Article

Exosome removal as a therapeutic adjuvant in cancer

Aethlon Medical Inc, 8910 University Center Lane, Suite 660, San Diego, CA, 92122, USA. .
Journal of Translational Medicine (Impact Factor: 3.93). 06/2012; 10(1):134. DOI: 10.1186/1479-5876-10-134
Source: PubMed

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.

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    • "Several studies have evaluated the selective target elimination of circulating exosomes to treat cancer. For example, the use of a preexisting adaptive dialysis-like affinity platform technology device, in which exosomes bearing pathogenic antigens can be specifically bound and removed by their corresponding antibodies or affinity agents [59]. In vitro studies have successfully demonstrated removal of cancer-derived exosomes from patient blood using a Hemopurifier (http://www.aethlonmedical.com/products/ "
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    ABSTRACT: The limitations of current chemotherapies have motivated research in developing new treatments. Growing evidences show that interaction between tumors and their microenvironment, but not tumor cells per se, is the key factor in tumor progression and therefore of obvious scientific interest and therapeutic value. Exosomes are small (30 to 100 nm) extracellular vesicles which have emerged as key mediators and communicators between cancer cells and other major cell types in the tumor microenvironment such as stromal fibroblasts, endothelial cells, and infiltrating immune cells as well as noncellular extracellular matrices through paracrine mechanisms. This review is to highlight the emerging role of exosomes in particular type of cancer, such as ovarian cancer, owing to its unique route of metastasis, which is capable of rapidly translating exosome research for clinical applications in diagnosis, prognosis, and potential treatment. Copyright © 2015. Published by Elsevier Ireland Ltd.
    No preview · Article · Jul 2015 · Cancer letters
    • "Furthermore, particularly in advanced cancers, many patients exhibit complications related to coagulation, that may also be due to elevated tissue-factor positive EV in the blood [94]. Whilst some developments attempt to achieve reduction of circulating EV using a blood-filtration approach [95], the wisdom of such a global EV-removal tool is currently unclear. Our knowledge is growing about EV in pathological situations; however there remains a major knowledge gap in terms of the roles of EV under normal, steadystate conditions. "
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    ABSTRACT: The tumour microenvironment is a highly complex and dynamic tissue. It comprises not only neoplastic cells, but also other resident cells within the milieu such as stroma and vascular cells in addition to a variable cellular infiltrate from the periphery. A host of soluble factors such as growth factors, chemokines, eicosanoids soluble metabolites and extracellular matrix components have been extensively documented as factors which modulate this environment. However, in recent years there has also been growing interests in the potential roles of extracellular vesicles (EV) in many of the processes governing the nature of cancerous tissue. In this brief review, we have assembled evidence describing several distinct functions for extracellular vesicles in modulating the microenvironment with examples that include immune evasion, angiogenesis and stromal activation. Whilst there remains a great deal to be learnt about the interplay between vesicles and the cancerous environment, it is becoming clear that vesicle-mediated communication has a major influence on key aspects of cancer growth and progression. We conclude that the design of future therapeutics should acknowledge the existence and roles of extracellular vesicles, and seriously consider strategies for circumventing their effects in vivo. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Feb 2015 · Seminars in Cell and Developmental Biology
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    • "Indeed, immune reactivity against the organism's own constituents is an ordinary finding intrinsic to the behavior of the surveillance functions of the immune system and thus an important component of normal physiology. Immune reactivity is, in fact, bidirectional—the immune system becomes Janus-like by facing inward and outward simultaneously (Tauber, (footnote continued) (Yu et al., 2007; Marleau et al., 2012), dendritic-derived exosomes can directly kill malignant cells (Munch et al., 2012). Given the apparent non-uniformity of exosome contents and the apparent diversity of their secretory patterns and context-dependent effects, these mediators are likely to prove difficult factors to characterize. "
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    ABSTRACT: Three interconnected positions are advocated: 1) although serving as a useful model, the immune self does not exist as such; 2) instead of a self/nonself demarcation, the immune system 'sees' itself, i.e., it does not ignore the 'self' or attack the 'other;' but exhibits a spectrum of responses, which when viewed from outside the system appear as discrimination of 'self' and 'nonself' based on certain criteria of reactivity. When immune reactions are conceived in terms of normal physiology and open exchange with the environment, where borders dividing host and foreign are elusive and changing, host defense is only part of the immune system's functions, which actually comprise two basic tasks: protection, i.e., to preserve host integrity, and maintenance of organismic identity. And thus 3) if the spectrum of immunity is enlarged, differentiating low reactive 'autoimmune' reactions from activated immune responses against the 'other' is only a matter of degree. Simply, all immunity is 'autoimmunity,' and the pathologic state of immunity directed at normal constituents of the organism is a particular case of dis-regulation, which appropriately is designated, autoimmune. Other uses of 'autoimmunity' and its congeners function as the semantic remnants of Burnet's original self/nonself theory and should be replaced. A new nomenclature is proposed, concinnity, which more accurately designates the physiology of the animal's ordinary housekeeping economy mediated by the immune system than 'autoimmunity' when used to describe such normal functions.
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