkers of Precocious and Advanced Stages of Breast Cancer Brain Metastases Development.

Triple negative breast cancer presents higher mortality and poorer survival rates than other breast cancer (BC) types, due to the proneness to brain metastases formation, which are usually diagnosed at advanced stages. Therefore, the discovery of BC brain metastases (BCBM) biomarkers appears pivotal for a timely intervention. With this work, we aimed to disclose microRNAs (miRNAs) and extracellular vesicles (EVs) in the circulation as biomarkers of BCBM formation. Using a BCBM animal model, we analyzed EVs in plasma by nanoparticle tracking analysis and ascertained their blood-brain barrier (BBB) origin by flow cytometry. We further evaluated circulating miRNAs by RT-qPCR and their brain expression by in situ hybridization. In parallel, a cellular model of BCBM formation, combining triple negative BC cells and BBB endothelial cells, was used to differentiate the origin of biomarkers. Established metastases were associated with an increased content of circulating EVs, particularly of BBB origin. Interestingly, deregulated miRNAs in the circulation were observed prior to BCBM detection, and their brain origin was suggested by matching alterations in brain parenchyma. In vitro studies indicated that miR-194-5p and miR-205-5p are expressed and released by BC cells, endothelial cells and during their interaction. These results highlight miRNAs and EVs as biomarkers of BCBM in early and advanced stages, respectively.

Plasma Extracellular Vesicle-Derived TIMP-1 mRNA as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma: A Pilot Study.

The tumor microenvironment has gained a lot of attention from the scientific community since it has a proven impact in the development of tumor progression and metastasis. Extracellular vesicles (EVs) are now considered one of the key players of tumor microenvironment modulation. Clear cell renal cell carcinoma (ccRCC) is the most lethal urological neoplasia and presents a high metastatic potential, which reinforces the need for the development of more effective predictive biomarkers. Our goal was to evaluate the applicability of EV-derived matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as prognostic biomarkers for ccRCC. To do so, we studied the plasma EV content of 32 patients with localized ccRCC and 29 patients with metastatic ccRCC. We observed that patients with localized disease and tumors larger than 7 cm presented higher levels of plasma EV-derived TIMP-1 mRNA when compared with patients presenting smaller tumors (p = 0.020). Moreover, patients with metastatic disease presented higher levels of EV-derived TIMP-1 mRNA when compared with patients with localized disease (p = 0.002) and when we stratified those patients in high and low levels of TIMP-1 EV-derived mRNA, the ones presenting higher levels had a lower overall survival (p = 0.030). EV-derived TIMP-1 mRNA may be a good prognostic biomarker candidate for ccRCC.

Knowledge and Practices of Pediatricians Regarding Functional Constipation in the State of Minas Gerais, Brazil.

OBJECTIVES: The aim of the study was to analyze the knowledge, approaches, and practices of pediatricians participating in a regional pediatric conference regarding functional constipation (FC) to identify knowledge gaps. METHODS: Cross-sectional regional study based on a semistructured questionnaire related to the Rome III criteria and the participant profiles. RESULTS: Of 400 questionnaires distributed, 264 (66.0%) were completed. Most pediatricians (76.7%) did not recognize the Rome III criteria, but the majority did recognize the following risk factors for FC: low-fiber diet (97.8%), family history (86.6%), onset of toilet training (76.4%), and weaning (62.4%). Foods considered high in fiber were oats (95.7%), leafy vegetables (95.3%), and wheat bran (93.2%). Digital rectal examination was not performed by 57.7% of nongastroenterologists. Complementary examinations were ordered in 27.5% and 72.5% of patients by general pediatricians and pediatric gastroenterologists, respectively, although the sample of gastroenterologists was not representative. The most prescribed drugs by nongastroenterologists were mineral oil (72.6%), magnesium hydroxide (52.1%), lactulose (41.0%), and polyethylene glycol (25.2%). Pediatric gastroenterologists prescribed magnesium hydroxide (91.7%), polyethylene glycol (91.7%), and mineral oil (58.3%). Most pediatricians (70.0%) considered the average treatment duration to be less than 1 year, although gastroenterologists considered it to be more than 1 year (54.6%). CONCLUSIONS: The knowledge of pediatricians regarding FC is inadequate. Constipation may not receive the public health attention it deserves within pediatric residency programs. The authors suggest that better education regarding FC should be included in medical school and residency program curricula to improve patient care.

Can Gender Nouns Influence the Stereotypes of Animals?

