Therapeutic Potential of Stem Cell-Mediated Sodium Iodide Symporter (NIS) Gene Delivery in Liver Cancer

Knoop, Kerstin; Kolokythas, Marie; Klutz, Kathrin; Willhauck, Michael J.; Wunderlich, Nathalie; Draganovici, Dan; Zach, Christian; Gildehaus, Franz Josef; Böning, Guido; Göke, B.; Wagner, Ernst; Nelson, Peter J.; Spitzweg, Christine

doi:10.1210/endo-meetings.2011.part3.p12.p2-679

Cited by 5 publications

(11 citation statements)

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“…Along this line, MSCs have been engineered to transduce NIS in hepatocellular cancer (Knoop et al 2011, Knoop et al 2015, Muller et al 2016 and breast cancer (Dwyer et al 2011) mouse models with specific 131 I tumor accumulation and significant delay of tumor growth. In addition, NIS has been used successfully used as a reporter to monitor MSC biodistribution and fate using lentiviral vectors (Shi et al 2014) and baculovirus (Pan et al 2013).…”

Section: Cellular Vectorsmentioning

confidence: 99%

Role of iodide metabolism in physiology and cancer

Vieja¹,

Santisteban²

2018

Endocrine-Related Cancer

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Iodide (I) metabolism is crucial for the synthesis of thyroid hormones (THs) in the thyroid and the subsequent action of these hormones in the organism. I is principally transported by the sodium iodide symporter (NIS) and by the anion exchanger PENDRIN, and recent studies have demonstrated the direct participation of new transporters including anoctamin 1 (ANO1), cystic fibrosis transmembrane conductance regulator (CFTR) and sodium multivitamin transporter (SMVT). Several of these transporters have been found expressed in various tissues, implicating them in I recycling. New research supports the exciting idea that I participates as a protective antioxidant and can be oxidized to hypoiodite, a potent oxidant involved in the host defense against microorganisms. This was possibly the original role of I in biological systems, before the appearance of TH in evolution. I per se participates in its own regulation, and new evidence indicates that it may be antineoplastic, anti-proliferative and cytotoxic in human cancer. Alterations in the expression of I transporters are associated with tumor development in a cancer-type-dependent manner and, accordingly, NIS, CFTR and ANO1 have been proposed as tumor markers. Radioactive iodide has been the mainstay adjuvant treatment for thyroid cancer for the last seven decades by virtue of its active transport by NIS. The rapid advancement of techniques that detect radioisotopes, in particular I, has made NIS a preferred target-specific theranostic agent.

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Section: Cellular Vectorsmentioning

confidence: 99%

Role of iodide metabolism in physiology and cancer

Vieja¹,

Santisteban²

2018

Endocrine-Related Cancer

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“…For HuH7 xenograft tumor establishment, 5 × 10 6 HuH7 cells in 100 µL PBS were injected subcutaneously into the right flank region as described previously (Knoop et al 2011). Tumor volumes were regularly measured and estimated using the equation: length × width × height × 0.52.…”

Section: Huh7 Xenograft Tumorsmentioning

confidence: 99%

“…At the same time, it can be used as an effective therapy gene after application of radioiodine 131 I (Spitzweg & Morris 2002, Baril et al 2010, Hingorani et al 2010, Penheiter et al 2012. A diverse series of studies have demonstrated the efficacy of NIS-mediated radioiodide accumulation in a variety of non-thyroidal tumors using different gene delivery vehicles for NIS transgene expression (Niu et al 2004, Dwyer et al 2006, Klutz et al 2009, 2011a,b,c, Peerlinck et al 2009, Ahn et al 2010, Huang et al 2011, Knoop et al 2011, Grunwald et al 2013a,b,c, Mansfield et al 2016. The use of genetically engineered MSCs to deliver NIS into various types of tumors has been demonstrated in many studies (Dwyer et al 2011, Knoop et al 2011.…”

Section: Introductionmentioning

confidence: 99%

“…A diverse series of studies have demonstrated the efficacy of NIS-mediated radioiodide accumulation in a variety of non-thyroidal tumors using different gene delivery vehicles for NIS transgene expression (Niu et al 2004, Dwyer et al 2006, Klutz et al 2009, 2011a,b,c, Peerlinck et al 2009, Ahn et al 2010, Huang et al 2011, Knoop et al 2011, Grunwald et al 2013a,b,c, Mansfield et al 2016. The use of genetically engineered MSCs to deliver NIS into various types of tumors has been demonstrated in many studies (Dwyer et al 2011, Knoop et al 2011. Although these results have shown comparably high levels of NIS transgene expression in the tumor microenvironment followed by a therapeutic effect of 131 I, with a delay in tumor growth and prolonged survival of treated animals, the use of specific gene promoters for NIS expression that are activated by tumor micromileu-derived signals has been shown to enhance the selectivity and effectiveness and limit the potential offtarget effects following MSC recruitment to tissues as part of normal tissue homeostasis (Von Luttichau et al 2005, Klutz et al 2009, 2011a,b,c, Knoop et al 2011, Grunwald et al 2013a,b,c, Muller et al 2016.…”

