Mesenchymal Stem Cell–Mediated Delivery of an Oncolytic Adenovirus Enhances Antitumor Efficacy in Hepatocellular Carcinoma

Yoon, A-Rum; Hong, Jae‐Keun; Li, Yan; Shin, Ha Chul; Lee, Hyunah; Kim, Hyun Soo; Yun, Chae‐Ok

doi:10.1158/0008-5472.can-18-3900

Cited by 69 publications

(72 citation statements)

References 52 publications

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“…All mice were housed for 1 week for acclimatization, and ad libitum access to food and water was provided. The experiment for assessing MSCs as cell carriers of oncolytic Ads was carried out for both in vitro and in vivo settings as follows 32 .…”

Section: Methodsmentioning

confidence: 99%

“…In vivo tumor growth analysis. The experimental design of using mesenchymal stem cells (MSCs) as cell carriers of oncolytic Ad and tumor growth data in response to oncolytic Ad has been reported in 32 . The study evaluates the therapeutic efficacy of oAd-loaded MSCs on luciferase-expressing orthotopic Hep 3B tumors which were treated with phosphate buffered saline (PBS), MSCs, oncolytic adenovirus (oAd), and MSCs infected with oAd (oAd-MSCs).…”

Section: Methodsmentioning

confidence: 99%

“…We use in vitro oAd-MSC data to inform the model parameters on cell lysis of infected MSCs. We assumed the same virus-mediated lysis for tumor cells because the results in 32 illustrate a MOI (dose)-dependent killing of tumor cells. The cell lysis is, ideally, different in MSC and hepatocellular carcinoma (HCC) cells, since virus replicates more proficiently within HCC.…”

Section: Methodsmentioning

confidence: 99%

“…(1)(2)(3)(4) to simultaneously fit the data of Fig. 5(B) of Yoon et al 32 , which corresponds to treatment using oncolytic Adenovirus (oAd) and mesenchymal stem cells (MSC) alone, and a combined treatment of oAd and MSCs. The model fitting was done with the variables E K and E C set to zero because the experimental data in 32 were obtained from immunodeficiency mice which do not mount any immune response to the tumor and/or virus.…”

Section: Methodsmentioning

confidence: 99%

“…A quantitative understanding of these interactions would help to design better and successful MSC-based virotherapies. In this contribution, we develop a mathematical model calibrated with our in vivo and in vitro experiments 32 to investigate the tumor response to the use of MSCs as cellular delivery vehicles for OVs.…”

mentioning

confidence: 99%

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Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Mahasa

Pillis

Ouifki

et al. 2020

Sci Rep

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Mesenchymal stem cells (MScs) loaded with oncolytic viruses are presently being investigated as a new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can, however, either promote or suppress tumor growth. To address the critical question of how MSCs loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor microenvironment, we developed and analyzed an integrated mathematical-experimental model. We used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy. We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the most impactful outcomes shown by this investigation, not inferred from the experiments alone, was the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful but necessary in achieving tumor control. considering the fact that it is still currently a controversial debate whether MSCs exert a pro-or anti-tumor action, mathematical models such as this one help to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Mahasa

Pillis

Ouifki

et al. 2020

Sci Rep

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Mesenchymal Stem Cell Exosomes and Cancer: Controversies and Prospects