Educating about animals in zoos and aquariums poses daily challenges for education teams, who must not only master biological content but also possess communication skills to adapt information for diverse ages and cultures. This research consists of two sequential studies designed to investigate the impact of grammatical genders on animal stereotypes and elicited emotions. In Study 1, four animals were independently chosen based on a set of predefined conditions, which were then used in Study 2. The second study explored whether the presence of grammatical genders in the Portuguese language influenced the perceived stereotypes of four animals (panda bear, giraffe, polar bear, and cheetah) using the Stereotype Content Model framework. For comparison, English-speaking participants were also surveyed, as English lacks grammatical genders. The results demonstrated that grammatical genders influenced the perceived gender, as well as, although only slightly, the warmth, competence, and elicited emotions of some animals. All animals under study were associated with the protective stereotype, regardless of the presence of grammatical gender. This study emphasizes the significance of subtle yet crucial elements in communication, such as grammatical genders, in shaping stereotypes and innate emotional associations concerning animals.

Assessment of the Implementation of the International Health Regulations during the COVID-19 Pandemic: Portugal as a Case Study.

INTRODUCTION: The International Health Regulations (IHR) were developed to prepare countries to deal with public health emergencies. The spread of SARS-CoV-2 underlined the need for international coordination, although few attempts were made to evaluate the integrated implementation of the IHR's core capacities in response to the COVID-19 pandemic. The aim of this study was to evaluate whether IHR shortcomings stem from non-compliance or regulatory issues, using Portugal as a European case study due to its size, organization, and previous discrepancies between self-reporting and peer assessment of the IHR's core capacities. METHODS: Fifteen public health medical residents involved in contact tracing in mainland Portugal interpreted the effectiveness of the IHR's core capabilities by reviewing the publicly available evidence and reflecting on their own field experience, then grading each core capability according to the IHR Monitoring Framework. The assessment of IHR enforcement considered efforts made before and after the onset of the pandemic, covering the period up to July 2021. RESULTS: Four out of nine core IHR capacities (surveillance; response; risk communication; and human resource capacity) were classified as level 1, the lowest. Only two were graded level 3 (preparedness; and laboratory), the highest. The remaining three) (national legislation, policy & financing; coordination and national focal point communication; and points of entry) were classified as level 2. CONCLUSION: Portugal exemplifies the extent to which implementation of the IHR was not fully achieved, which has resulted in the underperformance of several core capacities. There is a need to improve preparedness and international cooperation in order to harmonize and strengthen the global response to public health emergencies, with better political, institutional, and financial support.

Attachment security representations in institutionalized children and children living with their families: links to problem behaviour.

The present work analyses differences in the attachment representations of institutionalized children as compared with children from low and high educational level living with their natural families. Participants were 91 Portuguese children, 52% girls, aged 48-96 months. There were three different groups: 19 institutionalized children, 16 low educational level families' children and 56 from high educational level families'. Attachment representations were assessed for Security of the narratives of the Attachment Story Completion Task (ASCT). Psychopathological symptoms were assessed using the Child Behaviour Checklist for parents and caretakers. Verbal skills were assessed using the Wechsler Preschool and Primary Scale of Intelligence--Revised. Results show that institutionalized children have significantly lower security of attachment representations, less verbal skills and higher aggressive behaviour than the other two groups. Attachment representations were associated with social/withdrawal and aggression, independently of age, verbal skills and parents' education. The main effect of institutionalization on externalizing aggressive behaviour was completely mediated by the security of attachment representations.

Exercise Dependence and Anxiety in Cross-Trainers, Bodybuilders and Gym Exercisers During COVID19.

The World Health Organization declared the COVID-19 pandemic an international public health emergency in January 2020, and, soon thereafter, a worldwide adoption of quarantine and physical isolation measures restricted regular practitioners of indoor group physical exercise from many of their usual practices. Some, with exercise dependence (ED), may have experienced exercise withdrawal symptoms that triggered unhealthy anxiety levels. In February 2021, during Portugal's second COVID-19 lockdown, we characterized and compared ED and anxiety levels among different groups of indoor exercise practitioners (cross trainers [CG], bodybuilders [BG] and gym practitioners [GG]). In this cross-sectional study, we recruited 234 adult participants through the internet. To assess participants' ED and anxiety levels, we used Portuguese versions of the ED Scale-21 (EDS-21) and the State-Trait Anxiety Inventory (STAI-State; STAI-Trait). ED symptoms were evident in all participant subgroups, and we found no gender differences in ED. Anxiety was higher among women than men in CG and GG groups, and there were significant differences in ED between groups such that BG practitioners showed higher ED than GG and CG practitioners (small effect size). Bodybuilders reported most ED behavior, followed by CG and regular gym exercisers, but on some criteria BG and CG groups had similar ED levels. Our results are in line with prior ED prevalence reports conducted before COVID-19 restrictions among regular GG, but these are the first data to report a higher ED prevalence among BG and CG, relative to GG.