Section: Introductionmentioning

confidence: 99%

“…The use of genetically engineered MSCs to deliver NIS into various types of tumors has been demonstrated in many studies (Dwyer et al 2011, Knoop et al 2011. Although these results have shown comparably high levels of NIS transgene expression in the tumor microenvironment followed by a therapeutic effect of 131 I, with a delay in tumor growth and prolonged survival of treated animals, the use of specific gene promoters for NIS expression that are activated by tumor micromileu-derived signals has been shown to enhance the selectivity and effectiveness and limit the potential offtarget effects following MSC recruitment to tissues as part of normal tissue homeostasis (Von Luttichau et al 2005, Klutz et al 2009, 2011a,b,c, Knoop et al 2011, Grunwald et al 2013a,b,c, Muller et al 2016. We have studied various gene promoters for the delivery of MSC-transgene expression in tumor stroma.…”

Section: Introductionmentioning

confidence: 99%

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TGFB1-driven mesenchymal stem cell-mediated NIS gene transfer

Schug

Urnauer

Jaeckel

et al. 2019

Endocrine-Related Cancer

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Based on their excellent tumor-homing capacity, genetically engineered mesenchymal stem cells (MSCs) are under investigation as tumor-selective gene delivery vehicles. Transgenic expression of the sodium iodide symporter (NIS) in genetically engineered MSCs allows noninvasive tracking of MSC homing by imaging of functional NIS expression as well as therapeutic application of 131I. The use of tumor stroma-activated promoters can improve tumor-specific MSC-mediated transgene delivery. The essential role of transforming growth factor B1 (TGFB1) and the SMAD downstream target in the signaling between tumor and the surrounding stroma makes the biology of this pathway a potential option to better control NIS expression within the tumor milieu. Bone marrow-derived MSCs were stably transfected with a NIS-expressing plasmid driven by a synthetic SMAD-responsive promoter (SMAD-NIS-MSCs). Radioiodide uptake assays revealed a 4.9-fold increase in NIS-mediated perchlorate-sensitive iodide uptake in SMAD-NIS-MSCs after TGFB1 stimulation compared to unstimulated cells demonstrating the successful establishment of MSCs, which induce NIS expression in response to activation of TGFB1 signaling using a SMAD-responsive promoter. 123I-scintigraphy revealed significant tumor-specific radioiodide accumulation and thus NIS expression after systemic application of SMAD-NIS-MSCs into mice harboring subcutaneous tumors derived from the human hepatocellular carcinoma (HCC) cell line HuH7, which express TGFB1. 131I therapy in SMAD-NIS-MSCs-treated mice demonstrated a significant delay in tumor growth and prolonged survival. Making use of the tumoral TGFB1 signaling network in the context of MSC-mediated NIS gene delivery is a promising approach to foster tumor stroma-selectivity of NIS transgene expression and tailor NIS-based gene therapy to TGFB1-rich tumor environments.

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Lipid‐Peptide‐mRNA Nanoparticles Augment Radioiodine Uptake in Anaplastic Thyroid Cancer

Zhang

Lang

et al. 2022

Advanced Science

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Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid‐peptide‐mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase‐free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10‐fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 ( 131 I) accumulation in the tumor, thereby significantly inhibiting tumor growth. Overall, this work designs three arginine‐rich peptide nanoparticles, contributing to the choice of liposome cores for gene delivery. LPm NP can serve as a promising adjunctive therapy for patients with ATC by restoring iodine affinity and enhancing the therapeutic efficacy of radioactive iodine.

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Therapeutic Potential of Stem Cell-Mediated Sodium Iodide Symporter (NIS) Gene Delivery in Liver Cancer

Cited by 5 publications

References 0 publications

Role of iodide metabolism in physiology and cancer

Role of iodide metabolism in physiology and cancer

TGFB1-driven mesenchymal stem cell-mediated NIS gene transfer

Lipid‐Peptide‐mRNA Nanoparticles Augment Radioiodine Uptake in Anaplastic Thyroid Cancer

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