The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

The biology, function, and biomedical applications of exosomes

Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis

Exosome-Mediated Metastasis: Communication from a Distance.

Exosomes are common membrane-bound nanovesicles that contain diverse biomolecules, such as lipids, proteins, and nucleic acids. Exosomes are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Exosome secretion is a constitutive phenomenon that is involved in both physiological and pathological processes and determines both the exosomal surface molecules and the contents. Hence, we can exploit exosomes as biomarkers, vaccines and drug carriers and modify them rationally for therapeutic interventions. However, it is still a challenge to identify, isolate and quantify exosomes accurately, efficiently and selectively. Further studies on exosomes will explore their potential in translational medicine and provide new avenues for the creation of effective clinical diagnostics and therapeutic strategies; the use of exosomes in these applications can be called exosome theranostics. This review describes the fundamental processes of exosome formation and uptake. In addition, the physiological and pathological roles of exosomes in biology are also illustrated with a focus on how exosomes can be exploited or engineered as powerful tools in translational medicine.

Exosome Theranostics: Biology and Translational Medicine.

The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin–NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis.

/pdf/tumor-derived-exosomal-mir-1247-3p-induces-cancer-associated-pmrg1dlf78.pdf

Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.

Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.

/pdf/exosomal-transfer-of-stroma-derived-mir21-confers-paclitaxel-12k9kg76p7.pdf

Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1.

PurposeTo study the wider field (WF) swept-source OCT angiography (SS-OCTA) metrics, especially the nonperfusion area (NPA), in the diagnosing and staging of diabetic retinopathy (DR).DesignCross-sectional observational study (November 2018 to September 2020).ParticipantsA total of 473 eyes of 286 patients (69 eyes of 49 control patients and 404 eyes of 237 diabetic patients).MethodsWe imaged using 6 × 6 mm and 12 × 12 mm angiograms on WF SS-OCTA. Images were analyzed using the ARI Network and FIJI ImageJ. Mixed effects multiple regression models and receiver operating characteristic (ROC) analysis were used for statistical analyses.Main Outcome MeasuresQuantitative metrics such as vessel density (VD); vessel skeletonized density (VSD); foveal avascular zone (FAZ) area, circularity, and perimeter; and NPA in DR and their relative performance for its diagnosis and grading.ResultsAmong patients with diabetes (median age, 59 years), 51 eyes had no DR, 185 eyes (88 mild, 97 moderate-severe) had nonproliferative DR (NPDR), and 168 eyes had proliferative DR (PDR). Trend analysis revealed a progressive decline in superficial capillary plexus (SCP) VD and VSD, and increased NPA with increasing DR severity. Additionally, there was a significant reduction in deep capillary plexus (DCP) VD and VSD in early DR (mild NPDR), but the progressive reduction in advanced DR stages was not significant. The NPA was the best parameter to diagnose DR (area under the curve [AUC], 0.96), whereas all parameters combined on both angiograms efficiently diagnosed (AUC, 0.97) and differentiated between DR stages (AUC range, 0.83–0.97). The presence of diabetic macular edema was associated with reduced SCP and DCP VD and VSD within mild NPDR eyes, whereas increased VD and VSD in SCP were observed in the moderate-severe NPDR group.ConclusionsOur work highlights the importance of NPA, which can be measured more readily and easily with WF SS-OCTA compared with fluorescein angiography. It is quick and noninvasive, and thus can be an important adjunct for DR diagnosis and management. In our study, a combination of all OCTA metrics on both 6 × 6 mm and 12 × 12 mm angiograms had the best diagnostic accuracy for DR and its severity. Further longitudinal studies are needed to assess NPA as a biomarker for progression or regression of DR severity. To study the wider field (WF) swept-source OCT angiography (SS-OCTA) metrics, especially the nonperfusion area (NPA), in the diagnosing and staging of diabetic retinopathy (DR). Cross-sectional observational study (November 2018 to September 2020). A total of 473 eyes of 286 patients (69 eyes of 49 control patients and 404 eyes of 237 diabetic patients). We imaged using 6 × 6 mm and 12 × 12 mm angiograms on WF SS-OCTA. Images were analyzed using the ARI Network and FIJI ImageJ. Mixed effects multiple regression models and receiver operating characteristic (ROC) analysis were used for statistical analyses. Quantitative metrics such as vessel density (VD); vessel skeletonized density (VSD); foveal avascular zone (FAZ) area, circularity, and perimeter; and NPA in DR and their relative performance for its diagnosis and grading. Among patients with diabetes (median age, 59 years), 51 eyes had no DR, 185 eyes (88 mild, 97 moderate-severe) had nonproliferative DR (NPDR), and 168 eyes had proliferative DR (PDR). Trend analysis revealed a progressive decline in superficial capillary plexus (SCP) VD and VSD, and increased NPA with increasing DR severity. Additionally, there was a significant reduction in deep capillary plexus (DCP) VD and VSD in early DR (mild NPDR), but the progressive reduction in advanced DR stages was not significant. The NPA was the best parameter to diagnose DR (area under the curve [AUC], 0.96), whereas all parameters combined on both angiograms efficiently diagnosed (AUC, 0.97) and differentiated between DR stages (AUC range, 0.83–0.97). The presence of diabetic macular edema was associated with reduced SCP and DCP VD and VSD within mild NPDR eyes, whereas increased VD and VSD in SCP were observed in the moderate-severe NPDR group. Our work highlights the importance of NPA, which can be measured more readily and easily with WF SS-OCTA compared with fluorescein angiography. It is quick and noninvasive, and thus can be an important adjunct for DR diagnosis and management. In our study, a combination of all OCTA metrics on both 6 × 6 mm and 12 × 12 mm angiograms had the best diagnostic accuracy for DR and its severity. Further longitudinal studies are needed to assess NPA as a biomarker for progression or regression of DR severity. 

