In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV‐mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd‐sourcing, drawing on the unique EV expertise of academia‐based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

Quiz Ref ID Gastric cancer (GC) is the third most common cause of cancer-related mortality worldwide.¹ The 2 major subtypes, diffuse GC (DGC) and intestinal-type GC, are distinguished by molecular, epidemiologic, and morphologic features.² Although GC is usually sporadic, familial aggregation occurs in approximately 10% of cases.^3,4 Quiz Ref ID Clinically defined hereditary DGC (HDGC) (OMIM #137215) is characterized by early-onset, multigenerational DGC and lobular breast cancer. Clinical criteria for this entity was established by the International Gastric Cancer Linkage Consortium (IGCLC) (Table 1).^5,6 Approximately 40% of HDGC families have germline mutations in CDH1 (E-cadherin) (Ensembl ENSG00000039068; OMIM *192090), and over 100 different pathogenic germline mutations are reported across multiple ethnicities (eTable 1 in the Supplement).

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Gastric cancer is the second most common cause of cancer death worldwide.¹ Two major histopathological variants of this cancer have been described: an intestinal type and a diffuse type.² A decline in the overall incidence of gastric cancer can be attributed primarily to a decrease of the intestinal variant of gastric cancer with the diffuse type remaining stable or possibly even increasing.³