Mesenchymal stem cells expressing interleukin-18 inhibit breast cancer in a mouse model

Abstract

Development of an improved breast cancer therapy has been an elusive goal of cancer gene therapy for a long period of time. Human mesenchymal stem cells derived from umbilical cord (hUMSCs) genetically modified with the interleukin (IL)-18 gene (hUMSCs/IL-18) were previously demonstrated to be able to suppress the proliferation, migration and invasion of breast cancer cells in vitro. In the present study, the effect of hUMSCs/IL-18 on breast cancer in a mouse model was investigated. A total of 128 mice were divided into 2 studies (the early-effect study and the late-effect study), with 4 groups in each, including the PBS-, hUMSC-, hUMSC/vector- and hUMSC/IL-18-treated groups. All treatments were injected along with 200 µl PBS. Following therapy, the tumor size, histological examination, and expression of lymphocytes, Ki-67, cluster of differentiation 31 and cytokines [interleukin (IL)-18, IL-12, interferon (IFN)-γ and TNF-α] in each group were analyzed. Proliferation of cells (assessed by measuring tumor size and Ki-67 expression) and metastasis, (by determining pulmonary and hepatic metastasis) of breast cancer cells in the hUMSC/IL-18 group were significantly decreased compared with all other groups. hUMSCs/IL-18 suppressed tumor cell proliferation by activating immunocytes and immune cytokines, decreasing the proliferation index of proliferation marker protein Ki-67 of tumor cells and inhibiting tumor angiogenesis. Furthermore, hUMSCs/IL-18 were able to induce a more marked and improved therapeutic effect in the tumor sites, particularly in early tumors. The results of the present study indicate that hUMSCs/IL-18 were able to inhibit the proliferation and metastasis of breast cancer cells in vivo, possibly leading to an approach for a novel antitumor therapy in breast cancer.

Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT‐ME‐1 trial

“…Several preclinical studies have demonstrated anti‐tumor efficacy using genetically‐engineered MSCs to home transgenes to tumor stroma . In these studies, the modified gene either encoded for a secreted protein that had either a direct or indirect effects on tumor cells, or a ‘suicide’ gene that encoded for an enzyme that converted a prodrug into cytotoxic metabolites; an approach known as gene‐directed enzyme‐producing therapy (GDEPT) …”

Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy

“…It has been reported that human umbilical cord MSCs transduced with adenoviral vectors expressing IFNβ effectively inhibit the growth of breast cancer cells through induction of apoptosis (Shen et al, 2016). Interleukins are another group of cytokines used as tumor-suppressing agents (Chen et al, 2008;Liu et al, 2018). A recent study using lentiviral transductions showed that human umbilical cord MSCs expressing interleukin-18 inhibit the proliferation and metastasis of breast cancer in mice (Liu et al, 2018).…”

“…Interleukins are another group of cytokines used as tumor-suppressing agents (Chen et al, 2008;Liu et al, 2018). A recent study using lentiviral transductions showed that human umbilical cord MSCs expressing interleukin-18 inhibit the proliferation and metastasis of breast cancer in mice (Liu et al, 2018). Genetically engineered MSCs with TRAIL have also shown strong anti-tumor activity in different types of cancer (Ciavarella et al, 2012;Fakiruddin et al, 2014;Guo et al, 2016;Jiang et al, 2016).…”

The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

“…Furthermore, IL-18 inhibited HCC growth by priming NK cells trafficked to the liver [200]. Mesenchymal stem cells-expressing IL-18 inhibited the proliferation and metastasis of breast cancer cells by activating immunocytes and immune cytokines, downregulating the proliferation marker Ki-67 and suppressing tumor angiogenesis [201]. Collectively, IL-18-based immunotherapy might be a promising therapeutic strategy for cancer.…”