Defining Optimal Conditions for Tumor Extracellular Vesicle DNA Extraction for Mutation Profiling.

(1) Background: Extracellular vesicles (EVs) have emerged as crucial players in the communication between cells in both physiological and pathological scenarios. The functions of EVs are strongly determined by their molecular content, which includes all bioactive molecules, such as proteins, lipids, RNA, and, as more recently described, double-stranded DNA. It has been shown that in oncological settings DNA associated with EVs (EV-DNA) is representative of the genome of parental cells and that it reflects the mutational status of the tumor, gaining much attention as a promising source of biomarker mutant DNA. However, one of the challenges in studies of EV-DNA is the lack of standardization of protocols for the DNA extraction from EVs, as well as ways to assess quality control, which hinders its future implementation in clinics. (2) Methods: We performed a comprehensive comparison of commonly used approaches for EV-DNA extraction by assessing DNA quantity, quality, and suitability for downstream analyses. (3) Results: We here established strategic points to consider for EV-DNA preparation for mutational analyses, including qPCR and NGS. (4) Conclusions: We put in place a workflow that can be applied for the detection of clinically relevant mutations in the EV-DNA of cancer patients.

IgG+ Extracellular Vesicles Measure Therapeutic Response in Advanced Pancreatic Cancer.

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second-leading cause of cancer deaths by 2030. Imaging techniques are the standard for monitoring the therapy response in PDAC, but these techniques have considerable limits, including delayed disease progression detection and difficulty in distinguishing benign from malignant lesions. Extracellular vesicle (EV) liquid biopsy is an emerging diagnosis modality. Nonetheless, the majority of research for EV-based diagnosis relies on point analyses of EVs at specified times, while longitudinal EV population studies before and during therapeutic interventions remain largely unexplored. (2) Methods: We analyzed plasma EV protein composition at diagnosis and throughout PDAC therapy. (3) Results: We found that IgG is linked with the diagnosis of PDAC and the patient's response to therapy, and that the IgG+ EV population increases with disease progression and reduces with treatment response. Importantly, this covers PDAC patients devoid of the standard PDAC seric marker CA19.9 expression. We also observed that IgG is bound to EVs via the tumor antigen MAGE B1, and that this is independent of the patient's inflammatory condition and IgG seric levels. (4) Conclusions: We here propose that a population analysis of IgG+ EVs in PDAC plasma represents a novel method to supplement the monitoring of the PDAC treatment response.

Preschool children's mental representations of attachment: antecedents in their secure base behaviors and maternal attachment scripts.

This study examined the antecedents of preschool age children's mental representations of attachment, assessed using the Attachment Story Completion Task (ASCT). Antecedent predictors were maternal attachment scripts, assessed using the Attachment Script Assessment (ASA), and the child's secure base behaviors, assessed using the Attachment Q-Set (AQS). Participants were 121 mothers and their preschool children assessed in three samples (Portuguese sample, n = 31; US Midwestern sample, n = 38; US Southeastern sample, n = 52). AQS and ASA assessments were completed approximately 1.5 years before the ASCT data were collected. No cross-sample contrasts for the attachment variables were significant. Correlations and structural equation modeling (SEM) indicated that the three attachment measures were significantly associated and that both maternal secure base script knowledge and children's secure base behaviors (AQS) were uniquely and significantly associated with children's mental representations of attachment (ASCT). A test of the indirect effect between maternal scripts and child representations through children's secure base behaviors was not significant.

Durability of a New Thermal Aerogel-Based Rendering System under Distinct Accelerated Aging Conditions.

The widespread application of innovative thermal enhanced façade solutions requires an adequate durability evaluation. The present work intends to assess the durability of a new aerogel cement-based rendering system through the adaptation of different accelerated aging cycles, such as heating-freezing, freeze-thawing, and heat-cold. Several mechanical properties and also capillary and liquid water absorptions were tested for uncoated and coated specimens. A decrease in the mechanical strength, especially after freeze-thaw cycles, was observed. However, the water action promoted the late hydration of the cement paste contributing to the densification of the matrix and, consequently, the increase of the adhesive strength. Additionally, a decrease in the dynamic modulus of elasticity and an increase in the Poisson's ratio were observed after aging, which indicates a higher capacity of the render to adapt to substrate movements, contributing to a reduction of cracking.

