Disruption of Circulating Extracellular Vesicles as a Novel Therapeutic Strategy against Cancer Metastasis

Abstract

Metastasis is the main cause of cancer mortality for many types of cancer; however, difficulties remain in effectively preventing metastasis. It has been recently and widely reported that cancer-derived extracellular vesicles (EVs) contribute to cancer metastasis. Thus, therapeutic strategies targeting cancerderived EVs hold great promise because of the possibility of EVs driving the cancer microenvironment toward metastasis. Here, we provide a novel strategy for therapeutic antibody treatment to target cancer-derived EVs and inhibit the metastasis of breast cancer in a mouse model, establishing a rationale for further clinical investigation. Treatment with human-specific anti-CD9 or anti-CD63 antibodies significantly decreased metastasis to the lungs, lymph nodes, and thoracic cavity, although no obvious effects on primary xenograft tumor growths were observed. In in vitro and in vivo experiments, the EVs incubated with the targeted antibodies were preferentially internalized by macrophages, suggesting that antibody-tagged cancer-derived EVs would be eliminated by macrophages. Our results suggested that therapeutic antibody administration effectively suppresses EV-triggered metastasis in cancer and that the removal of EVs could be a novel strategy for cancer therapy.

Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer

“…If we were able to effectively inhibit the function of malignant EVs during surgery by administration of an inhibitor in the peritoneal cavity, this treatment could prevent or reduce future metastasis. As our recent report, we disrupted cancer-derived EVs by therapeutic antibody administration in a metastatic cancer mouse model and drastically suppressed metastatic cells62.…”

Extracellular vesicles in the tumor microenvironment: Therapeutic resistance, clinical biomarkers, and targeting strategies

“…To date, this strategy has been proposed and tested in preclinical trials. For instance, intravenous administration of monoclonal antibodies against human CD9 and CD63 depletes breast cancer derived EVs and minimizes lung‐, lymph node, and thoracic cavity oriented metastases in a xenograft mouse model . Trastuzumab (Herceptin), the therapeutic antibody specific for erb‐b2 receptor tyrosine kinase 2 (Her2), evokes diverse anticancer effects such as Her2 signaling inhibition and natural killer (NK) cell induced antibody‐dependent cell cytotoxicity (ADCC) .…”

“…Much like a double‐edged sword, EVs have both beneficial and adverse effects on human health, with their impact on cancer patients mostly negative. Early preclinical trials targeting EVs have demonstrated their efficacy in delaying primary tumor growth and reducing the metastatic potential, although cancer progression was not completely abolished . Thus, it remains unclear if EV‐targeting strategies hold the potential to become stand‐alone cancer therapeutics, yet they do have a strong promise to improve therapeutic outcome of cancer patients upon combination with radiation, chemotherapy, and targeted agents.…”

“…For instance, intravenous administration of monoclonal antibodies against human CD9 and CD63 depletes breast cancer derived EVs and minimizes lung-, lymph node, and thoracic cavity oriented metastases in a xenograft mouse model. 159 Trastuzumab (Herceptin), the therapeutic antibody specific for erb-b2 receptor tyrosine kinase 2 (Her2), evokes diverse anticancer effects such as Her2 signaling inhibition and natural killer (NK) cell induced antibody-dependent cell cytotoxicity (ADCC). 160 However, the antigen receptor also resides on the surface of BCa-associated EVs, 161 thus potentially allowing it to bind and sequester Her2-targeting agents such as Trastuzumab to counteract drug actions.…”

“…Early preclinical trials targeting EVs have demonstrated their efficacy in delaying primary tumor growth and reducing the metastatic potential, although cancer progression was not completely abolished. 159 Thus, it remains unclear if EV-targeting strategies hold the potential to become stand-alone cancer therapeutics, yet they do have a strong promise to improve therapeutic outcome of cancer patients upon combination with radiation, chemotherapy, and targeted agents. However, given the fact that the TME is composed of highly heterogeneous cell types and each can generate EVs of distinct components including mRNA, protein, lipid, and various other biologically active materials, it seems impractical to target all the stroma-released or cancer cell secreted EVs with a single agent.…”