http://www.ophthalmologyscience.org/article/S2666914522000331/pdf

Nonperfusion Area and Other Vascular Metrics by Wider Field Swept-Source OCT Angiography as Biomarkers of Diabetic Retinopathy Severity

Prevalence of venous loops and association with retinal ischemia in diabetic retinopathy using widefield swept-source OCT angiography

46 Objective: To determine whether swept-source optical coherence tomographic angiography (SS- 47 OCTA) can demonstrate choroidal perfusion abnormalities seen on fluorescein angiography (FA) 48 in giant cell arteritis (GCA). 49 Design: Observational case series. 50 Participants: Six eyes of 3 patients with bilateral ischemic optic neuropathy secondary to GCA, 51 and one control patient without ocular involvement from biopsy-confirmed GCA. 52 Methods: En face SS-OCTA (DRI OCT Triton, Topcon, Tokyo, Japan) and FA centered on the 53 macula were obtained at presentation. SS-OCTA was segmented into superficial and deep retinal 54 capillary plexuses and the choriocapillaris laminae. SS-OCTA images were independently 55 analyzed for perfusion abnormalities and compared with corresponding FA images. 56 Main Outcome Measures: Correspondence of choroidal angiographic abnormalities on SS- 57 OCTA and FA. 58 Results: SS-OCTA showed decreased angiographic signal within the choriocapillaris in 5/6 eyes 59 and corresponded to hypoperfusion abnormalities on FA in similar geographic distributions in 60 5/5 eyes. SS-OCTA also showed dilation of the deep retinal capillary plexus overlying the area 61 of choroidal hypoperfusion in one eye. In the one eye without angiographic signal abnormalities 62 on SS-OCTA, no perfusion changes were noted on FA. One control patient without ocular 63 involvement from biopsy-confirmed GCA did not show choroidal perfusion changes on SS- 64 OCTA or FA. 65 Conclusions: This case series demonstrates comparability between SS-OCTA and FA in 66 detection and characterization of choroidal hypoperfusion secondary to GCA. As a rapid and 67

Detection of Choroidal Hypoperfusion in Giant Cell Arteritis Using Swept-Source Optical Coherence Tomographic Angiography.

Structure-function associations between contrast sensitivity and widefield swept-source optical coherence tomography angiography in diabetic macular edema.

Edward S. Lu

Papers

Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1.

Nonperfusion Area and Other Vascular Metrics by Wider Field Swept-Source OCT Angiography as Biomarkers of Diabetic Retinopathy Severity

Prevalence of venous loops and association with retinal ischemia in diabetic retinopathy using widefield swept-source OCT angiography

Detection of Choroidal Hypoperfusion in Giant Cell Arteritis Using Swept-Source Optical Coherence Tomographic Angiography.

Structure-function associations between contrast sensitivity and widefield swept-source optical coherence tomography angiography in diabetic macular edema.