Long-term efficacy and safety of eslicarbazepine acetate: results of a 1-year open-label extension study in partial-onset seizures in adults with epilepsy.

PURPOSE: To evaluate the long-term efficacy and safety of once daily eslicarbazepine acetate (ESL) as adjunctive therapy for partial-onset seizures in adults with epilepsy. METHODS: One-year open-label treatment extension with ESL in patients who completed a placebo-controlled pivotal study (Epilepsia 2009; 50: 454-463). Starting dose was 800 mg once daily, for 4 weeks; thereafter, dose could be titrated up or down. Doses of concomitant antiepileptic drugs were to be kept stable. RESULTS: Overall, 314 patients were enrolled. The intent-to-treat population consisted of 312 patients, and 239 (76.6%) completed 1 year of treatment. ESL median dose was 800 mg once daily. Compared to baseline, median seizure frequency decreased by 39% during the first 4 weeks and between 48% and 56% thereafter. The responder rate (≥50% seizure reduction) was 41% during weeks 1-4 and, thereafter ranged between 48% and 53%. The proportion of seizure-free patients per 12-week interval ranged between 8.7% and 12.5%. Quality of life, as measured by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), and depressive symptoms, as measured by the Montgomery Asberg Depression Rating Scale (MADRS), improved significantly compared to baseline. Treatment-emergent adverse events (TEAEs) were reported by 51% of patients. The most frequent TEAEs were headache (10%), dizziness (10%), diplopia (5%), and nasopharyngitis (5%). TEAEs were mostly (97%) of mild to moderate intensity. Eleven patients (3.5%) discontinued due to TEAEs. There were no results of laboratory tests raising safety concerns. DISCUSSION: Sustained therapeutic effect, favorable tolerability and safety, and an improvement in quality of life and depressive symptoms were observed during long-term add-on treatment of partial-onset seizures in adults with once daily ESL.

Employing Flow Cytometry to Extracellular Vesicles Sample Microvolume Analysis and Quality Control.

Extracellular Vesicles (EVs), membrane vesicles released by all cells, are emerging mediators of cell-cell communication. By carrying biomolecules from tissues to biofluids, EVs have attracted attention as non-invasive sources of clinical biomarkers in liquid biopsies. EVs-based liquid biopsies usually require EVs isolation before content analysis, which frequently increases sample volume requirements. We here present a Flow Cytometry (FC) strategy that does not require isolation or concentration of EVs prior to staining. By doing so, it enables population analysis of EVs in samples characterized by challenging small volumes, while reducing overall sample processing time. To illustrate its application, we performed longitudinal non-lethal population analysis of EVs in mouse plasma and in single-animal collections of murine vitreous humor. By quantifying the proportion of vesicular particles in purified and non-purified biological samples, this method also serves as a precious tool to quality control isolates of EVs purified by different protocols. Our FC strategy has an unexplored clinical potential to analyze EVs in biofluids with intrinsically limited volumes and to multiply the number of different analytes in EVs that can be studied from a single collection of biofluid.

Transcriptome Reprogramming of CD11b+ Bone Marrow Cells by Pancreatic Cancer Extracellular Vesicles.

Pancreatic cancers (PC) are highly metastatic with poor prognosis, mainly due to delayed detection. We previously showed that PC-derived extracellular vesicles (EVs) act on macrophages residing in the liver, eliciting extracellular matrix remodeling in this organ and marked hepatic accumulation of CD11b+ bone marrow (BM) cells, which support PC liver metastasis. We here show that PC-EVs also bind to CD11b+ BM cells and induce the expansion of this cell population. Transcriptomic characterization of these cells shows that PC-EVs upregulate IgG and IgA genes, which have been linked to the presence of monocytes/macrophages in tumor microenvironments. We also report here the transcriptional downregulation of genes linked to monocyte/macrophage activation, trafficking, and expression of inflammatory molecules. Together, these results show for the first time the existence of a PC-BM communication axis mediated by EVs with a potential role in PC tumor microenvironments.

Extracellular Vesicles Enriched in hsa-miR-301a-3p and hsa-miR-1293 Dynamics in Clear Cell Renal Cell Carcinoma Patients: Potential Biomarkers of Metastatic Disease.

