Human neural stem cells expressing carboxyl esterase target and inhibit tumor growth of lung cancer brain metastases

Abstract BACKGROUND There are currently no satisfactory treatments or experimental models showing autonomic dysfunction for intramedullary spinal cord gliomas (ISCG). OBJECTIVE To develop a rat model of ISCG and investigate whether genetically engineered human neural stem cells (F3.hNSCs) could be developed into effective therapies for ISCG. METHODS Immunodeficient/Rowett Nude rats received C6 implantation of G55 human glioblastoma cells (10K/each). F3.hNSCs engineered to express either cytosine deaminase gene only (i.e., F3.CD) or dual genes of CD and thymidine kinase (i.e., F3.CD-TK) converted benign 5-fluorocytosine and ganciclovir into oncolytic 5-fluorouracil and ganciclovir-triphosphate, respectively. ISCG rats received injection of F3.CD-TK, F3.CD, or F3.CD-TK debris near the tumor epicenter 7 days after G55 seeding, followed with 5-FC (500 mg/kg/5 mL) and ganciclovir administrations (25 mg/kg/1 mL/day × 5/each repeat, intraperitoneal injection). Per humane standards for animals, loss of weight-bearing stepping in the hindlimb was used to determine post-tumor survival. Also evaluated were autonomic functions and tumor growth rate in vivo. RESULTS ISCG rats with F3.CD-TK treatment survived significantly longer (37.5 ± 4.78 days) than those receiving F3.CD (21.5 ± 1.75 days) or F3.CD-TK debris (19.3 ± 0.85 days; n = 4/group; P <.05, median rank test), with significantly improved autonomic function and reduced tumor growth rate. F3.DC-TK cells migrated diffusively into ISCG clusters to mediate oncolytic effect. CONCLUSION Dual gene-engineered human neural stem cell regimen markedly prolonged survival in a rat model that emulates somatomotor and autonomic dysfunctions of human cervical ISCG. F3.CD-TK may provide a novel approach to treating clinical ISCG.

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Human Neural Stem Cells Can Target and Deliver Therapeutic Genes to Breast Cancer Brain Metastases

Molecular Therapy ◽

10.1038/mt.2008.290 ◽

2009 ◽

Vol 17 (3) ◽

pp. 570-575 ◽

Cited By ~ 44

Author(s):

Kyeung Min Joo ◽

In H Park ◽

Ji Y Shin ◽

Juyoun Jin ◽

Bong Gu Kang ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Brain Metastases ◽

Neural Stem Cells ◽

Human Neural Stem Cells ◽

Breast Cancer Brain Metastases ◽

Therapeutic Genes

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Genetically engineered human neural stem cells with rabbit carboxyl esterase can target brain metastasis from breast cancer

Cancer Letters ◽

10.1016/j.canlet.2011.07.001 ◽

2011 ◽

Vol 311 (2) ◽

pp. 152-159 ◽

Cited By ~ 33

Author(s):

Ho Jun Seol ◽

Juyoun Jin ◽

Dong-Ho Seong ◽

Kyeung Min Joo ◽

Wonyoung Kang ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Brain Metastasis ◽

Neural Stem Cells ◽

Genetically Engineered ◽

Human Neural Stem Cells ◽

Carboxyl Esterase

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Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2112491119 ◽

2021 ◽

Vol 119 (1) ◽

pp. e2112491119

Author(s):

Alex Cordero ◽

Matthew D. Ramsey ◽

Deepak Kanojia ◽

Jawad Fares ◽

Edgar Petrosyan ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Brain Metastases ◽

Neural Stem Cells ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Breast Cancer Patients ◽

Human Neural Stem Cells ◽

Breast Cancer Brain Metastases

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood–brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

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Human Neural Stem Cells Overexpressing a Carboxylesterase Inhibit Bladder Tumor Growth

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-15-0636 ◽

2016 ◽

Vol 15 (6) ◽

pp. 1201-1207 ◽

Cited By ~ 2

Author(s):

Sung S. Choi ◽

Byung Hoon Chi ◽

In Ho Chang ◽

Kyung Do Kim ◽

Sang-Rae Lee ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Tumor Growth ◽

Bladder Tumor ◽

Human Neural Stem Cells

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mRNA-Driven Generation of Transgene-Free Neural Stem Cells from Human Urine-Derived Cells

Cells ◽

10.3390/cells8091043 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1043 ◽

Cited By ~ 1

Author(s):

Phil Jun Kang ◽

Daryeon Son ◽

Tae Hee Ko ◽

Wonjun Hong ◽

Wonjin Yun ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Human Urine ◽

Neurological Disorders ◽

Therapeutic Potential ◽

Embryonic Stem ◽

Global Gene Expression ◽

Patient Specific ◽

Human Neural Stem Cells

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

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BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets

International Journal of Molecular Sciences ◽

10.3390/ijms22083913 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3913

Author(s):

Satoshi Nakata ◽

Ming Yuan ◽

Jeffrey A. Rubens ◽

Ulf D. Kahlert ◽

Jarek Maciaczyk ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Tandem Duplication ◽

Target Genes ◽

Cellular Growth ◽

Central Nervous System Tumor ◽

Internal Tandem Duplication ◽

Invasion And Migration ◽

Human Neural Stem Cells ◽

And Migration

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.

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