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Tumor specific hypoxia-activated expression of cardiac peptides using an engineered subtype of Escherichia coli suppresses tumor growth, angiogenesis and metastasis in mouse model of breast cancer
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  • Behrad Darvishi,
  • Mitra samadi,
  • Keivan Majidzadeh,
  • malihe salehi,
  • Neda Jalili,
  • Zeinab Noorinejad,
  • Marjan mosayebzadeh,
  • Ahad mohamadnajad,
  • Azade Sharifkhatibi,
  • Shima Moradi,
  • Leila Farahmand
Behrad Darvishi
Breast cancer research center motamed cancer institute
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Mitra samadi
Breast cancer research center motamed cancer institute
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Keivan Majidzadeh
Breast cancer research center motamed cancer institute
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malihe salehi
Breast cancer research center motamed cancer institute
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Neda Jalili
Breast cancer research centaer motamed cancer institute
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Zeinab Noorinejad
breast cancer research center motamed cancer institute
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Marjan mosayebzadeh
Breast cancer research center motamed cancer institute
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Ahad mohamadnajad
Cancer Institute of Iran, Tehran University of Medical Sciences
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Azade Sharifkhatibi
Breast cancer research center motamed cancer institute
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Shima Moradi
Breast cancer research center motamed cancer institute
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Leila Farahmand
Breast cancer research center motamed cancer institute
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Peer review status:POSTED

07 Apr 2020Submitted to Biotechnology and Bioengineering
08 Apr 2020Assigned to Editor
08 Apr 2020Submission Checks Completed

Abstract

Background Application of genetically modified non-pathogenic bacteria expressing specific anti-tumor proteins under certain conditions specific to tumors is an effective approach for selective targeting of tumors. We developed here, for the first time, a novel spatiotemporal cancer targeted therapy applying engineered E. coli bacteria with capability of expressing cardiac peptides under hypoxic conditions of tumor. Method E. coli BW25133 was transformed with construction of co-expressing cardiac hormones and GFP. Bacteria bearing constructs were then IV administered in mice bearing tumors and then tumor localization, as well as tumor proliferation, invasion and angiogenesis biomarkers (Ki-67, VEGFR, CD31and MMP9), changes in cytokine profile, suppression of tumor growth and survival were analyzed. Results IV Administered bacteria bearing constructs could specifically localize at tumor site and express cardiac peptides under hypoxic conditions. Administration of bacteria significantly enhanced survival rate, suppressed tumor progression and lowered expression levels of MMP-9, VEGFR2, CD31and Ki67 as potent markers for angiogenesis, tumor proliferation and metastasis. Furthermore, applied bacteria resulted in significant reduction in the expression of IL-1β, IL-6, GC-SF, IL-12 and TNF-α proinflammatory cytokines, whereas increasing IL-10, IL-17A and INF-γ cytokines. Conclusion Overall, administration of E. coli bearing cardiac hormone expression construct could effectively suppress tumor growth, angiogenesis, invasion and metastasis while enhancing survival rate in mice model of breast cancer.