Aethlon Medical, Inc., today released the following note authored by its Chairman and CEO, Jim Joyce.
In 2012, researchers published the discovery that small particles known as exosomes are secreted by tumors to seed the creation and spread of cancer metastases. These same tumor-secreted exosomes have also been implicated in death of immune cells necessary to combat cancer and they facilitate the ability of tumors to create their own blood supply for survival. The Aethlon Hemopurifier® is the first therapeutic strategy to address these vital targets in cancer care. Based on our early research in the field, we have issued patent protection that provides an opportunity to establish a dominant position within the marketplace. In this regard, we envision the elimination of tumor-secreted exosomes through Hemopurifier® therapy will optimize the performance of cancer therapies and augment the immune system's ability to combat cancer. Based on evidence that our Hemopurifier® captures exosomes underlying breast cancer, I am pleased to provide you with the following review authored by Dr. Annette Marleau , our Director of Tumor Immunology.
Current Perspectives on Breast Cancer Exosomes
Breast cancer represents a challenging clinical scenario that exhibits heterogeneous molecular types and enormous diversity of malignant behavior of tumors between patients. As the second most common cancer afflicting women in the United States, it is estimated that 1 in 8 women will be diagnosed with invasive breast cancer in their lifetime (1). Significant improvements in disease-free survival have been achieved; however, there is still a need to address the aggressive and metastatic forms of breast cancer.
Advances in the understanding of breast cancer pathogenesis at a molecular level have pointed toward central roles for exosomes, nano-vesicles released in abundance by cancer cells. Exosomes are packed with proteins and genetic material from the tumor, and act as cellular messengers that distribute these malignant factors systemically to target cells, including cancer cells as well as healthy cells. Recently, the dissemination of pro-cancer cargo by exosomes is has been appreciated as promoting several critical aspects of cancer pathogenesis, including signaling for tumor growth, metastasis, angiogenesis, and resistance to chemo- and immunotherapeutic agents. These scientific discoveries, some of which are discussed below, have been accompanied by a growing interest in means for targeting exosomes therapeutically.
Recent studies have identified several mechanisms underlying the secretion of breast cancer exosomes and their uptake by target cells. In the breast tumor microenvironment, hypoxia is a pathological state of oxygen deprivation that affects the expression of genes required for many critical aspects of cancer progression. A study by Dr. Jonathan Gleadle 's laboratory in the journal BMC Cancer demonstrated that hypoxia stimulates exosome secretion by breast cancer cells (2), which can serve as a means for distributing a supply of cancer-promoting signals for the tumor mass. These investigations and many others also point toward exosomes as biomarkers for predicting the aggressiveness of a tumor.
Adding to the understanding of the physiological triggers of exosome secretion, Dr. Josiah Ochieng 's group reported in PLoS One that exosomes are secreted in response to detachment of breast cancer cells from extracellular matrices (3). In turn, the secreted exosomes concentrate on the surfaces of breast cancer cells to facilitate their re-adhesion to surfaces. This study implicates cancer-secreted exosomes as having crucial roles in tissue invasion by metastasizing breast cancer cells. Aberrant glycosylation is a hallmark of cancer that promotes adhesiveness of cancer cells to one another and to extracellular matrices, endowing them with invasive and metastatic phenotypes. Indeed, tumor-secreted exosomes also display highly glycosylated surface structures (4), which could serve as binding targets of lectin affinity capture agents for pulling nanovesicles out of the circulatory system.
Recent studies have also provided considerable insight into the impact of breast cancer exosomes as vehicles for spreading oncogenic signals to diverse target cells. A pivotal publication in PNAS by Dr. Richard Cerione 's group at Cornell University showed that the transfer of cargo by cancer exosomes is involved in cellular transformation, whereby healthy cells acquired the growth characteristics of tumor cells (5). Along these same lines is the recent publication in PLoS One, authored by Drs. Chang Lau and David Wong at UCLA, where breast cancer exosomes interacted with salivary gland cells, as evidenced by changes in the protein and genetic composition of exosomes secreted by the target cells(6). This report provides mechanistic insight as to how tumors are capable of communicating with target cells at distant sites via secretion of exosomes, making a therapeutic strategy for systemic removal of exosomes an attractive possibility for slowing cancer progression.
Significantly, there is also evidence that breast cancer exosomes might exert a direct role in resistance of tumors to therapeutic agents. In a paper by Dr. Serenella Pupa and colleagues published in the Journal of Cellular Physiology, exosomes from breast cancer cells that over-expressed the HER2 oncoprotein also displayed surface HER2, which bound to and sequestered the therapeutic antibody Herceptin in vitro (7). It was suggested that this decoy effect of cancer exosomes could lower the therapeutic benefits of immunotherapeutic agents, particularly in patients with advanced cancer where the exosome burden is expected to be high. On this basis, a strategy aimed at alleviating the exosome load might prove to be a promising adjunct therapy to improve the benefits of standard of care breast cancer treatments.
(2) King HW, Michael MZ and Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 2012; 12:421.
(3) Koumangoye RB, Sakwe AM, Goodwin JS, Patel T, Ocheing J. Detachment of breast tumor cells induces rapid secretion of exosomes which subsequently mediate cellular adhesion and spreading. PLoS One 2011; 6(9)e24234.
(4) Batista BS, Eng WS, Pilobello KT, Hendricks-Munoz KD, Mahal LK. Identification of a conserved glycan signature for microvesicles.J Proteome Res. 2011 Oct 7;10(10): 4624-33.
(5) Antonyak MA, Li B, Boroughs LK, Johnson JL, Druso JE, Bryant KL, Holowka DA, Cerione RA. Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. ProcNatlAcadSci U S A. 2011 Mar 22; 108(12):4852-7.
(6) Lau CS, Wong DT. Breast cancer exosome-like microvesicles and salivary gland cells interplay alters salivary gland cell-derived exosome-like microvesicles in vitro. PLoS One. 2012; 7(3):e33037.
(7) Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, Morelli D, Villa A, Della Mina P, Menard S, Filipazzi P, Rivoltini L, Tagliabue E, Pupa SM. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol. 2012 Feb; 227(2):658-67.