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Neoplasia and cancer pathogenesis
Use of induced pluripotent stem cells (IPSC) encoded with anti-grp78 shrna induces apoptosis/type i pcd after a gene-silencing bystander effect for circumvention of vinorelbine-induced angiogenesis, and inhibition of metastatic spread in advanced gist
  1. J Giannios *1,
  2. S Delis2,
  3. N Alexandropulos3
  1. 1Translational Cancer Medicine, Erasinio Oncology Hospital, Athens, Greece
  2. 2GI Surgery, Agia Olga Hospital, Athens, Greece
  3. 3Biogenetics Department, Ippokration Hospital, Athens, Greece

Abstract

Introduction Vinorelbine in advanced gastro-intestinal stromal tumour (GIST) cells induces tumour relapse with enhanced angiogenesis and metastasis by inducing an innate cancer cellular stress response, which enhances the expression of GRP78 that blocks cell death or apoptosis increasing growth, and spread of GIST due to chemoresistance. We aim to circumvent this with the use of induced pluripotent stem cells encoded with antisense GRP78 shRNA.

Methods We take induced pluripotent stem cells(iPSCs), which we infected them with a DNA vector that encoded an RNA molecule of 67 nucleotides. The sequence of this small hairpin RNA (shRNA) is designed to suppress the GRP78 gene. GIST cells were obtained from patients, and they were implanted in animal models, which were treated with vinorelbine. After tumour relapse, there was induction of enhanced angiogenesis, and metastasis. These chemoresistant tumour cells were treated with the induced pluripotent stem cells, which were encoded with shRNA against GRP78.

Results Post-treatment, stem cells encoded with anti-GRP78 shRNA converted dicer into a siRNA molecule generating a long lasting RNAi silencing effect of GRP78, which spreads to adjacent tumour cells inducing a gene silencing bystander effect (GSBE). Capillary growth into the tumours were blocked, while VEGF and bFGF were downregulated. PKG was upregulated inhibiting b-catenin. Integration of endothelial precursor cells and tumour cells was blocked inhibiting growth of mosaic blood vessels. This leads to inhibition of tumour spread or metastasis, while the existing tumours die from lack of nutrients/oxygen, and a waste disposal pathway. TEM exhibited induction of type I PCD or apoptosis in tumour cells leading to a bystander killing effect. Thus, anti-GRP78 induced pluripotent stem cells (iPSCs) circumvented vinorelbine induced angiogenesis, and metastasis eradicating chemoresistant GIST cells.

Conclusion Vinorelbine induced angiogenesis, and metastatic spread in GIST are circumvented with induced pluripotent stem cells (iPSCs) encoded with anti-GRP78 shRNA, which induces apoptosis after a gene silencing bystander effect (GSBE).

  • induced pluripotent stem cells
  • shRNA
  • angiogenesis
  • chemoresistance
  • apoptosis/type I PCD
  • GIST.

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Footnotes

  • Competing interests None.

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