Clear cell renal cell carcinoma (ccRCC) is the most aggressive subtype of kidney cancer and up to 40% of patients submitted to surgery with a curative intent will relapse. Thus, the aim of this study was to analyze the applicability of an Extracellular vesicle (EV) derived miRNA profile as potential prognosis biomarkers in ccRCC patients. We analyzed a nine-miRNA profile in plasma EVs from 32 ccRCC patients with localized disease (before and after surgery) and in 37 patients with metastatic disease. We observed that the levels of EV-derived hsa-miR-25-3p, hsa-miR-126-5p, hsa-miR-200c-3p, and hsa-miR-301a-3p decreased after surgery, whereas hsa-miR-1293 EV-levels increased. Furthermore, metastatic patients presented higher levels of hsa-miR-301a-3p and lower levels of hsa-miR-1293 when compared to patients with localized disease after surgery. Functional enrichment analysis of the targets of the four miRNAs that decreased after surgery resulted in an enrichment of terms related to cell cycle, proliferation, and metabolism, suggesting that EV-miRNA enrichment in the presence of the tumor could represent an epigenetic mechanism to sustain tumor development. Taken together, these results suggest that EVs content varies depending on the presence or absence of the disease and that an increase of EV-derived hsa-miR-301a-3p, and decrease of EV-derived hsa-miR-1293, may be potential biomarkers of metastatic ccRCC.

Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study.

PURPOSE: To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with >or=4 partial-onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1-2 antiepileptic drugs (AEDs). METHODS: This multicenter, parallel-group study had an 8-week, single-blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once-daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double-blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400-mg steps to the full maintenance dose (12 weeks). RESULTS: Seizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200-mg (p = 0.0003) and 800-mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of log-transformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56-62% of patients), lamotrigine (25-27%), and valproic acid (22-28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate. DISCUSSION: ESL, 800 and 1,200 mg once-daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.

Susceptibility Perturbation MRI Maps Tumor Infiltration into Mesorectal Lymph Nodes.

Noninvasive characterization of lymph node involvement in cancer is an enduring onerous challenge. In rectal cancer, pathologic lymph node status constitutes the most important determinant of local recurrence and overall survival, and patients with involved lymph nodes may benefit from preoperative chemo and/or radiotherapy. However, knowledge of lymph node status before surgery is currently hampered by limited imaging accuracy. Here, we introduce Susceptibility-Perturbation MRI (SPI) as a novel source of contrast to map malignant infiltration into mesorectal lymph nodes. SPI involves multigradient echo (MGE) signal decays presenting a nonmonoexponential nature, which we show is sensitive to the underlying microstructure via susceptibility perturbations. Using numerical simulations, we predicted that the large cell morphology and the high cellularity of tumor within affected mesorectal lymph nodes would induce signature SPI decays. We validated this prediction in mesorectal lymph nodes excised from total mesorectal excision specimens of patients with rectal cancer using ultrahigh field (16.4 T) MRI. SPI signals distinguished benign from malignant nodal tissue, both qualitatively and quantitatively, and our histologic analyses confirmed cellularity and cell size were the likely underlying sources for the differences observed. SPI was then adapted to a clinical 1.5 T scanner, added to patients' staging protocol, and compared with conventional assessment by two expert radiologists. Nonmonoexponential decays, similar to those observed in the ex vivo study, were demonstrated, and SPI classified lymph nodes more accurately than standard high-resolution T2-weighted imaging assessment. These findings suggest this simple, yet highly informative, method can improve rectal cancer patient selection for neoadjuvant therapy. SIGNIFICANCE: These findings introduce an MRI methodology tailored to detect magnetic susceptibility perturbations induced by subtle alterations in tissue microstructure.

Exosomes as emerging players in cancer biology.

Oncologic diseases do not behave as isolated entities. Instead, they are based on complex systemic networks involving cell-cell communication between cancerous and healthy cells of the host, which may either facilitate or prevent cancer progression. In addition to cell-cell contacts, cells communicate through secreted factors in a process modulated by ligand concentration, receptor availability and synergy amongst several signaling circuits. Of these secreted factors, exosomes, 30-150 nm membrane vesicles of endocytic origin released by virtually all cells, have emerged as important cell-cell communication players both in physiological and pathological scenarios by being carriers of all the main biomolecules, including lipids, proteins, DNAs, messenger RNAs and microRNA, and performing intercellular transfer of components, locally and systemically. By acting both in tumor and non-tumor cells, such as fibroblasts, leukocytes, endothelial and progenitor cells, tumor- and non-tumor cells-derived exosomes can modulate tumor growth and invasion, tumor-associated angiogenesis, tissue inflammation and the immune system. In this Review, we summarize the main findings of the literature on the roles of exosomes in mediating interactions between tumor and tumor-associated cells. We also discuss how the molecular composition analysis of circulating exosomes in clinical settings has emerged as an attractive non-invasive source of liquid biopsies for early diagnosis, prognosis and follow-up of patients with oncologic diseases.