Image-guided, Tumor Stroma-targeted 131I Therapy of Hepatocellular Cancer After Systemic Mesenchymal Stem Cell-mediated NIS Gene Delivery

Abstract

Due to its dual role as reporter and therapy gene, the sodium iodide symporter (NIS) allows noninvasive imaging of functional NIS expression by (123)I-scintigraphy or (124)I-PET imaging before the application of a therapeutic dose of (131)I. NIS expression provides a novel mechanism for the evaluation of mesenchymal stem cells (MSCs) as gene delivery vehicles for tumor therapy. In the current study, we stably transfected bone marrow-derived CD34(-) MSCs with NIS cDNA (NIS-MSC), which revealed high levels of functional NIS protein expression. In mixed populations of NIS-MSCs and hepatocellular cancer (HCC) cells, clonogenic assays showed a 55% reduction of HCC cell survival after (131)I application. We then investigated body distribution of NIS-MSCs by (123)I-scintigraphy and (124)I-PET imaging following intravenous (i.v.) injection of NIS-MSCs in a HCC xenograft mouse model demonstrating active MSC recruitment into the tumor stroma which was confirmed by immunohistochemistry and ex vivo γ-counter analysis. Three cycles of systemic MSC-mediated NIS gene delivery followed by (131)I application resulted in a significant delay in tumor growth. Our results demonstrate tumor-specific accumulation and therapeutic efficacy of radioiodine after MSC-mediated NIS gene delivery in HCC tumors, opening the prospect of NIS-mediated radionuclide therapy of metastatic cancer using MSCs as gene delivery vehicles.

Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3

“…However, depending on the approach used, MSCbased cancer gene therapy can include the destruction of exogenously applied engineered MSCs in the context of therapy, which is likely to overcome any endogenous tumour-promoting effects of adoptively applied MSCs. This was demonstrated in our previous work using MSCs as delivery vehicles for tumour-selective NIS gene delivery, showing no tumour growth-promoting effects in subcutaneous HuH7 or hepatic colon cancer metastasis xenograft mouse models where a significant therapeutic effect of 131 I or 188 Re was seen (Knoop et al 2011, Knoop et al 2013. Moreover, we did not observe an effect of thyroid hormone status or tetrac treatment on the growth of the HCC xenograft model used in this study, which we attribute to the absence of integrin avb3 on HuH7 cells and also to the short time frame for the assessment of tumour stroma-mediated effects on tumour growth in our experimental setting.…”

“…An array of growth factors, including PDGF, insulin-like growth factor 1 (IGF1), HGF, EGF and VEGF, as well as chemokines, such as RANTES/CCL5, CCL22 and, to a lower extent, SDF-1/CXCL12 and their respective receptors, have been implicated in MSC migration (Ponte et al 2007, Spaeth et al 2008) and many of these have been shown in this and other studies to be regulated by thyroid hormones via differential gene expression and receptor crosstalk (Davis et al 2011, Hercbergs et al 2012. Modulation of recruitment and engraftment efficiency of MSCs is of clinical interest, in settings of tissue regeneration, in the context of general tumour growth and the emerging field of MSC-based gene delivery in cancer therapy (Knoop et al 2011, Knoop et al 2013, Uchibori et al 2014. As the tumour stroma plays such a key role in tumour growth, angiogenesis and metastatic potential, it has become an important target for tumour therapy.…”

“…In a HuH7 tumour xenograft model, mice were injected daily with 20 ng/g body weight L-T 4 (euthyroid; nZ7), 100 ng/g body weight L-T 4 (hyperthyroid; nZ8), saline (hypothyroid; nZ8) or 20 ng/g body weight L-T 4 C10 mg/g body weight tetrac (euthyroidCtetrac; nZ8). promoter are actively recruited to experimental HCC as well as disseminated colon cancer liver metastases and induce anti-tumour effects after application of 131 I or 188 Re based on NIS-mediated radioiodine accumulation (Knoop et al 2011, Knoop et al 2013. However, full therapeutic potential can only be exploited when MSCs are efficiently recruited to their site of action.…”

“…Similarities between the wound-healing process and tumour stroma formation have led to the suggestion that tumours are 'wounds that do not heal' (Dvorak 1986). We and others have shown that MSCs are actively recruited to growing tumour stroma (Conrad et al 2007, Zischek et al 2009, Knoop et al 2011, Knoop et al 2013) mediated by high local concentrations of inflammatory chemokines and growth factors (Ponte et al 2007, Spaeth et al 2008, Kholodenko et al 2013. This tumour tropism constitutes the basis for the 'Trojan horse' approach, in which MSCs are used as shuttle vectors to deliver therapeutic agents into growing tumours , Dwyer et al 2011, Dembinski et al 2013, Zhu et al 2014, Zhang et al 2015, as we have successfully demonstrated in our previous work using the sodium iodide symporter (NIS) (Knoop et al 2011, Knoop et al 2013 and herpes simplex virus type 1 thymidine kinase (HSV-TK) (Zischek et al 2009 as therapy genes in various tumour models.…”

Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells

“…Human MSC do not develop into tumors [14], but some reports indicate that MSC participate in the pathogenesis of cancer by transforming into cancer-associated fibroblasts (CAFs) [15][16][17][18][19]. Some studies indicated that, when injected systemically, MSC migrate to sites of inflammation and diseased tissues [20][21][22][23]. The in vivo tropism toward gliomas has been extensively studied.…”