The Antitumor Effect of Gene-Engineered Exosomes in the Treatment of Brain Metastasis of Breast Cancer

Abstract

Strategies for treating brain metastases of breast cancer have demonstrated limited efficacy due to the blood-brain barrier (BBB). Gene therapy could improve the efficacy of chemotherapeutic drugs. Exosomes derived from the mesenchymal stem cells (MSCs) are small membrane-based gene vectors that can pass through the BBB. CXCR4 is the most commonly found chemokine receptor in human cancer cells. Furthermore, the SDF-1/CXCR4 axis plays an important role in the homing of MSCs for tumor cell diffusion and metastasis. TRAIL can selectively induce apoptosis in transformed cells without significant toxic side effects in normal tissues. In this study, exosomes were isolated from MSC CXCR4+TRAIL transduced with CXCR4 and TRAIL using a lentiviral vector. Synergistic antitumor study showed that exosome CXCR4+TRAIL exerted significant activity as a cooperative agent with carboplatin in an MDA-MB-231Br SCID mouse model, potentially engendering a novel strategy for advancing the treatment of brain metastases of breast cancer. Based on this study, further investigation of the effect of the vector on BBB and inducing apoptosis of brain tumors is warranted. In addition, the safety of the vector in animals during the treatment needs to be evaluated.

RETRACTED: Mesenchymal Stem/Stromal Cell-Based Delivery: A Rapidly Evolving Strategy for Cancer Therapy

“…Stimulating apoptosis in N1-S1, HepG2, and MHCC97-H cell line in vitro and in vivo by upregulation of caspase-3, and death receptors 4 (DR4) and 5 (DR5) expression (Deng et al, 2014) Glioma Delayed tumor growth resulted in prolonged survival in U87MG cell-bearing mice (Yang et al, 2009;Xia et al, 2015) Mesothelioma Delayed tumor growth in HMESO cell xenografts (Lathrop et al, 2015) Sarcoma Inhibition of tumor cell proliferation in tumor-bearing mice by inducing the caspase activation (Guiho et al, 2016) Colorectal cancer Stimulation of the antitumor effects by MSCs-TRAIL plus 5-FU on HCT116 cell-bearing nude mice (Yu et al, 2013) Brain metastatic breast cancer Tumor cell apoptosis by MSCs genetically modified to co-overexpress CXCR4 and TRAIL in MDA-MB-23-bearing mice (Liu M. et al, 2020) Esophageal cancer Inhibition of tumor growth in vitro and in Eca-109 cell-bearing mice (Li et al, 2014)…”

Roles of Mesenchymal Stem Cell-Derived Exosomes in Cancer Development and Targeted Therapy

“…As previously mentioned, Liu et al [83] were the first to use TRAIL in combination with CXCR4. CXCR4 is the most common chemokine receptor in human cancer cells.…”

“…The delivery system showed good antitumor activity in vitro; it effectively reversed the multidrug resistance of tumors and improved the sensitivity of chemotherapy drugs. In another study, researchers obtained CXCR4/TRAIL-rich exosomes from MSCs overexpressing Stem Cells International both CXCR4 and TRAIL, and these exosomes acted synergistically with carboplatin (a first-line drug for the treatment of metastatic breast cancer) to exert antibreast metastasis effects in vivo [83]. Drug resistance has reduced the efficacy of chemotherapy and radiotherapy, which are first-line cancer treatments [75].…”

“…Therefore, a new generation of tumor treatment methods, including EVs, immunotherapy, and nanotechnology, is being gradually developed [75,84]. Currently, MSCs are the only known cells capable of producing exosomes on a large scale [75,83,85]. Thus, MSC-EXs seem to be the most promising carriers for delivering specific drugs to tumor cells.…”

Challenges and advances in clinical applications of mesenchymal stromal cells

“…Similarly, CXCR4/TRAIL-enriched exosomes were successfully obtained from MSCs overexpressing both CXCR4 and TRAIL. These exosomes exerted activity as a cooperative agent with carboplatin against brain metastasis of breast cancer in vivo, improving the efficacy of chemotherapy and highlighting a novel synergistic protocol with anticancer agents to treat brain diseases [ 205 , 206 ]. Moreover, in a Phase 1 clinical trial, IL-12 was engineered to express on the exosome surface using Codiak’s proprietary engEx Platform.…”