Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma

Abstract

Malignant pleural mesothelioma is a rare but devastating cancer of the pleural lining with no effective treatment. The tumour is often diffusely spread throughout the chest cavity, making surgical resection difficult, while systemic chemotherapy offers limited benefit. Bone marrow-derived mesenchymal stem cells (MSCs) home to and incorporate into tumour stroma, making them good candidates to deliver anticancer therapies. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic molecule that selectively induces apoptosis in cancer cells, leaving healthy cells unaffected. We hypothesised that human MSCs expressing TRAIL (MSCTRAIL) would home to an in vivo model of malignant pleural mesothelioma and reduce tumour growth. Human MSCs transduced with a lentiviral vector encoding TRAIL were shown in vitro to kill multiple malignant mesothelioma cell lines as predicted by sensitivity to recombinant TRAIL (rTRAIL). In vivo MSC homing was delineated using dual fluorescence and bioluminescent imaging, and we observed that higher levels of MSC engraftment occur after intravenous delivery compared with intrapleural delivery of MSCs. Finally, we show that intravenous delivery of MSCTRAIL results in a reduction in malignant pleural mesothelioma tumour growth in vivo via an increase in tumour cell apoptosis.

Genetically modified mesenchymal stromal cells in cancer therapy

“…One of the key properties of MSCs is their tumor tropism, that is, their propensity to move toward sites of tumor [19], [20]. The precise mechanism through which this process occurs is unknown, but it has been demonstrated in multiple cancer models including glioma [21], [22], breast carcinoma [23], lung cancer [24], [25], malignant mesothelioma [26], hepatocellular carcinoma [27], [28], colon cancer [29], pancreatic cancer [30], [31], ovarian cancer [32], melanoma [33] and Kaposi sarcoma [34]. The tropism is thought to be mediated through paracrine signaling between the tumor microenvironment and corresponding receptor expression in MSCs.…”

“…The choice of genetic modification will be determined by the aim of the therapy. Some genetic modification is designed to improve homing by overexpression of key chemokines such as CXCR4 [70] and epidermal growth factor receptor [71], and others aim to deliver a specific therapeutic protein, such as the pro-apoptotic molecule TNF-related apoptosis inducing ligand (TRAIL) [25], [26], [72]. Other modifications being assessed for therapeutic efficacy in a variety of pre-clinical disease models include interferon (IFN)-β (IFNβ) [21], [33], [73], [74], IL-12 [75], [76], IFN-ɣ [77], angiopoietin 1 [78], endothelial nitric oxide synthase [79] and vascular endothelial growth factor (VEGF) [80].…”

Year in review 2014: basic science and epidemiology

“…Gene manipulation in vivo can be achieved using delivery via viral vectors—an approach which has led to successful reduction of MCP-1 and structural remodelling in a chronic heart failure model 20. Similarly, human mesenchymal stem cells (MSCs) engineered to express tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) successfully incorporate into malignant pleural mesothelioma and induce cancer cell death 21. MSCs were tracked in vivo by bioluminescent and fluorescent imaging to delineate the location of the cells delivered to the lungs, highlighting the need for systemic rather than topical application of cells.…”

Hyperthermia treatment of tumors by mesenchymal stem cell-delivered superparamagnetic iron oxide nanoparticles

“…For instance, it may well be difficult to prove, a priori, that an introduced MSC might not, on arrival at a tumor site, itself differentiate into a tumor cell -thereby potentially exacerbating rather than improving the situation. Although our previous data suggest that normal MSCs do not affect tumor growth in an orthotopic lung tumor model, 27 in such a case, the ability to kill by hyperthermia, the introduced MSC might well be seen to be an imperative fail-safe characteristic.…”