Adipose Tissue–Derived Human Mesenchymal Stem Cells Mediated Prodrug Cancer Gene Therapy

Abstract

Human adipose tissue-derived mesenchymal stem cells (AT-MSC) are considered to be a promising source of autologous stem cells in personalized cell-based therapies. Tumor tracking properties of MSC provide an attractive opportunity for targeted transgene delivery into the sites of tumor formation. In the present study, we addressed whether the suicide gene introduction into human AT-MSC could produce a tumor-specific prodrug converting cellular vehicle for targeted chemotherapy. We prepared yeast fusion cytosine deaminase::uracil phosphoribosyltransferase gene-expressing cells [cytosine deaminase (CD)-expressing AT-MSC (CD-AT-MSC)] by retrovirus transduction. We explored their therapeutic potential on a model of human colon cancer in the presence of prodrug 5-fluorocytosine (5-FC). Gene manipulation of human AT-MSC did not sensitize CD-AT-MSC to 5-FC, thus overcoming the inherent disadvantage of suicide effect on cellular vehicle. CD-AT-MSC in combination with 5-FC augmented the bystander effect and selective cytotoxicity on target tumor cells HT-29 in direct coculture in vitro. We confirmed directed migration ability of AT-MSC and CD-AT-MSC toward tumor cells HT-29 in vitro. Moreover, we achieved significant inhibition of s.c. tumor xenograft growth by s.c. or i.v. administered CD-AT-MSC in immunocompromised mice treated with 5-FC. We confirmed the ability of CD-AT-MSC to deliver the CD transgene to the site of tumor formation and mediate strong antitumor effect in vivo. Taken together, these data characterize MSC derived from adipose tissue as suitable delivery vehicles for prodrug converting gene and show their utility for a personalized cell-based targeted cancer gene therapy. [Cancer Res 2007;67(13):6304-13]

TRAIL-transduced multipotent mesenchymal stromal cells (TRAIL-MSC) overcome TRAIL resistance in selected CRC cell lines in vitro and in vivo

“…However, others have shown that MSC with ectopic gene expression can inhibit growth of pulmonary and subcutaneous xenografts after systemic transplantation. 26,27 In accordance with preliminary data in our model, we hypothesize that under optimized conditions, tumor integration of TRAIL-MSC may be enhanced, resulting in a potent anti-tumor activity.…”

Hyperthermia‐treated mesenchymal stem cells exert antitumor effects on human carcinoma cell line

“…31 Because of such properties, MSCs are considered potentially efficient vehicles for cancer therapeutic genes. 32 The tumor stroma plays a supporting role in the propagation or dissemination of tumors by producing protumorigenic cytokines. 33 A prior study demonstrated that with the exposure to tumor cell-conditioned medium, migration of MSCs was promoted with an increase in stromal cell-derived factor-1 protein production.…”

Les cellules souches mésenchymateuses

“…L'administration de CSM que l'on force à exprimer la thymidine kinase permet de réduire fortement la croissance de tumeurs de la prostate [23]. Un autre système de prodrogue, cette fois fondé sur l'utilisation de la cytosine désaminase (CD), a été utilisé pour traiter des souris qui présentaient une tumeur du côlon [24]. Dans ces études, les auteurs ont fait exprimer à des CSM la CD, ont injecté ces cellules aux animaux qu'ils ont ensuite traités avec du 5'fluorouracile (5-FU).…”