Exosome removal as a therapeutic adjuvant in cancer

Abstract

Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30–100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles < 200 nm from the entire circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT™ device, the Hemopurifier®, to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible therapeutic approaches for targeting immune suppressive exosomes in cancer patients, and the anticipated significance of these strategies for reversing immune dysfunction and improving responses to standard of care treatments.

The 786-0 renal cancer cell-derived exosomes promote angiogenesis by downregulating the expression of hepatocyte cell adhesion molecule

“…Consistent with a number of previous studies (10,(25)(26)(27), 786-0 cell-derived exosomes were observed to increase the formation of tubular stuctures in HUVECs compared with the control group. However, the underlying molecular mechanism of this effect remains unclear.…”

“…The tumor cell-derived exosome is known to manipulate the surrounding microenvironment to promote angiogenesis, invasion and metastasis, as well as escape immune surveillance (10). In the present study, exosomes secreted from the human renal cancer cell line, 786-0, were found to facilitate tubular formation via regulation of hepaCAM and VEGF expression of HUVECs.…”

“…Previous studies reported that extracellular organelles are important mediators of intercellular community (4)(5)(6)(7)(8)(9). Tumor cell-derived exosomes are associated with numerous events in cancer pathogenesis and development, including tumor angiogenesis (10).…”

Glycosylation of extracellular vesicles: current knowledge, tools and clinical perspectives

“…Glycosylation-targeted capture of exosomes is also the basis for an upcoming plasmapheresis device, Aethlon’s hemopurifier. The hemopurifier is a hollow fibre cartridge functionalised with lectins and antibodies, to be used with dialysis systems for the extracorporeal capture of circulating exosomes from blood [85]. Tumour-derived exosomes are directly immunosuppressive in some contexts [86] and can also sequester immunotherapeutic antibodies through antigen display [87].…”

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

“…Recent study showed that exosomes removal might be an adjuvant therapy for malignancies due to the vital roles of these cell-derived microparticles in therapeutic resistance. 109 The intuitive mechanisms of drug resistance involving exosomes might be the sequestration of cytotoxic drugs in the intracellular microvesicles and the subsequent expulsion, to wipe out drug effect within the cells. 110 The results of Luciani et al 111 are in accord with the above conclusion and demonstrated that lymphoma, adenocarcinoma, and melanoma cells confiscated drugs such as vinblastin, 5-flurouracil, and cisplatin in their endosomal compartments.…”