Yassine

Alaaeddine

2021

Advanced Biology

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stem cells and are characterized by a capacity of self-renewal as well as an ability to differentiate along different lineages. [3,4] They can be isolated from various sources in the human body such as the adipose tissue, the bone marrow, the umbilical cord, and many others. [5][6][7] According to the International Society for Cellular Therapy, cells should meet the following criteria to be considered as MSCs: first, cells should be plastic-adherent in tissue culture flasks. Second, more than 95% of the cell population must express the clusters of differentiation CD105, CD73, and CD90, and less than 2% must lack the expression of CD45, CD34, CD79α or CD19, CD14 or CD11b, and human leukocyte antigen class II. Third, the cells must be able to differentiate, in vitro, into osteoblasts, adipocytes, and chondroblasts. [8] Furthermore, MSCs are naturally immunosuppressive; they efficiently modulate the immune response by suppressing lymphocyte proliferation, and by inhibiting complement activation as well as dendritic cell differentiation from monocytes. [9][10][11][12][13] Thus, due to their proprieties, including their wound-tropism and their production of molecules that stimulate healing and endogenous repair, MSCs are considered as a new promising and encouraging therapeutic strategy to treat a variety of diseases and conditions in clinical practice. Lately, many studies have reported that MSCs can influence oncogenesis and cancer cell behavior by modifying the tumor microenvironment (TME). Those studies have suggested that MSCs can reprogram the TME by secreting many factors that modulate immune response as well as tumor behavior either by suppressing or by enhancing tumor growth and progression. Accordingly, the effect of MSCs on the tumor microenvironment is mainly due to their secretome-based paracrine activity consisting of soluble molecules and other factors conveyed by extracellular vesicles. [14][15][16][17] Exosomes, a type of extracellular vesicles, are membrane nanovesicles that contain some genetic material such as DNA, messenger RNAs (mRNAs), and micro-RNAs (miRNAs or miRs). [18] These latter are small single-stranded noncoding RNAs that negatively regulate gene expression, and are implicated in the development of many cancer types. [19,20] Present in the secretome of mesenchymal stromal cells, miRNAs, and other soluble molecules are delivered, via the exosomes, to the proximity of tumors where they dynamically interact with cancer cells and alter their phenotype. [15] Therefore, studies that Mesenchymal stem cells (MSCs) have displayed a novel therapeutic strategy for a wide range of diseases and conditions. Their secretome and exosomebased paracrine activity are considered as the main processes harboring their diverse therapeutic properties. Several investigations have examined the effects of MSC-derived exosomes on cancer growth, yet, controversial results have always emerged. Although MSC-derived exosomes are able to rigorously enforce the repression of cancer proliferation and progression, it is s...

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Magnetic‐Powered Janus Cell Robots Loaded with Oncolytic Adenovirus for Active and Targeted Virotherapy of Bladder Cancer

et al. 2022

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for various fields, such as drug delivery, [1,2] biosensing, [3] detoxification, [4] and environmental remediation. [5] These miniaturized machines can convert local fuel or external energy (e.g., magnetic, ultrasound, or light) to driving force and obtain selfpropulsion in dynamic surroundings. [6] Due to the increasing demands and rigorous requirements of biomedical community, the composition of microrobots has been evolving from rigid and inorganic materials to functional and endogenous cells. [7] Incorporating natural cells with synthetic micromachines creates an elegant platform with synergistic properties of cell biofunctionalities and effective propulsion. The cargo-loading capability of cells is employed by cell-based microrobots to actively deliver drugs, [2,[8][9][10][11] such as red blood cell (RBC)based micromotors loaded with doxorubicin (DOX) and photosensitizer, [10,11] and neutrophil-based microrobots carrying paclitaxel (PTX). [2] However, the utilized chemotherapeutic agents in the robotic system are not specific to cancerous cells and occur drug leakage during transport, inducing unavoidable toxicity to normal regions along with limited therapeutic efficacy and undesired side effects. [12] Such compromised biosafety and antitumor index hinder the practical A unique robotic medical platform is designed by utilizing cell robots as the active "Trojan horse" of oncolytic adenovirus (OA), capable of tumor-selective binding and killing. The OA-loaded cell robots are fabricated by entirely modifying OA-infected 293T cells with cyclic arginine-glycine-aspartic acid tripeptide (cRGD) to specifically bind with bladder cancer cells, followed by asymmetric immobilization of Fe 3 O 4 nanoparticles (NPs) on the cell surface. OA can replicate in host cells and induce cytolysis to release the virus progeny to the surrounding tumor sites for sustainable infection and oncolysis. The asymmetric coating of magnetic NPs bestows the cell robots with effective movement in various media and wireless manipulation with directional migration in a microfluidic device and bladder mold under magnetic control, further enabling steerable movement and prolonged retention of cell robots in the mouse bladder. The biorecognition of cRGD and robust, controllable propulsion of cell robots work synergistically to greatly enhance their tissue penetration and anticancer efficacy in the 3D cancer spheroid and orthotopic mouse bladder tumor model. Overall, this study integrates cell-based microrobots with virotherapy to generate an attractive robotic system with tumor specificity, expanding the operation scope of cell robots in biomedical community.

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Mesenchymal Stem Cell–Mediated Delivery of an Oncolytic Adenovirus Enhances Antitumor Efficacy in Hepatocellular Carcinoma

Cited by 69 publications

References 52 publications

Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Mesenchymal Stem Cell Exosomes and Cancer: Controversies and Prospects

Magnetic‐Powered Janus Cell Robots Loaded with Oncolytic Adenovirus for Active and Targeted Virotherapy of Bladder Cancer

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